Annals of the ICRP,Volume 28, Issues 1-2, March 1998, Pages 1-157

Genetic susceptibility to cancer: ICRP Publication 79

Approved by the Commission in May 1997
Available online 25 May 1999.
Abstract
A as! "rou# o$ %he I&'P &ommi%%ee 1 ('a)ia%ion *$$ec%s+ has revie,e) relevan% )a%a ,i%h %he
ob-ec%ive o$ a)vising %he Main &ommission o$ %he I&'P on %he #ossible im#lica%ions $or ra)iological
#ro%ec%ion o$ emerging vie,s on gene%ic susce#%ibili%y %o cancer (&ha#%er 1+.
&ha#%er 2 consi)ers ./A )amage an) i%s #rocessing0re#air a$%er ionising ra)ia%ion an) serves
#rinci#ally %o )emons%ra%e %ha% a $e, rare cancer-#rone, human recessive gene%ic )isor)ers sho, ./A
re#air )e$iciency an) #ro$oun) increases in ra)iosensi%ivi%y. 1ess )rama%ic changes in ra)iosensi%ivi%y
are also a##aren% in a ,i)er range o$ such )isor)ers. he cellular mechanisms %ha% un)erly %he
associa%ion be%,een ./A )amage #rocessing an) %umorigenesis are )iscusse).
&ha#%er 2 revie,s %he mechanisms an) gene%ics o$ soli) %umours illus%ra%ing %he ,ays in ,hich
mu%a%ions in #ro%o-oncogenes, %umour su##ressor genes %oge%her ,i%h %hose in ./A re#air an) cell
cycle con%rol genes can con%ribu%e %o %umour )evelo#men%. 3#eci$ic e4am#les are given o$ ho, germ
line mu%a%ion o$ such genes can #re)is#ose %o $amilial cancer. I% is -u)ge) %ha% u# %o 55 o$ all soli)
%umours have a recognisable gene%ic com#onen%. 6eri%able organ-s#eci$ic e$$ec%s are mos% usual an)
cancers o$ %he breas% an) colon %en) %o sho, %he mos% obvious gene%ic com#onen%s. &learly )iscernible
gene%ic e$$ec%s are seen ,hen rare )ominan% germ line mu%a%ions e4#ress s%rongly as $amilial cancer
(high #ene%rance mu%a%ions+, bu% %he e4is%ence o$ #erha#s less rare lo, #ene%rance mu%a%ions an) gene7
gene in%erac%ions are recognise) bu% no% ,ell un)ers%oo).
&ha#%er 8 consi)ers %he mechanisms an) gene%ics o$ lym#ho-haemo#oie%ic %umours. 3#eci$ic
chromosomal %ransloca%ions an) #ro%o-oncogene ac%iva%ion even%s are much more $re9uen% in human
leu!aemia0lym#homa %han in soli) %umours. "ene%ic #re)is#osi%ion %o leu!aemia0lym#homa is $oun) in
a number o$ non-$amilial recessive gene%ic )isor)ers o$ ./A #rocessing an)0or chromosomal
ins%abili%y. :amilial mani$es%a%ion o$ susce#%ibili%y %o %hese %umours is, ho,ever, e4%remely rare. he
gene%ic com#onen%, al%hough #oorly )e$ine), is -u)ge) %o be less %han %ha% o$ soli) %umours an)
e4#resse) largely in chil)hoo).
&ha#%er 5 revie,s an) )iscusses limi%e) )a%a %ha% commen% u#on %umorigenic ra)iosensi%ivi%y in
cancer-#rone gene%ic con)i%ions. :rom !no,le)ge o$ %he $un)amen%al #rocesses involve) i% is -u)ge)
%ha% in mos%, bu% no% all, cases gene%ic susce#%ibili%y %o s#on%aneous %umours ,ill be accom#anie) by a
grea%er-%han-normal ris! a$%er ra)ia%ion. A revie, o$ e#i)emiological, clinical an) e4#erimen%al )a%a
relevan% %o %his issue sugges%s %ha% al%hough a ,i)e range o$ )i$$eren% sensi%ivi%ies may be involve), a
$ac%or o$ 1; increase in sensi%ivi%y broa)ly accor)s ,i%h %he limi%e) human )a%a available. his in%erim
-u)gemen% o$ a $ac%or o$ 1; increase in ra)ia%ion ris! in such human gene%ic )isor)ers is ma)e $or %he
#ur#oses o$ illus%ra%ive mo)elling an) calcula%ion. In a))i%ion, s#eci$ic a%%en%ion is given %o breas%
1
cancer ris! in he%ero<ygo%es $or %he ra)iosensi%ive human )isor)er, a%a4ia-%elangiec%asia= %his
associa%ion, ,hile in no ,ay )iscoun%e), is -u)ge) %o be less s%rong %han %ha% claime) by some.
&ha#%er > )iscusses an) )evelo#s com#u%a%ional mo)elling #roce)ures %ha% aim %o )escribe %he im#ac%
o$ gene%ic $ac%ors on ra)ia%ion-%umorigenesis in human #o#ula%ions. *s%ima%es o$ %he #revalence o$
!no,n cancer-#rone gene%ic )isor)ers are ma)e bu% breas% cancer susce#%ibili%y is use) %o illus%ra%e %he
a##lica%ion o$ %he mo)el )evelo#e). he mos% im#or%an% message %o emerge $rom %his ,or! is %ha%,
even a% an assume) high level o$ ra)ia%ion sensi%ivi%y, %he #revalence o$ $amilial (high #ene%rance+
gene%ic )isor)ers in %he #o#ula%ion is %oo lo, (?15+ $or %here %o be a signi$ican% im#ac% on ris! in
%y#ical human #o#ula%ions. In #rinci#le, ho,ever, %here is %he #o%en%ial $or such im#ac% in a%y#ical
inbre) sub-#o#ula%ions ,here %hese mu%a%ions can be more common. hese mo)elling #roce)ures are
also use) %o illus%ra%e ho, incom#le%e #ene%rance o$ %hese mu%a%ions ,ill )ilu%e any im#ac% on
#o#ula%ion ris!.
In con-unc%ion ,i%h %he Main &ommission o$ %he I&'P, in &ha#%er 7 %he as! "rou# )iscusses %he
#o%en%ial im#lica%ions o$ %he main re#or% $or ra)iological #ro%ec%ion. heir #rinci#al conclusions are@ (i+
ha% curren% es%ima%es o$ ra)ia%ion cancer ris! alrea)y inclu)e an un!no,n con%ribu%ion $rom
gene%ically ra)iosensi%ive sub-#o#ula%ions. (ii+ Asing %he )a%a ci%e), %he li!ely con%ribu%ion %o ra)ia%ion
ris! $rom $amilial cancer )isor)ers is %oo lo, %o genera%e an unacce#%able )is%or%ion o$ curren%
es%ima%es o$ cancer ris! in %he vas% ma-ori%y o$ human #o#ula%ions. (iii+ here is insu$$icien% !no,le)ge
%o -u)ge %he con%ribu%ion %o ris! $rom mu%a%ions o$ lo, #ene%rance %ha% )o no% e4#ress as $amilial
cancer. (iv+ Because o$ %he high ris! o$ s#on%aneous cancer in $amilial )isor)ers, lo, )oses o$ ra)ia%ion
(say 1;; m3v+ are mos% unli!ely %o im#ac% signi$ican%ly on li$e-%ime cancer ris! in an a$$ec%e)
in)ivi)ual= a% high )oses, such as %hose e4#erience) in ra)io%hera#y, %his rela%ive ris! may ho,ever
become im#or%an%. (v+ Because organ-s#eci$ic cancer ris! is #re)ic%e) in mos% $amilial )isor)ers, %he
absolu%e increase overall in ris! %o an a$$ec%e) in)ivi)ual ,ill be )ilu%e), ie. com#aring normal an)
a$$ec%e) in)ivi)uals. (vi+ he u%ili%y o$ gene%ic %es%ing $or cancer #re)is#osi%ion in %he con%e4% o$
ra)iological #ro%ec%ion is curren%ly limi%e) by %echnical $ac%ors an) concerns on #re)ic%ive #o,er. In %he
$u%ure gene%ic %es%ing may $in) selec%e) use #rior %o cer%ain me)ical e4#osures %o ra)ia%ion, bu% %he
value o$ such #roce)ures, as a##lie) %o lo,-)ose occu#a%ionally e4#ose) in)ivi)uals, is o#en %o )oub%=
i% ,oul) also be sub-ec% %o ma-or e%hical scru%iny ou%si)e %he remi% o$ %he I&'P.
he as! "rou# an) %he Main &ommission o$ %he I&'P s%ress %ha%, because o$ %he curren% lac! o$
!no,le)ge, %he above -u)gemen%s shoul) be regar)e) as #reliminary. he re#or% serves #rinci#ally %o
#rovi)e a $rame,or! on ,hich %o )evelo# $ur%her vie,s in %his ra#i)ly a)vancing area o$ human
gene%ics.
Article utline
1. In%ro)uc%ion
2. ./A )amage an) re#air
2.1. he ./A )amage s#ec%rum a$%er ra)ia%ion
2.2. Pos%-irra)ia%ion cellular ./A re#air an) mu%agenesis
2.2.1. .amage %o ./A nucleo%i)e bases
2.2.2. 3ingle s%ran) brea!s (ssb+ in ./A
2.2.2. .ouble s%ran) lesions in ./A
2.2.8. ./A re#air an) recombina%ional #rocesses
2.2.5. 6uman a%a4ia-%elangiec%asia
2
2.2.>. 'a)ia%ion mu%agenesis an) i%s rela%ionshi# %o ./A re#air
2.2.7. &hromosomal s%ruc%ure an) ra)ia%ion mu%agenesis
2.2.8. "enomic ins%abili%y
2.2. 6uman gene%ic )isor)ers a$$ec%ing ./A re#air an) genomic ins%abili%y
2.8. 3ummary an) conclusions
2. Mechanisms an) gene%ics o$ soli) %umours
2.1. Cncogenes
2.2. umour su##ressor genes
2.2.1. umour su##ressor genes in %he cell cycle
2.2.2. he p53 gene in ./A )amage chec!#oin% con%rol
2.2.2. 3oma%ic mu%a%ions o$ p53 in human %umours
2.2. ./A re#air an) re#lica%ion genes in soli) %umours
2.8. "ene%ic susce#%ibili%y %o soli) %umours
2.8.1. 6eri%able breas% an) ovarian cancer
2.8.2. 6eri%able colon cancer
2.8.2. 6eri%able renal cancer
2.8.8. 6eri%able %umours o$ %he nervous sys%em
2.8.5. 6eri%able #ros%a%e an) %es%icular cancer
2.8.>. 6eri%able s!in cancer
2.8.7. 6eri%able cancers o$ %he en)ocrine sys%em
2.8.8. "enes associa%e) ,i%h cancer a% mul%i#le si%es
2.5. he origin o$ mu%a%ions in %umour-associa%e) genes
2.5.1. "ermline mu%a%ions o$ %umour-su##ressor genes
2.5.2. Pre$eren%ial involvemen% o$ #aren%al alleles in %umour gene mu%a%ions
2.5.2. *vi)ence $or mu%a%ional mosaicism
2.>. he gene%ic com#onen% o$ soli) %umours
2.7. 3ummary
8. Mechanisms an) gene%ics o$ lym#ho-haemo#oie%ic neo#lasia
8.1. Mechanisms o$ in)uc%ion o$ lym#ho-haemo#oie%ic neo#lasia
8.1.1. 3%ruc%ure an) $unc%ion o$ %he lym#ho-haemo#oie%ic sys%em
8.1.2. 1ym#ho-haemo#oie%ic neo#lasia
8.1.2. &y%ogene%ic an) molecular mechanisms o$ lym#ho-haemo#oie%ic neo#lasia
8.1.2.1. &hromosome %ransloca%ions
8.1.2.2. &hromosome )ele%ions an) numerical changes
8.1.2.2. C%her #ro%o-oncogene an) %umour su##ressor mu%a%ions
8.1.2.8. "enomic ins%abili%y in haemo#oie%ic neo#lasia
8.2. "ene%ic susce#%ibili%y %o lym#ho-haemo#oie%ic neo#lasia
8.2.1. :amily s%u)ies
8.2.2. 3%u)ies ,i%h %,ins
8.2.2. &ancer $amily syn)romes
8.2.8. &hromosome ins%abili%y syn)romes
8.2.8.1. A%a4ia-%elangiec%asia
8.2.8.2. Bloom syn)rome
8.2.8.2. :anconi anaemia
8.2.8.8. 6eri%able chromosomal $ragile si%es
8.2.5. &hromosomal an) )evelo#men%al abnormali%ies
8.2.5.1. &hromosomal abnormali%ies
8.2.5.2. .evelo#men%al abnormali%ies
3
8.2.>. Immunological )e$iciencies
8.2.7. *#igene%ic $ac%ors
8.2.8. he gene%ic com#onen% o$ lym#ho-haemo#oie%ic neo#lasia
8.2. 3ummary an) conclusions
5. *vi)ence on associa%ions be%,een %umorigenic ra)iosensi%ivi%y an) heri%able #re)is#osi%ion %o cancer
5.1. Mechanis%ic as#ec%s o$ %umorigenic ra)iosensi%ivi%y
5.1.1. "ene%ic )e$ec%s in ./A #rocessing
5.1.2. "ene%ic )e$ec%s in %umour su##ressor genes
5.1.2. "ene%ic )e$ec%s in #ro%o-oncogenes
5.2. 'o)en% mo)els o$ cancer #re)is#osi%ion
5.2.1. ./A re#air )e$icien% ro)en%s
5.2.2. umour su##ressor gene )e$icien% ro)en%s
5.2.2.1. Mice )e$icien% in #52
5.2.2.2. Mice )e$icien% in A#c
5.2.2.2. 'a%s )e$icien% in sc2
5.2.2. 'ela%ive %umour ris! in )i$$eren% mouse s%rains
5.2. 'a)io%hera#eu%ic observa%ion
5.2.1. 'e%inoblas%oma
5.2.2. /evoi) basal cell carcinoma syn)rome
5.2.2. 1i7:raumeni syn)rome an) neuro$ibroma%osis
5.2.8. C%her gene%ic con)i%ions an) $amilial associa%ions
5.8. *#i)emiological as#ec%s o$ %umorigenic ra)iosensi%ivi%y
5.8.1. Breas% cancer ris! in a%a4ia-%elangiec%asia he%ero<ygo%es
5.8.2. &on%ribu%ions $rom $amily s%u)ies an) mo)i$iers o$ cancer ris!
5.8.2. 3usce#%ibili%y %o ra)ia%ion carcinogenesis in Da#anese A-bomb survivors
5.8.8. "ene%ic an) molecular s%u)ies in irra)ia%e) #o#ula%ions
5.8.5. 3%a%is%ical consi)era%ions an) mo)elling
5.8.>. Irra)ia%e) grou#s $or #o%en%ial s%u)y
5.8.>.1. Breas% cancer among A-bomb survivors
5.8.>.2. Breas% cancer in o%her irra)ia%e) #o#ula%ions
5.8.>.2. &olon cancer among A-bomb survivors
5.8.>.8. Cvarian cancer among A-bomb survivors
5.5. Cverall -u)gemen%s on gene%ically )e%ermine) %umorigenic ra)iosensi%ivi%y
5.>. 3ummary an) conclusions
>. &om#u%a%ional mo)elling o$ %he im#ac% o$ gene%ic $ac%ors in ra)ia%ion carcinogenesis
>.1. :amilial cancer genes@ es%ima%es o$ mu%an% gene $re9uencies
>.1.1.1. BRCA1 an) BRCA2 in $amilial breas% cancers
>.1.1.2. Mu%a%ions in ./A misma%ch re#air genes an) here)i%ary non-#oly#osis colon cancer (6/P&&+
>.2. Po#ula%ion gene%ic mo)els o$ cancer #re)is#osi%ion an) ra)iosensi%ivi%y
>.2.1.1. 6ar)y Eeinberg e9uilibrium
>.2.2. A Men)elian single locus, au%osomal )ominan% mo)el o$ cancer susce#%ibili%y an)
ra)iosensi%ivi%y@ A hy#o%he%ical numerical e4ercise
>.2.2. Au%osomal )ominan% mo)el o$ cancer susce#%ibili%y an) ra)iosensi%ivi%y ,hich incor#ora%es
)i$$erences in #ene%rance an) )ose-)e#en)ence o$ ra)iosensi%ivi%y )i$$eren%ials
>.2.2.1. .e$ini%ion o$ %he mo)el@ incor#ora%ion o$ cancer susce#%ibili%y an) incom#le%e #ene%rance
>.2.2.2. Incor#ora%ion o$ )ose )e#en)ence o$ ra)iosensi%ivi%y )i$$eren%ial in %he mo)el
>.2.8. /umerical a##lica%ions
4
>.2.8.1. 'a%ionale $or %he #arame%er values chosen $or a##lying %he mo)el $or breas% cancer an)
here)i%ary non-#oly#osis colon cancer
>.2.8.2. 'esul%s@ breas% cancer
>.2.8.2. 6ere)i%ary non-#oly#osis colon cancer
>.2.5. &ancer #re)is#osi%ion an) ra)iosensi%ivi%y )ue %o recessive mu%a%ions a% an au%osomal locus
>.2. 3ummary an) conclusions
7. Im#lica%ions $or ra)iological #ro%ec%ion o$ )a%a on cancer susce#%ibili%y
7.1. :amilial cancer involving genes o$ high #ene%rance
7.1.1. :amilial cancer an) ris!s in a #o#ula%ion
7.1.2. :amilial cancer an) in)ivi)ual ris!
7.2. &ancer involving genes o$ lo, #ene%rance
7.2. Areas o$ $u%ure research in ra)iological #ro%ec%ion
7.8. he a##lica%ion o$ )iagnos%ic %echnologies
7.5. 3ummary an) conclusions $or ra)iological #ro%ec%ion
7.5.1. *s%ima%ion o$ ris!s in ,hole #o#ula%ions
7.5.2. 'is!s in in)ivi)uals ,i%h $amilial cancer
7.5.2. "ene%ic %es%ing $or cancer susce#%ibili%y in %he con%e4% o$ ra)iological #ro%ec%ion
7.5.8. &onclu)ing remar!s
'e$erences
1! Introduction
he las% %,o )eca)es have ,i%nesse) a s#ec%acular increase in our $un)amen%al un)ers%an)ing o$ %he
cancer #rocess. his has come abou% largely %hrough %he )evelo#men% o$ #o,er$ul molecular gene%ic
%echni9ues %ha% have allo,e) cancer-associa%e) genes %o be i)en%i$ie), isola%e), $unc%ionally
charac%erise), an) ma##e) %o s#eci$ic regions o$ %he human genome. hese same %echni9ues, %oge%her
,i%h a)vances in e#i)emiology an) clinical s%u)ies, have revolu%ionise) human gene%ics an) cou#le)
,i%h a)vances in cancer biology have allo,e) %he charac%erisa%ion o$ a signi$ican% number o$ heri%able
)isor)ers associa%e) ,i%h a $amilial #re)is#osi%ion %o neo#lasia.
In a))i%ion %o %he bene$i%s accruing %o clinical an) me)ical gene%ic -u)gemen%s %his a)vance in
!no,le)ge also has #o%en%ially im#or%an% socio-economic im#lica%ions. Inclu)e) in %his la%%er ca%egory
is %he 9ues%ion as %o ,he%her germ line gene mu%a%ions %ha% #re)is#ose %o s#on%aneously arising human
cancer also im#ose an increase) cancer ris! a$%er e4#osure %o environmen%al geno%o4ic agen%s such as
ionising ra)ia%ion.
&urren% I&'P recommen)a%ions on ra)iological #ro%ec%ion #rovi)e) in Publication 60 (I&'P, 1991+ are
base) essen%ially on %he es%ima%ion o$ e4cess cancer ris! a$%er e4#osure o$ ,hole #o#ula%ions. 3ince
ho,ever all such #o#ula%ions ,ill be gene%ically he%erogeneous, %here is a s%rong e4#ec%a%ion %ha%, even
%a!ing accoun% o$ all o%her e4ogenous $ac%ors, %he e4cess cancer ris! #er uni% o$ )ose $ollo,ing
ra)ia%ion e4#osure ,ill be non-uni$orm because o$ s#eci$ic )i$$erences in gene%ic ma!e-u# be%,een
in)ivi)uals.
Cn %he above basis, %his re#or% see!s %o revie, $un)amen%al, clinical, an) e#i)emiological )a%a relevan%
%o a heri%able cancer #re)is#osi%ion an) $rom %his %o ma!e in%erim -u)gemen%s on %umorigenic
ra)iosensi%ivi%y in %he gene%ic )isor)ers o$ %his %y#e an) also on %he li!ely con%ribu%ion %ha% gene%ic
$ac%ors may ma!e %o ra)ia%ion-in)uce) cancer in %he human #o#ula%ion.
5
I% is ho,ever im#or%an% %o s%ress a% %he ou%se% %ha%, in %he con%e4% o$ ra)ia%ion e$$ec%s, )irec%ly
in$orma%ive e#i)emiological )a%a on a cancer #re)is#osi%ion are essen%ially lac!ing. :or %his reason
em#hasis is #lace) on %he im#lica%ions o$ )a%a $rom e4#erimen%al s%u)ies an) clinical observa%ions, on
%he )evelo#men% o$ com#u%a%ional gene%ic mo)els o$ cancer ris! an) on #ossible research s%ra%egies $or
%he $u%ure. oge%her, %hese are in%en)e) %o #rovi)e a $rame,or! %o $acili%a%e $u%ure -u)gemen%s by %he
&ommission on %his #o%en%ially im#or%an% as#ec% o$ ra)iological #ro%ec%ion.
he as! "rou# me% %o revie, )a%a an) com#ile %heir re#or% be%,een 1992 an) 199>. he re#or% ,as
essen%ially com#le%e) an) a)o#%e) by %he &ommission )uring 1997 ,i%h minor revisions in early 1998.
"! #$A dama%e and repair
hroughou% %his re#or% re$erence ,ill be ma)e %o s#eci$ic cancer-#rone human gene%ic )isor)ers an) %he
clinical, e#i)emiological, an) cellular0molecular )a%a %ha% serve %o )e$ine %heir #heno%y#es. 3ince
ho,ever a #rime ob-ec%ive o$ %his re#or% is %o revie, %umorigenic mechanisms a$%er ra)ia%ion in rela%ion
%o a cancer #re)is#osi%ion, i% is im#or%an% %o brie$ly consi)er )a%a rela%ing %o ra)ia%ion-in)uce) cellular
)amage, ./A re#air mechanisms, an) mu%agenic #rocesses.
Assessmen% o$ %he na%ure an) e4%en% o$ ra)ia%ion-in)uce) cellular )amage has #reoccu#ie) ra)ia%ion
biology $or many )eca)es. Al%hough enumera%ion o$ such in)uce) lesions is un)oub%e)ly a##ro#ria%e,
evalua%ion o$ %he $orms o$ cellular )amage %ha% are mos% relevan% %o neo#las%ic )evelo#men% is o$
#rinci#al im#or%ance $or %he #ur#ose o$ %his re#or%. In or)er %o achieve such meaning$ul evalua%ions, i%
is necessary %o %a!e $ull accoun% o$ %he na%ure o$ %he cellular lesions %ha% #rinci#ally charac%erise %he
neo#las%ic s%a%e i%sel$. In %his ,ay i% becomes #ossible %o correla%e s#eci$ic ra)ia%ion-in)uce) cellular
even%s i)en%i$ie) in mo)el e4#erimen%al sys%ems ,i%h %he in vivo in)uc%ion o$ %umours. I% is $or%una%e
%ha%, $rom %he revie,s o$ %he mechanisms o$ neo#las%ic )evelo#men% #rovi)e) in 3ec%ion 2 an) 3ec%ion
8 o$ %his re#or%, i% is #ossible %o i)en%i$y gene mu%a%ions an) chromosomal even%s inclu)ing loss o$
he%ero<ygosi%y (chromosomal an) gene )ele%ions+ as cri%ical even%s in %umorigenesis.
his sec%ion consi)ers %he na%ure o$ ra)ia%ion-in)uce) genomic lesions in soma%ic cells an) %he cellular
re#air #rocesses ,hich correc% %hese or lea) %o gene an) chromosomal mu%a%ions= also )escribe) are %he
soma%ic cell mu%an%s an) human gene%ic )isor)ers in ,hich %he #rocessing o$ ra)ia%ion-in)uce) ./A
)amage is believe) %o be im#aire). Ee have elec%e) %o avoi) )iscussion o$ %he s#eci$ic e$$ec%s o$
ul%raviole% ra)ia%ion (AV'+ an) chemical geno%o4ic agen%s e4ce#% ,here %hey )irec%ly con%ribu%e %o our
broa) un)ers%an)ing o$ %he #roblem in han).
"!1! &he #$A dama%e spectrum after radiation
he na%ure o$ %he ini%ial ./A )amage #ro)uce) by ionising ra)ia%ions an) %he e$$ec%s o$ ra)ia%ion
9uali%y have been e4%ensively revie,e) (Ear), 1988 an) Ear), 1991= Price, 1992= Prise, 1998+. here
is a s%rong consensus %ha% cellular ./A is %he cri%ical %arge% $or ra)iobiological e$$ec%s an) %ha%
)i$$erences in ra)ia%ion %rac! s%ruc%ure in$luence %he na%ure o$ in)uce) ./A lesions an) %heir cellular
conse9uences.
he ./A molecules o$ cellular nuclei may no% al,ays re#resen% %he )irec% %arge% $or energy loss even%s
$rom ra)ia%ion an) ./A )amage may be me)ia%e) by %he #ro)uc%s o$ %he ra)iolysis o$ ,a%er or #erha#s
o%her cellular cons%i%uen%s. hese ra)iolysis #ro)uc%s, i.e. reac%ive chemical ra)icals, ,hich re#resen%
%he #rimary s%age o$ %he )amage in)uc%ion #rocess, are inca#able o$ )i$$using over signi$ican% cellular
6
)imensions because o$ en)ogenous scavenging ca#aci%y. As a conse9uence, ra)ia%ion ac%ion on ./A is
essen%ially a local #rocess.
'a)ical in)uce) )amage as a conse9uence o$ a ra)ia%ion %rac! in%ersec%ion o$ ./A may occur ,i%hin
all %he chemical moie%ies o$ ./A an), since i% is local in na%ure, 1*-)e#en)en% clus%ering o$ ./A
lesions is %o be e4#ec%e). 3#on%aneous chemical reversal o$ such ./A lesions may occur bu%, i$ no%, %he
)amage) si%e becomes %he #o%en%ial subs%ra%e $or en<yme-me)ia%e) re#air ,hich ei%her res%ores %he
molecular lesion %o i%s original un)amage) s%a%e or resul%s in s%able ./A )amage, i.e. gene or
chromosomal mu%a%ion.
'a)ia%ion-in)uce) ./A lesions recognisable a% %he biochemical level are largely )e$ine) by %he na%ure
o$ %he assay %echni9ue em#loye) an) inclu)e )amage %o ./A nucleo%i)e bases, single an) )ouble
s%ran) brea!s in %he sugar-#hos#ha%e ./A bac!bones, an) ./A7./A or ./A7#ro%ein cross lin!s.
&om#le4 lesions involving local clus%ering o$ )i$$eren% $orms o$ molecular )amage are also believe) %o
occur an) may be cri%ical $or ra)ia%ion 9uali%y e$$ec%s (Ear), 1991= Prise, 1998+.
"!"! Post'irradiation cellular #$A repair and muta%enesis
"!"!1! #ama%e to #$A nucleotide bases
./A base )amage can arise $rom )irec% ra)ia%ion in%erac%ion ,i%h %he macromolecule or #erha#s mos%
$re9uen%ly via %he genera%ion o$ reac%ive $ree ra)icals in %he ,a%er shell surroun)ing ./A. Various
classes o$ reac%ions are involve) in %he ra)ical a%%ac! on ./A bases an) in %he case o$ ./A base
)issocia%ion, o4i)a%ion, an) cross-lin!ing %he local biological $unc%ion o$ ./A is $re9uen%ly im#aire)
or los%.
Amongs% %he #rinci#al ./A base )amage in)uce) by ionising ra)ia%ion are 8-hy)ro4y)eo4yguanosine
(8-C6)"+ an) %hymine glycols al%hough a broa) range o$ o%her $orms o$ o4i)a%ive )amage has been
charac%erise) (Ear), 1988 an) Ear), 1991+. 8-C6)" may be regar)e) as %he $orm o$ in)uce) ./A
base )amage o$ grea%es% #o%en%ial biological signi$icance. I% is !no,n %o be remove) by a ./A base
re#air mechanism (chou e% al., 1991+ bu%, mos% im#or%an%ly, since i% is a mis-co)ing lesion i% is
#o%en%ially mu%agenic (Eoo)s e% al., 199;+. he available )a%a sugges% ho,ever %ha% such base )amage
,ill #lay only a minor role in ra)ia%ion mu%agenesis (Ear), 1995+.
"!"!"! (in%le strand brea)s *ssb+ in #$A
I% a##ears %ha% ./A ssb )o no% con%ribu%e grea%ly %o %he #rocess o$ ra)ia%ion mu%agenesis. hese lesions
are re#aire) ra#i)ly (Fohn e% al., 1981+ an), since such re#air u%ilises %he base se9uence on %he
un)amage) com#lemen%ary ./A s%ran), re#air $i)eli%y is e4#ec%e) %o be high. he $irs% s%e# in %he
re#air #rocess is %he ac%ion o$ an e4onuclease (#hos#ho)ies%erase+ %ha% serves %o remove ss./A a% %he
)amage) si%e. he resul%ing single s%ran) ga# is %hen $ille) by %he ac%ion o$ ./A #olymerase ,i%h a
shor% re#air #a%ch o$ 1 or 2 nucleo%i)es= ./A s%ran) re-oining is subse9uen%ly achieve) #robably via
%he ac%ion o$ ./A ligase 1.
3ome mu%an% ro)en% cells hy#ersensi%ive %o %he inac%iva%ing e$$ec%s o$ ionising ra)ia%ion have im#aire)
./A ssb re#air bu% )a%a $or one such mu%an% (irs 13:+ reveals i% %o be hy#omu%able (G)<ienic!a an)
Dongmans, 1998+. hus, ,hile ./A ssb may no% be com#le%ely neu%ral in %erms o$ biological e$$ec%s,
%hey are clearly no% a ma-or con%ribu%or %o ra)ia%ion mu%agenesis (:uller an) Pain%er, 1988+.
7
"!"!,! #ouble strand lesions in #$A
./A )ouble s%ran) lesions inclu)ing $ran! brea!s are believe) %o be %he lesion %y#e o$ grea%es%
im#or%ance in %he in)uc%ion by ra)ia%ion o$ cell le%hal even%s, chromosomal abnormali%ies, an) gene
mu%a%ions ("oo)hea), 1998+. :or %he #ur#oses o$ sim#lici%y %he use o$ %he %erm ./A )ouble s%ran)
brea! ()sb+ ,ill be use) in %he %e4% %o )escribe collec%ively all $orms o$ ./A )ouble s%ran) lesion.
Misre#air or non-re#air o$ a #ro#or%ion o$ coinci)en% lesions in ./A is %o be e4#ec%e) %hrough ./A
)isloca%ion an)0or %he non-availabili%y o$ an un)amage) com#lemen%ary se9uence $or #olymerase
ac%ion. 3uch misre#air may inclu)e %he in%erac%ion o$ ./A )sb %hrough some $orm o$ illegi%ima%e
recombina%ion in or)er %o $orm %he chromosomal e4changes an) in%ers%i%ial )ele%ions %ha% are
charac%eris%ic o$ ra)ia%ion an) ,hich are im#lica%e) in neo#las%ic )evelo#men% (3ec%ion 2 an) 3ec%ion
8+. he biological im#or%ance o$ ./A )sb in ra)ia%ion res#onse is mos% clearly evi)en% $rom s%u)ies o$
mu%an% ro)en% cell lines %ha% are )e$ec%ive in %he re#air o$ ra)ia%ion in)uce) )amage (able 2.1=
hac!er, 1992, &ollins, 1992, Deggo, 1998= G)<ienic!a, 1995+.
able 2.1. 'a)iosensi%ivi%y an) re#air )e$iciency in ro)en% soma%ic cell mu%an%s
he xrs cells o$ able 2.1 are ra)iosensi%ive an) )emons%ra%e bo%h an enhance) in)uc%ion o$
chromosomal )amage ei%her measure) biochemically (/agasa,a e% al., 1991+ or by #rema%ure
chromosome con)ensa%ion %echni9ues (Ilia!is an) Pan%elias, 199;+. .irec% )emons%ra%ion o$ %he
im#or%ance o$ ./A )sb in %he #ro)uc%ion o$ chromosome aberra%ions is $ur%her #rovi)e) by %he
correla%ion in %he %ime course o$ %he loss o$ ./A )sb an) aberra%ion yiel). :or mu%a%ion in)uc%ion, a
$ive $ol) hy#ermu%able s%a%e is observe) ,hen mu%a%ions a% %he hprt or tk locus ,ere assesse) a% e9ual
ra)ia%ion )oses in %he gene%ic com#lemen%a%ion grou# 5 sensi%ive mu%an%s in com#arison ,i%h %heir
con%rols. Ehen, ho,ever, %he res#onse a% e9ui%o4ic )oses is com#are) %hese cells sho,e) a similar or
re)uce) in)uce) mu%an% $re9uency in com#arison ,i%h %he #aren%al cell line. hese resul%s im#ly %ha%
%he e4cess o$ ./A )sb )e%ec%e) a% a given level o$ )ose in %hese ra)ia%ion sensi%ive cells is #rocesse)
via a re#air #a%h,ay ,hich is essen%ially error #rone= %he resul% a% e9ui%o4ic )oses $ur%her sugges%s %ha%
%here is a close rela%ionshi# be%,een %he re#air o$ #o%en%ially mu%agenic an) le%hal lesions involving
./A )sb. his accor)s ,i%h early )a%a rela%ing %o %he le%hal an) mu%agenic e$$ec%s o$ lo, 1* ra)ia%ion
in human an) ro)en% cells (hac!er an) &o4, 1975= hac!er, 1992+.
"!"!-! #$A repair and recombinational processes
he cen%ral role o$ ./A )sb re#air has been reveale) by %he gene%ic analysis o$ ro)en% cell ./A re#air
mu%an%s (able 2.1+. In combina%ion ,i%h ./A ssb )e$ec%ive mu%an%s, %his com#ila%ion sho,s %ha% %here
8
are a% leas% seven human genes involve) in %he re#air o$ ./A )amage in)uce) by ionising ra)ia%ion,
i.e. XRCC1XRCC7, o$ ,hich $ive are involve) in ./A )sb re#air. A $ur%her gene%ic a##roach ,hich
e4#loi%s %he evolu%ionary conserva%ion o$ ./A re#air genes has ma)e i% #ossible %o clone a $ur%her $our
human homologues o$ %he yeas% ra >, 51, 52, an) 58 genes= %hese la%%er %hree genes are also involve)
in ./A )sb re#air (able 2.2+. he $irs% )irec% evi)ence %ha% recombina%ion ,as im#or%an% in %he re#air
o$ ./A )sb in)uce) by ionising ra)ia%ion )erive) $rom s%u)ies on %he ra)ia%ion res#onse o$ a severe
combine) immune )e$iciency (sci+ mu%an% o$ %he labora%ory mouse (Bie)ermann e% al., 1991=
6en)ric!son e% al., 1991+. In %his au%osomal recessive )isor)er ,hole animal ra)iosensi%ivi%y is
re$lec%e) a% %he cellular level an) is accom#anie) by )e$ec%s in %he re#air o$ ./A )sb an) im#aire)
recombina%ion o$ !"#$% immune se9uences ,hich in %urn genera%es %he immuno)e$iciency #heno%y#e
o$ %hese animals. !"#$% recombina%ion re9uires several ./A brea!age an) re-oining s%e#s, an) is
)irec%e) %o,ar)s conserve) recombina%ion signal se9uences %ha% $lan! each o$ %he germline V, ., an) D
genomic segmen%s (see also 3ec%ion 8+. his recombina%ion #rocess u%ilises an array o$ cellular
com#onen%s an) %he evi)ence available sugges%s %ha% %he ./A )sb re#air machinery ,hich is use)
rou%inely %o han)le ./A )amage is recrui%e) %o #ar%ici#a%e in %he ./A )sb re-oining s%e#s o$ !"#$%
recombina%ion. he rela%ionshi# be%,een com#e%en% !"#$% recombina%ion an) )sb re#air is $ur%her
evi)ence) by %he observa%ion %ha% %hose ra)iosensi%ive mu%an%s ,hich are com#e%en% %o carry ou% ./A
)sb re#air have normal !"#$% re-oining (Pergola e% al., 1992= accioli e% al., 1992= hac!er, 1998+.
able 2.2. 6uman homologues o$ yeas% genes involve) in ra)ia%ion res#onse
he ./A )sb re#air )e$ec%ive xrs mu%an%s are )e$ec%ive in %he ./A en)-bin)ing ac%ivi%y o$ a
he%ero)imeric #ro%ein !no,n as Fu ()e Vries e% al., 1989= 'a%hmell an) &hu, 1998+ an) a gene
enco)ing %he Fu 8; !. subuni% an) %he XRCC5 gene ma# %o %he same loca%ion a% human chromosome
2922725 (6a$e<#aras% e% al., 1992+. &u'0 c./A correc%s bo%h %he !"#$% re-oining )e$ec% an) %he
ra)ia%ion sensi%ivi%y o$ xrs cells an), since bo%h #heno%y#es co-segrega%e in human0hams%er hybri)s
con%aining segmen%s o$ human chromosome 2, i% ,as -u)ge) %ha% %he 8; Fu subuni% ,as almos%
cer%ainly %he #ro)uc% o$ %he XRCC5 gene (accioli e% al., 1998+. A )irec% )emons%ra%ion o$ %his
rela%ionshi# ,as available ,hen %he )e$ec% in ./A )sb re#air ,as correc%e) by in%ro)ucing %he &u'0
gene in%o xrs(6 cells ('oss e% al., 1995+. In a))i%ion %o %he 8; !. subuni%, Fu is com#ose) o$ a secon)
%igh%ly boun) 7; !. com#onen%, an) %he bin)ing o$ %hese #e#%i)es %o ./A %ermini ac%iva%es a %hir) 25;
!. subuni% ,i%h #ro%ein !inase ac%ivi%y. his com#le4 is !no,n as ./A7PF an) %he !inase ac%ivi%y o$
%his is %o%ally )e#en)en% u#on %he bin)ing o$ Fu %o %he bro!en ./A en)s. he large 25; !. subuni% o$
Fu has been sho,n %o be %he #ro)uc% o$ %he XRCC7 gene on chromosome 8911 (Blun% e% al., 1995+ an)
is clearly also %he #ro)uc% o$ %he gene %ha% )e%ermines murine sci #heno%y#e. "ene%ic an) biochemical
s%u)ies on %he human )isor)er a%a4ia-%elangiec%asia (A-+ #rovi)e a))i%ional im#or%an% in$orma%ion on
%he role o$ ./A re#air an) recombina%ional #rocesses in ra)ia%ion res#onse. he recen% i)en%i$ica%ion o$
%he $irs% human cells %ha% are clearly )e$ec%ive in )sb re#air (Ba)ie e% al., 1995+ may assis% in $ur%her
mechanis%ic s%u)ies.
9
"!"!.! /uman ata0ia'telan%iectasia
he im#or%ance o$ ./A )sb re#air has been reveale) by %he s%u)y o$ %he human au%osomal recessive
cancer #rone syn)rome a%a4ia-%elangiec%asia (A-+ (3e)g,ic! an) Bo)er, 1991= aylor, 1992= Bun)ey,
1998+. he syn)rome is charac%erise) by cerebellar a%a4ia as a conse9uence o$ #rogressive
neuro)egenera%ion %oge%her ,i%h #ermanen%ly )ila%e) bloo) vessels, !no,n as %elangiec%ases,
#ar%icularly in %he eye bu% ,hich may occur on %he ears or nose. I%s $re9uency in %he #o#ula%ion is
aroun) one in 2;;,;;; (Eoo)s e% al., 199;+. Bo%h cellular an) humoral immune )e$iciencies are
common an) %here is a consi)erably eleva%e) inci)ence o$ %umours. A##ro4ima%ely 1;5 o$ A-
#a%ien%s )evelo# cancer in %he $irs% %,o )eca)es o$ li$e, %he ma-ori%y o$ %hese %umours are o$
haemo#oie%ic origin (see 3ec%ion 8+ an) some may ,ell be associa%e) ,i%h %he a##earance o$
s#on%aneous chromosome %ransloca%ions be%,een chromosomes 7 an) 18 ,hich can e4#an) %o $orm
large clones in %he circula%ing -cell #o#ula%ions o$ some #a%ien%s (aylor, 1982+. he high $re9uency o$
chromosome aberra%ions in bloo) )erive) cells has le) %o %his syn)rome being )e$ine) as a
Hchromosome brea!age or chromosome ins%abili%y syn)romeI. he syn)rome became %he $ocus o$
ra)iobiological in%eres% $ollo,ing %he )emons%ra%ion %ha% a )rama%ic clinical ra)iosensi%ivi%y (&unli$$e e%
al., 1975+ ,as re$lec%e) a% %he cellular level by hy#ersensi%ivi%y %o bo%h %he le%hal an) chromosome
brea!age ac%ion o$ ionising ra)ia%ion (aylor e% al., 1975= aylor, 1982+. 6y#ersensi%ivi%y %o %he le%hal
e$$ec%s o$ ra)ia%ion has been seen in all cell %y#es %es%e) %o )a%e (&ole e% al., 1988+ an) %here is some
evi)ence im#lica%ing %he misre#air o$ ./A )sb in %he )isor)er (&o4 e% al., 198>= hac!er, 1992+, a
$ea%ure %ha% may be consis%en% ,i%h %he immunological )e$ec%s in %he )isor)er. :ormal inves%iga%ions on
%he re#air o$ )sb in A- cells have genera%e) con$lic%ing resul%s. he mos% recen% o$ %hese (see :oray e%
al., 1995+ inclu)e) lo, )ose-ra%e irra)ia%ion an) e4%en)e) re#air %imes an) are consis%en% in sho,ing
higher levels o$ resi)ual )sb %han in normal cells. In a))i%ion %here is evi)ence %ha%, )uring > h #os%-
irra)ia%ion, re#air in A- is $as%er %han normal (:oray e% al., 1995+. 6o,ever, %he search $or a
biochemically )e$ine) )e$ec% in %he re#air o$ ionising ra)ia%ion )amage in A- has #rove) )i$$icul%.
3everal labora%ories have #ro)uce) convincing evi)ence $or an abnormal cellular res#onse o$ ./A
syn%hesis $ollo,ing %rea%men% ,i%h ionising ra)ia%ion ,hich may rela%e %o %he $as%er early re#air in A-
cells. hus, in normal cells %here is a mar!e) inhibi%ion o$ ./A syn%hesis $ollo,ing ra)ia%ion ,hich is
no% observe) in A- cells (6oul)s,or%h an) 1avin, 198;= Pain%er an) Joung, 198;+. his cellular
#heno%y#e, %erme) ra)ioresis%an% ./A syn%hesis, has been use) %o carry ou% gene%ic com#lemen%a%ion
%es%s ,hich sugges%e) %ha% A- coul) be sub)ivi)e) in%o $our com#lemen%a%ion grou#s (Das#ers e% al.,
1988, bu% see #aragra#h 22+. he relevance o$ a )e$ec% giving ra)ioresis%an% ./A syn%hesis is no%
ho,ever obvious. In %he HA- li!eI ra)ia%ion-sensi%ive hams%er cell mu%an%s (able 2.1+ %rans$ec%ion
,i%h a human gene $rom chromosome 89 correc%s %he ./A syn%hesis )e$ec% bu% )oes no% ameliora%e %he
le%hal or clas%ogenic e$$ec%s o$ ra)ia%ion (Verhaegh e% al., 1995+. In a))i%ion %o %he abnormali%y in
ra)ia%ion resis%an% ./A syn%hesis A- cells also sho, o%her #er%urba%ions in #rogression %hrough %he
cell cycle (hac!er, 1998+. 3ince A- cells remain hy#ersensi%ive un)er con)i%ions ,here %hey are no%
#roli$era%ing an) ,here, by )e$ini%ion, %he cell cycle abnormali%ies canno% be o#era%ing, %here mus% be
a))i%ional mechanisms o$ )e$ec%ive ./A re#air (hac!er, 1998+.
3ubse9uen% gene%ic lin!age s%u)ies sho,e) $irs% %ha% %he A- gene(s+ ma##e) %o chromosome 11922.22
("a%%i e% al., 1988+ an) %ha% %hree o$ %he com#lemen%a%ion grou#s ma##e) %o %he same region. :inally,
3avi%s!y e% al. (1995+ succee)e) in cloning a c./A covering a signi$ican% #ar% o$ %he gene inclu)ing
%he im#or%an% $unc%ional )omains. he si%e o$ %he mu%a%ion in %he A)* gene ,as ne4% i)en%i$ie) in a
number o$ A- #a%ien%s, some #rove) %o be homo<ygo%es, o%hers com#oun) he%ero<ygo%es. hese
resul%s lai) %o res% %he conce#% o$ a series o$ com#lemen%a%ion grou#s in A- because an i)en%ical
homo<ygous mu%a%ion ,as $oun) %o be #resen% in %,o in)ivi)uals #reviously assigne) %o )is%inc%
10
com#lemen%a%ion grou#s. he ma-ori%y o$ %he mu%a%ions i)en%i$ie) %o )a%e are $rame shi$%s resul%ing in a
%o%al loss o$ $unc%ion o$ %he gene #ro)uc%, a resul% ,hich migh% be consi)ere) sur#rising in %he ligh% o$
%he mul%i-sys%em na%ure o$ %he )isease. A##ro4ima%ely 2;5 o$ A- #a%ien%s $rom ,i%hin %he Ani%e)
Fing)om are recognise) as having in%erme)ia%e ra)ia%ion sensi%ivi%y an) %o e4hibi% mil)er clinical
sym#%oms (aylor e% al., 199>+. hey also sho, a common ha#lo%y#e an) are com#oun) he%ero<ygo%es
charac%erise) by a large 128b# inser%ion a% #osi%ion 57>805 in one allele ,hich lea)s %o a $rameshi$% an)
%ermina%ion o$ %he message. he secon) mu%a%ion in %his grou# varies $rom #a%ien% %o #a%ien% an) i% is
#robably %his secon), less severe, mu%a%ion ,hich )e%ermines %he #heno%y#e. An#ublishe) in$orma%ion
on %he )is%ribu%ion o$ mu%a%ions, again $rom ,i%hin %he Ani%e) Fing)om, sugges%s %ha% %hey are almos%
all com#oun) he%ero<ygo%es an) %ha% %here is no common mu%a%ion.
he mos% im#or%an% conse9uences ,hich $lo, $rom %hese s%u)ies concern %he #re)ic%e) na%ure an)
mo)e o$ ac%ion o$ %he gene #ro)uc%. he A- gene #ro)uc% is a #ro%ein ,i%h consi)erable homology
,i%h a $amily o$ signal %rans)uc%ion molecules genera%e) by a gene $amily !no,n as %he
#hos#ha%i)ylinosi%ol (PI+ 2-!inase $amily. he signal %rans)uc%ion molecules inclu)e %he C'1 an)
C'2 #ro%eins $rom yeas% (6elli,ell e% al., 1998+, %he mC' an) 'A: #ro%ein in ra% an) %he :'AP
#ro%ein $rom humans (3abers e% al., 1995+. 6o,ever, %he mos% in%eres%ing com#arison is ,i%h %he ra2
gene o$ +chi,osaccharo-.c/s po-b/ an) i%s homologue :3'I (M*&1+ o$ +accharo-.c/s c/r/0isia/.
hese genes are involve) in %he chec!#oin% res#onse %o ./A )amage giving )elaye) #rogression
%hrough %he cell cycle ,hich, i% is believe), ma4imises %he o##or%uni%y $or cellular re#air. In +1 po-b/
%he mu%a%e) gene con$ers hy#ersensi%ivi%y %o %he le%hal e$$ec%s o$ bo%h AV-& an) ionising ra)ia%ion (Al-
Fho)airy an) &arr, 1992+. hese mu%an%s have been sub-ec%e) %o e4%ensive gene%ic analysis an) are
involve) in bo%h %he ./A-)amage chec!#oin% sys%em an) recovery an) re#air #rocesses ,hich, as ye%,
have no% been )e$ine) (1ehmann an) &arr, 1995+. his )ual role o$ %he ra3 #ro%ein is very reminiscen%
o$ %he res#onses o$ A- cells %o ra)ia%ion an) sugges%s %ha% %here e4is%s a $amily o$ genes, common %o
all eu!aryo%es, ,hich is involve) in bo%h re#air an) moni%oring o$ ./A )amage. hrough s%u)ies on
%he localisa%ion0$unc%ion o$ A)* #ro%ein an) %he #heno%y#e o$ A)* null mice i% is becoming more clear
%ha% A)* #lays a com#le4 an) in%erac%ive role in ./A )amage recogni%ion, ./A rearrangemen% an)
cell cycle arres%. hese )a%a ,hich are summarise) by 6oe!s%ra (1997+ im#ly in%erac%ion be%,een
A)*2 A)R (RA#2-rela%e)+, p53 an) RA#51 #ro%eins in ./A )amage res#onse. I% is also s#ecula%e)
%ha% %here may be similar in%erac%ions ,i%h BRCA #ro%eins (see 3ec%ion 2.2+.
Cverall, %he cancer-#roneness o$ A- #a%ien%s seems li!ely %o be rela%e) %o %he chromosome ins%abili%y
charac%eris%ic o$ %he syn)rome ,i%h misre#air o$ ./A )sb, )isru#%e) signal %rans)uc%ion an) im#aire)
cell cycle chec!#oin% $unc%ions as causa%ive mechanisms.
"!"!1! Radiation muta%enesis and its relationship to #$A repair
he accuracy an) com#e%ence o$ relevan% ./A re#air #rocesses are $ur%her reveale) in s%u)ies o$
mu%a%ion in human cell lines o$ variable ra)iosensi%ivi%y. Fen% e% al. (1998+ )emons%ra%e)
hy#omu%abili%y a% %he hprt locus in a ra)iosensi%ive human bla))er cell line AI-38;b ,hen i% ,as
com#are) ,i%h %he #aren%al line (M"6-A1+ an) i% ,as s#ecula%e) %ha% %he hy#omu%abili%y ,as a
re$lec%ion o$ %he #oor recovery o$ mul%ilocus lesions involving %he %arge% hprt gene an) closely lin!e)
essen%ial se9uences. 3u##or% $or %his in%er#re%a%ion is #rovi)e) by inves%iga%ion o$ %he res#onse o$ %,o
human lym#hoblas%oi) lines, EI-12-/3 an) F>, isola%e) $rom %he same original )onor isola%e.
Mu%abili%y ,as e4amine) a% %,o s%ruc%urally )i$$eren% gene%ic loci, hprt an) tk (Amun)son e% al., 1992+.
A% %he hemi<ygous hprt locus %he res#onse %o 4-ray in)uce) mu%a%ion is very similar in %he %,o cell
lines ,hich )i$$er in %heir ra)iosensi%ivi%y, F> #roving %o be signi$ican%ly more ra)iosensi%ive. he
11
!ine%ics o$ %he mu%a%ion in)uc%ion curves ,ere linear $or F> an) linear 9ua)ra%ic $or EI-12-/3. EI-
12-/3 cells #rove) ho,ever %o be 5;-$ol) more mu%able a% %he he%ero<ygous tk locus %han F> cells.
Previous s%u)ies by %he grou# sho,e) %ha% in F> cells one allele (tk
K0L
+ ,as u# %o 1;-$ol) more
mu%able by 4 rays %han %he al%erna%ive allele (tk
L0L
+ an) %ha% %his ,as e4#laine) by %he lac! o$ recovery o$
tk mu%an%s ,i%h associa%e) loss o$ he%ero<ygosi%y (1C6+, i.e large )ele%ions. All %he mu%an%s analyse)
$rom EI-12-/3 )eriva%ives ,ere sho,n %o have los% he%ero<ygosi%y a% %he tk locus bu% ha) none%heless
re%aine) %,o co#ies o$ %he gene im#lying %ha% mu%a%ion in)uc%ion involve) ./A recombina%ional
#rocesses.
:ur%her su##or% $or %he involvemen% o$ recombina%ion #rocesses has been gaine) $rom molecular
analysis o$ mu%a%ions a% %he hprt locus. .es#i%e %he hemi<ygous s%a%e o$ hprt, %he availabili%y o$
#seu)ogenes in #rinci#le allo,s $or hprt #ar%ici#a%ion in recombina%ion even%s. he $ac% %ha% !"#$%
me)ia%e) )ele%ions are res#onsible $or %he ma-ori%y class o$ hprt mu%a%ions recovere) $rom $oe%al -
lym#hocy%es o$ human origin (:uscoe e% al., 1991+ is also relevan% %o %his argumen%. /on-homologous
recombina%ion-li!e even%s have been recor)e) amongs% ra)ia%ion-in)uce) hprt )ele%ion mu%an%s $rom
human $ibroblas%s (Morris an) hac!er, 1992+ an) $rom a human myeloi) leu!aemia line (Monna% e%
al., 1992a an) Monna% e% al., 1992b+. In essence, non-homologous recombina%ion re#resen%s an error-
#rone #a%h,ay $or re#air an) may accoun% $or %he in)uc%ion o$ a signi$ican% #ro#or%ion o$ ra)ia%ion-
in)uce) chromosomal mu%a%ions.
In con%ras% %o %hese resul%s, %he &hinese hams%er irs lines have mo)era%e ra)ia%ion hy#ersensi%ivi%y
combine) ,i%h near normal ./A )sb re#air ca#aci%y an) are #ro$icien% in !"#$% re-oining (hac!er
an) Eil!inson, 1995+. hese observa%ions sugges% %ha% ra)ia%ion hy#ersensi%ivi%y in res#ec% o$ cell
le%hali%y an) gene mu%a%ion in some mu%an% cell lines may have origins in mechanisms o%her %han over%
)e$ec%s in ./A )sb re#air an) recombina%ion.
:ur%her su##or% $or %he #o%en%ial ra)iobiological im#or%ance o$ ./A )sb re#air an) recombina%ional
#rocesses comes $rom a))i%ional inves%iga%ions o$ %he sci #heno%y#e. 'o%h e% al. (1992+ sho,e) %ha%
%he !"#$% co)ing in%erme)ia%es in sci %hymocy%es are mani$es% as hair#in s%ruc%ures an) %he genera%ion
o$ such s%ruc%ures is %he normal #a%h,ay $or rearrangemen% ,hile $ailure %o resolve %hese may re#resen%
%he sci #heno%y#e. hus, bo%h %he sci #heno%y#e an) %he associa%e) ./A )sb re#air )e$iciency
#robably )erive $rom recombina%ional errors in ./A #rocessing ,hich may involve higher or)er ./A
s%ruc%ures. 3imilar argumen%s have been ma)e in res#ec% o$ %he involvemen% o$ higher-or)er ./A
s%ruc%ures in %he $orma%ion o$ neo#lasia-rela%e) chromosomal even%s (see $or e4am#le, Bou$$ler e% al.,
1992+.
he im#or%ance o$ ./A )sb $or ra)ia%ion mu%agenesis is also believe) %o be re$lec%e) in %he
#re)ominance o$ a ./A )ele%ion mechanism in many o$ %he soma%ic genes o$ re#air #ro$icien% cells
analyse) in vi%ro (hac!er, 198> an) hac!er, 1992= 3an!aranarayanan, 1991+. Al%hough ra)ia%ion-
in)uce) ./A base #air mu%a%ions have been i)en%i$ie) in some soma%ic mu%a%ion sys%ems, in %he
absence o$ genomic cons%rain%s im#ose) by, $or e4am#le, %he #ro4imi%y o$ essen%ial $lan!ing genes,
ra)ia%ion mu%agenesis may #rinci#ally #rocee) via ./A )ele%ion %hrough misre#air or
misrecombina%ion a% ./A )sb.
"!"!7! Chromosomal structure and radiation muta%enesis
he im#or%ance o$ chromosomal s%ruc%ure $or ra)ia%ion-in)uce) gene mu%a%ion is evi)en% $rom a
number o$ s%u)ies (see hac!er, 1992+. C$ #rinci#al im#or%ance is %he rela%ionshi# be%,een %he ./A
12
)ele%ion mechanism %ha% #re)omina%es a$%er ra)ia%ion an) %he %olerance o$ genomic regions %o ./A loss
even%s. In a))i%ion %o %he )a%a ci%e) in 3ec%ion 2.2.> %his $ea%ure is clearly illus%ra%e) by s%u)ies on
mu%a%ion in)uc%ion a% %he aprt locus (see Meu%h an) Bha%%acharyya, 1998+.
he aprt gene is au%osomally enco)e) an), %hus, normally #resen% as %,o co#ies in %he genome. In
or)er %o s%u)y in)uce) mu%agenesis i% is %here$ore necessary %o use cell lines having one allele carrying
a #oin% mu%a%ion (he%ero<ygo%es+ or )ele%e) (hemi<ygo%es+ as #ar% o$ a larger chromosome loss even%. In
%his ,ay %he remaining ,il) %y#e co#y o$ aprt is available as a %arge% $or ra)ia%ion. Asing such cell lines
i% has been sho,n %ha% aprt hemi<ygous cells have grea%ly re)uce) mu%abili%y com#are) ,i%h
he%ero<ygo%es an) %ha% unli!e he%ero<ygo%es $e, large ./A )ele%ions are associa%e) ,i%h aprt
mu%a%ion. Al%hough ye% %o be $ully con$irme) a% %he molecular level %hese )a%a are ,holly consis%en%
,i%h %he #resence o$ an essen%ial gene in %he chromosomal segmen% enco)ing aprt. Cn %his basis
homo<ygous loss o$ %he essen%ial gene is no% com#a%ible ,i%h cell viabili%y, %hus largely res%ric%ing %he
s#ec%rum o$ mu%a%ional )amage observe) in aprt hemi<ygo%es %o in%ragenic even%s ,i%h a
commensura%e )ecrease in %he a##aren% mu%agenic e$$iciency o$ ra)ia%ion.
I% may be conclu)e) %here$ore %ha% %he mu%agenic ra)iosensi%ivi%y o$ $unc%ionally similar genes shoul)
be e4#ec%e) %o be non-uni$orm an) ,ill be highly )e#en)en% u#on %he $unc%ion an) ac%ivi%y o$ $lan!ing
se9uences ,hich in %urn is )e#en)en% u#on chromosomal loca%ion. I% $ollo,s $rom %his %ha% since %he
cri%icali%y o$ gene $unc%ion ,ill %en) %o )i$$er be%,een cell %y#es in a given s#ecies, organ-s#eci$ic
e$$ec%s on %he %olerance o$ ra)ia%ion-in)uce) genomic losses shoul) be an%ici#a%e). "iven %he !no,n
)i$$erences in genomic organisa%ion, such %olerance %o loss is also e4#ec%e) %o )i$$er be%,een
mammalian s#ecies. he #ossible im#lica%ions o$ %hese mu%agenesis $ac%ors $or %umour su##ressor gene
loss in ra)ia%ion carcinogenesis are )iscusse) in 3ec%ion 5.
*$$ec%s o$ chroma%in s%ruc%ure on %he re#air o$ AV' )amage are ,ell es%ablishe). ./A #ho%o#ro)uc%s
#resen% in %he %ranscribe) ./A s%ran) are re#aire) #re$eren%ially (e.g. Van Geelan) e% al., 1998+ an)
hprt mu%a%ion in)uc%ion corres#on)ingly #rocee)s #rinci#ally via mu%a%ion o$ %he non-%ranscribe)
s%ran) (Vreiling e% al., 1991+. :or AV' in)uce) ./A )amage %here is also a )i$$erence in re#air
be%,een ac%ive an) inac%ive genes in %he genome ,hich #robably re$lec%s chroma%in-)e#en)en% genome
)omain e$$ec%s on re#air. oge%her ,i%h %he !no,n role o$ AV' ./A re#air #ro%eins in gene
%ranscri#%ion, %he e4is%ence o$ such )i$$eren%ial re#air may e4#lain some o$ %he com#le4 an) une4#ec%e)
clinical mani$es%a%ions o$ ./A #ho%o#ro)uc% re#air-)e$icien% human gene%ic )isor)ers (Arle%% an)
1ehman, 1995+.
Much less in$orma%ion is available on %he genomic )is%ribu%ion o$ re#air o$ ionising ra)ia%ion-in)uce)
)amage. 1ea)on an) &oo#er (1992+ have sho,n %ha% #re$eren%ial re#air o$ ra)ia%ion )amage occurs
,i%hin %he %ranscribe) s%ran) o$ ./A o$ human cells o$ normal ra)iosensi%ivi%y ,hile in a
ra)iosensi%ive cell line o$ &oc!ayne syn)rome (grou# B+ %here ,as no ./A s%ran)-selec%ive re#air in
s#i%e o$ a normal overall ra%e o$ re#air. he cy%ological inves%iga%ions o$ Pan)i%a an) 6i%%leman (1998+
sugges% %ha% cells o$ A- #a%ien%s an) A- he%ero<ygo%es have an al%ere) chroma%in s%ruc%ure an) %ha%
%his may be associa%e) in increase) ra)iosensi%ivi%y. A%m, %he #ro%ein mu%a%e) in A-, has been sho,n %o
localise %o syna#se) chromosome a4es )uring meiosis, $ur%her im#lica%ing %he gene in chromosome
s%ruc%ure an) $unc%ion (Feegan e% al., 199>+.
.i$$erences in %he s%a%e o$ con)ensa%ion o$ nucleo#ro%ein com#le4es in chroma%in may be e4#ec%e) %o
in$luence ra)ical scavenging an) #os%-irra)ia%ion ./A re#air ra%es (e.g. Cleinic! an) &hiu, 1998+ bu%
as ye% i% is no% #ossible %o rela%e such e$$ec%s %o mu%agenesis.
13
"!"!2! Genomic instability
he curren% consensus is %ha% %he )evelo#men% o$ neo#lasia is a mul%is%age #rocess (:earon an)
Vogels%ein, 199;= see also 3ec%ion 2+. he assum#%ion o$ in)e#en)ence $or $ive or more s%e#s in %his
#rocess, each ,i%h a s#on%aneous ra%e o$ say 1;
L7
#er cell genera%ion is no% biologically $easible an)
several lines o$ evi)ence #oin% %o,ar)s %he ac9uisi%ion o$ inheren% genomic ins%abili%y a% a rela%ively
early s%age o$ neo#las%ic )evelo#men% in or)er %o accelera%e %he neo#las%ic #rocess (see 3ec%ion 2+.
C$ #ossible relevance %o %his is %he in)uc%ion o$ genomic ins%abili%y by ionising ra)ia%ion. *arlier
s%u)ies on %he !ine%ics o$ %he in)uc%ion o$ malignan% %rans$orma%ion o$ mouse 1;102 cells (Fenne)y e%
al., 198; an) Fenne)y e% al., 1988+ sugges%e) %ha% ra)ia%ion in)uces a %y#e o$ genomic ins%abili%y in a
large $rac%ion o$ %he cell #o#ula%ion lea)ing %o %he occurrence o$ %he ac%ual %rans$orming even% amongs%
%he #rogeny o$ %he original irra)ia%e) cells a$%er many genera%ions o$ cell re#lica%ion. &hang an) 1i%%le
(1992+ an) &hang an) 1i%%le (1998+ e4amine) %he $re9uency o$ mu%a%ions in clonal #o#ula%ions )erive)
$rom single cells surviving ra)ia%ion e4#osure. hey sho,e) %ha% %he ra%e o$ mu%a%ion a% %he hprt locus
o$ a cul%ure) hams%er cell line ,as #ersis%en%ly eleva%e) $or u# %o 5; #o#ula%ion )oublings $ollo,ing
ra)ia%ion e4#osure. he s#ec%rum o$ ./A s%ruc%ural changes $or %hese la%e-arising mu%a%ions )i$$ere)
signi$ican%ly $rom %ha% o$ )irec% ra)ia%ion-in)uce) mu%an%s in %ha% %hey ,ere #rimarily %he resul% o$
small scale even%s (#oin% mu%a%ions+ ra%her %han )ele%ions (1i%%le, 1998+. A #ersis%en%ly enhance)
mu%a%ion ra%e $ollo,ing irra)ia%ion has also been )escribe) by 3imons an) /ieric!er (1998+ in a mouse
lym#homa cell line by use o$ a $luc%ua%ion analysis o$ hprt mu%agenesis. 1i e% al. (1998+ re#or%e)
$in)ing eleva%e) $re9uency o$ microsa%elli%e mu%a%ions in human lym#hoblas%oi) cell clones selec%e) $or
in)uce) mu%a%ion a% %he )& locus. oge%her %hese )a%a on mul%i#le mu%a%ional even%s im#ly %ha% in some
cellular sys%ems %here is in)uc%ion o$ some $orm o$ %rans-ac%ing mu%agenic #rocess, bu% %he na%ure o$
%his #rocess an) i%s gene%ic con%rol remain unresolve).
A% %he chromosomal level, #ersis%en% al#ha-#ar%icle in)uce) genomic ins%abili%y has been re#or%e) in
some bu% no% all bone marro, sam#les $rom mouse s%rains an) human )onors (Fa)him e% al., 1998+ an)
Mar)er an) Morgan (1992+ have re#or%e) on %he in)uc%ion o$ )elaye) chromosomal ins%abili%y in
hams%er cells irra)ia%e) in vi%ro. Pam#$er an) 3%re$$er (1989+ irra)ia%e) mouse embryos in %he single-
cell <ygo%e s%age, an) sho,e) %ha% cells )erive) $rom s!in bio#sies o$ %he ma%ure $oe%us e4hibi%e) an
increase) $re9uency o$ chromosomal aberra%ions an) micronuclei as com#are) ,i%h animals receiving
no irra)ia%ion a% %his early s%age in )evelo#men%. he mechanisms un)erlying %hese chromosomal
ins%abili%y e$$ec%s a$%er ra)ia%ion are ho,ever #oorly un)ers%oo) an) %heir relevance %o neo#las%ic
)evelo#men% remains %o be es%ablishe).
"enomic ins%abili%y may also be mo)ula%e) by e#igene%ic $ac%ors ac%ing in vivo. Pa9ue%%e an) 1i%%le
(1998+ isola%e) several 4-ray %rans$orme) y#e III $oci $rom mouse &26 1;102 cells, an) s#li% each o$
%hem in%o %,o grou#s. Cne grou# ,as in-ec%e) in%o syngeneic, non-immunosu##resse) &26 mice,
,hile %he o%her ,as cul%iva%e) in vi%ro $or 25 #assages (abou% > mon%hs+. A$%er 27> mon%hs, ./A ,as
e4%rac%e) $rom %he sub-clones gro,n ei%her in vivo or in vi%ro, an) analyse) by a ./A $inger#rin%ing
assay $or ins%abili%y in mouse minisa%elli%e se9uences. A high $re9uency o$ genomic rearrangemen%s
(5;71;;5+ ,as $oun) in sub-clones )erive) $rom %he %umours %ha% arose in vivo, ,hereas %he $re9uency
,as very lo, (?1;5+ in sub-clones cul%iva%e) in vi%ro $or a roughly similar number o$ #o#ula%ion
)oublings.
C$ #erha#s more relevance %o %umorigenesis is %he genomic ins%abili%y %ha% may be associa%e) ,i%h %he
(A"""+n %elomeric re#ea% se9uence arrays %ha% serve #rinci#ally %o ca# an) %hereby s%abilise %he
14
%ermini o$ mammalian chromosomes (Blac!burn, 1991 an) Blac!burn, 1998+. elomere leng%h shor%ens
by aroun) 5;715; base #airs #er cell )ivision an) is believe) %o limi% %he #roli$era%ive ca#aci%y o$
normal human )i#loi) cells. I% has been #ro#ose) %ha% ,hen %elomeric leng%h shor%ens %o a cri%ical level,
su##ression o$ cell senescence is rela4e) such %ha% cells #rogressively lose #roli$era%ive ca#aci%y= such
%elomeric shor%ening is also believe) %o )es%abilise chromosomes such %ha% %hey are more #rone %o
#ar%ici#a%e s#on%aneously in brea!age7$usion cycles resul%ing in %he increase in chromosomal
abnormali%ies %ha% charac%erises %he senescence #rocess. *sca#e $rom such senescence an) subse9uen%
cell immor%alisa%ion via %he re-s%abilisa%ion o$ %elomeres is no, believe) %o involve %he reac%iva%ion o$
%he en<yme %elomerase ,hich is normally silen% in human soma%ic cells (Fim e% al., 1998+. hus
%elomerase reac%iva%ion may be vie,e) as a crucial s%e# in malignan% )evelo#men% an) %he genes %ha%
con%rol %elomere se9uence #rocessing may ,ell ac% as %arge%s $or neo#las%ic change (Fi#ling, 1995+.
In %he con%e4% o$ ionising ra)ia%ion %here is evi)ence %ha% in)uce) li$e-s#an e4%ension o$ human )i#loi)
$ibroblas%s may involve %he e4#ansion o$ clones carrying uns%able %elomeric rearrangemen%s (Mar%ins e%
al., 1992+. here is also evi)ence %ha% %elomeric se9uence arrays #lay a role in ./A )amage res#onse,
chromosome brea! healing (Blac!burn, 1991 an) Blac!burn, 1998+ an) ,hen loca%e) a% in%ers%i%ial
si%es may re#resen% #re$eren%ial loca%ions $or %he e4#ression o$ ra)ia%ion-in)uce) chromosomal
rearrangemen%s (Bou$$ler e% al., 1992+. he role o$ %hese re#ea% se9uence arrays in some o$ %he
chromosomal even%s associa%e) ,i%h haemo#oie%ic neo#lasia is )iscusse) in 3ec%ion 8.
"!,! /uman %enetic disorders affectin% #$A repair and %enomic instability
he #rinci#al human gene%ic )isor)ers associa%e) ,i%h ./A re#air )e$iciency, hy#ersensi%ivi%y %o
ionising ra)ia%ion an)0or inheren% genomic ins%abili%y, have alrea)y been no%e). :or %he sa!e o$
com#le%eness able 2.2 #rovi)es a summary o$ %he claims %ha% have been ma)e in res#ec% o$
ra)iosensi%ivi%y in a range o$ human gene%ic )isor)ers. I% is im#or%an% %o s%ress ho,ever %ha% many o$
%hese claims are con%en%ious. A ma-or #roblem in all such analyses is %he e4%en% %o ,hich %echnical
$ac%ors clou) -u)gemen%s on in%rinsic cellular ra)iosensi%ivi%y. In %his con%e4% %he )a%a o$ able 2.8
illus%ra%e %he range o$ cellular ra)iosensi%ivi%y %ha% has been ascribe) %o )i$$eren% se%s o$ os%ensibly
normal human )onors. here can be li%%le )oub% %ha% a signi$ican% elemen% in %he a##aren% )i$$erences in
normal human cellular ra)iosensi%ivi%y sugges%e) by %hese )a%a is o$ %echnical an) no% gene%ic origin. In
a))i%ion, since in vi%ro cellular ra)iosensi%ivi%y is a gross #heno%y#e an) single mu%an% gene e$$ec%s are
being sough% in he%erogenous gene%ic bac!groun)s, only %he mos% highly #ene%ran% mu%a%ions ,ill be
clearly )is%inguishe). "iven %hese #roblems, on %he basis o$ %he )a%a available on ra)ia%ion-in)uce) cell
inac%iva%ion (able 2.2 an) 2.8+, i% is -u)ge) %ha% i% is only %he gene%ic )isor)ers a%a4ia-%elangiec%asia
an) /i-megen brea!age syn)rome (/B3+ %ha% sho, unambiguous evi)ence o$ ra)ia%ion
hy#ersensi%ivi%y %o %he le%hal e$$ec%s o$ ionising ra)ia%ion.
able 2.2. &laims an) coun%er-claims $or cellular ra)iosensi%ivi%y in 22 human gene%ic )isor)ers
15
able 2.8. 'a)iosensi%ivi%y o$ $ibroblas%s an) lym#hocy%es $rom se%s o$ normal human )onors
a
16
&ell inac%iva%ion %en)s ho,ever %o be a ra%her cru)e measure o$ cellular ra)iosensi%ivi%y an) %here are
)a%a sho,ing %ha% a number o$ cancer-#rone gene%ic con)i%ions are associa%e) ,i%h chromosomal
ra)iosensi%ivi%y. able 2.5 lis%s %hose )isor)ers in ,hich chromosomal ra)iosensi%ivi%y is -u)ge) %o be
increase), albei% mo)era%ely in mos% cases. In a))i%ion %o A- an) /B3 ,hich sho, mar!e) increases,
cer%ain )isor)ers associa%e) ,i%h %umour su##ressor gene mu%a%ion are also some,ha% increase) in
sensi%ivi%y, e.g. 1i7:raumeni syn)rome, re%inoblas%oma an) nevoi) basal cell carcinoma syn)rome.
Al%hough s%ill uncer%ain i% may be %ha%, in %hese )isor)ers, %he conse9uences o$ mu%a%ion o$ cer%ain
%umour su##ressor genes $or cell cycle con%rol may #rovi)e an e4#lana%ion $or %he e$$ec% (see 3ec%ion
2+.
able 2.5. 6uman gene%ic )isor)ers sho,ing evi)ence o$ chromosomal ra)iosensi%ivi%y
17
/e, cell cycle-base) assays o$ cellular ra)iosensi%ivi%y in human lym#hocy%es hol) #romise o$ a
grea%er #o,er o$ )iscrimina%ion %han %ha% #rovi)e) by conven%ional me%ho)s. he )a%a o$ 3an$or) an)
Parsha) (199;+ ,hich im#ly a )egree o$ chromosomal ra)iosensi%ivi%y in a broa) range o$ cancer-
#re)is#osing gene%ic )isor)ers remain some,ha% con%en%ious bu% %he recen% ,or! o$ 3co%% e% al. (1998+
an) Dones e% al., (1995a+ an) Dones e% al., (1995b+ is -u)ge) %o be more convincing an) no% only has
achieve) %he )iscrimina%ion o$ ra)iosensi%ivi%y in A- he%ero<ygo%es bu% also raises %he #ossibili%y %ha% a
signi$ican% $rac%ion ( 8;5+ o$ unselec%e) breas% cancer #a%ien%s are also charac%erise) by increase)
chromosomal ra)iosensi%ivi%y (:ig. 2.1, see also 3ec%ion 2+. Ehile %he inheri%ance o$ %his #heno%y#e in
breas% cancer #a%ien%s has ye% %o be es%ablishe), i% is o$ clear im#or%ance %ha% %he a##lica%ion o$ %hese
%echni9ues is e4%en)e) in or)er %o gain a more com#le%e #ic%ure o$ human chromosomal ra)iosensi%ivi%y
an) i%s #ossible rela%ionshi# ,i%h a cancer #re)is#osi%ion.
:ig. 2.1. &hromosome )amage in human lym#hocy%es e4#ose) %o ;.5 "y 4 rays in "2 #hase o$ %he cell
cycle ()a%a $rom 3co%% e% al., 1998+. o# #anel@ heal%hy con%rols, 78 )onors (111 sam#les+, 29 male an)
25 $emale (no se4 e$$ec%+, age) 57>8 (no age e$$ec%+, meanM92.8 (3. 12.>+ (coe$$icien% o$ varia%ion
185+, )i$$erence be%,een )onors p?;.;;1. Mi))le #anel@ obliga%e A- he%ero<ygo%es, 28 )onors (2;
sam#les+, age) 277>7 (no age e$$ec%+, meanM185 (8;.8+ (285+. Bo%%om #anel@ breas% cancer #a%ien%s, 5;
)onors, age) 25772 (no age e$$ec%+, meanM1;9 (2>.8+ (255+. Ver%ical line gives ma4imum
)iscrimina%ion be%,een con%rols an) A- he%ero<ygo%es. Bo%h A- he%ero<ygo%e an) breas% cancer
grou#s are signi$ican%ly more sensi%ive %han con%rols (Mann7Ehi%ney %es%, p?;.;;1+.
'a#i)ly )evelo#ing evi)ence on %he $unc%ion o$ %he breas% cancer susce#%ibili%y genes BRCA1 an)
BRCA2 sugges% %ha% %he associa%e) gene%ic )isor)ers may also be inclu)e) in %he ./A re#air ca%egory.
his evi)ence, summarise) an) )iscusse) by Brugarolas an) Dac!s (1997+, im#lies %ha% in combina%ion
18
BRCA1 an) BRCA2 #ro%eins in%erac% ,i%h Ra51 %o regula%e %he re#air o$ ./A )sb. Ano%her s%ran) %o
%his argumen% is %ha% )evelo#men%al arres% in BRCA1 an) BRCA2 null mice is #ar%ially rescue) by
mu%a%ion o$ p53. he im#lica%ion o$ %his la%%er resul% is %ha% in %he absence o$ p53 #ro%ein, unre#aire)
./A )amage in %he null mice $ails %o $ully ac%iva%e cellular gro,%h arres% #a%h,ays.
Vie,e) overall, %he mechanis%ic lin!s be%,een heri%able cellular ra)iosensi%ivi%y, human #re)is#osi%ion
%o neo#lasia an) o%her heal%h e$$ec%s are less ,ell es%ablishe) %han %hose $or AV'. In %he case o$ AV'
sensi%ivi%y %he na%ure o$ %he ./A re#air )e$iciencies in 4ero)erma #igmen%osum, &oc!ayne syn)rome
an) %richo%hio)ys%ro#hy are becoming increasingly ,ell un)ers%oo) an) many o$ %he res#onsible genes
are clone) an) charac%erise) (see Arle%% an) 1ehman, 1995+. C$ #ar%icular no%e is %he clear in)ica%ion
%ha% sensi%ivi%y %o %he in vi%ro cell le%hal e$$ec%s o$ AV' is no% al,ays re$lec%e) in #roneness %o
neo#lasia in vivo an) %ha%, ,i%h or ,i%hou% e4cess cancer, AV' re#air )e$iciency may be mani$es% by
)evelo#men%al abnormali%ies #robably as a conse9uence o$ re#air-rela%e) #er%urba%ion o$ gene
e4#ression.
I% seems li!ely %ha% a similar e4#lana%ion a##lies %o )isease mani$es%a%ion in ra)iosensi%ive a%a4ia-
%elangiec%asia an) i% is an%ici#a%e) %ha% $ur%her molecular cloning an) charac%erisa%ion o$ genes relevan%
%o human ra)iosensi%ivi%y ,ill clari$y %he #osi%ion in res#ec% o$ %he com#le4 rela%ionshi#s be%,een
)e$iciency in %hese genes, cancer #roneness an) o%her human heal%h e$$ec%s.
In %he mean%ime, a s%rong message %ha% emerges $rom AV' an) ionising ra)ia%ion s%u)ies is %ha% in vi%ro
human cellular ra)iosensi%ivi%y is no% a reliable #re)ic%or o$ in vivo cancer #roneness nor, by
im#lica%ion, %umorigenic ra)iosensi%ivi%y. I% is %here$ore ,holly ina##ro#ria%e %o ma!e -u)gemen%s u#on
%he )is%ribu%ion o$ ra)ia%ion-in)uce) cancer in human #o#ula%ions on %he basis o$ )a%a surveys o$ %he
%y#e #resen%e) in able 2.2 an) 2.8.
:inally, i% is no, ,ell recognise) %ha% o%her human germ line )e$ec%s in ./A re#air an) genomic
main%enance sho, associa%ions ,i%h cancer susce#%ibili%y. he mos% com#elling e4am#les o$ %hese are
./A misma%ch re#air )e$iciencies in here)i%ary non-#oly#osis colon cancer (see 3ec%ion 2+ an) p53
%umour su##ressor gene mu%a%ion in %he 1i7:raumeni syn)rome (see 3ec%ion 2, 3ec%ion 8 an) 3ec%ion
5+. In a))i%ion, heri%able genomic ins%abili%y is associa%e) ,i%h %he less ,ell un)ers%oo) cancer-#rone
)isor)ers :anconi anaemia an) Bloom syn)rome (see 3ec%ion 8+= con%en%ious claims o$ such
associa%ions have also been ma)e $or o%her )isor)ers. A summary o$ %he curren% #osi%ion regar)ing
heri%able cancer, ./A re#air )e$iciency an) genomic ins%abili%y is #rovi)e) in able 2.>. I% is -u)ge)
%ha% i% is only in %he cases o$ a%a4ia-%elangiec%asia an) /i-megen brea!age syn)rome %ha% %here is a clear
lin! be%,een in vi%ro ra)iosensi%ivi%y an) heri%able cancer susce#%ibili%y an) even $or %hese )isor)ers
much remains %o be learne) o$ %he molecular mechanisms involve).
able 2.>. 6uman )isor)ers a$$ec%ing ./A re#air an) genomic main%enance
19
In s#i%e o$ reserva%ions on %he )egree %o ,hich heri%able cellular ra)iosensi%ivi%y may correla%e ,i%h
human cancer #re)is#osi%ion, a signi$ican% cancer con%ribu%ion $rom lo, #ene%rance re#air-rela%e)
mu%a%ions o$ %he %y#e sugges%e) by %he ,or! o$ 3co%% e% al. (1998+ shoul) no% be )iscoun%e) an) i% is
e4#ec%e) %ha% $ur%her s%u)ies ,ill clari$y %he #o%en%ial role o$ BRCA mu%a%ions in cellular ra)ia%ion
res#onse.
"!-! (ummary and conclusions
1. &ellular ./A )amage a$%er ionising ra)ia%ion is me)ia%e) )irec%ly or in)irec%ly by in)uce) chemical
ra)icals. 'a)ical in)uc%ion local %o ./A is -u)ge) %o be mos% im#or%an%.
2. ./A )ouble-s%ran) lesions a##ear %o be ra)iobiologically $ar more im#or%an% %han ./A single-
s%ran) lesions or base )amage. 6igh 1* ra)ia%ion-in)uce) ./A )amage may be more com#le4 %han
%ha% #ro)uce) by lo, 1* an), as a conse9uence, a##ears %o be sub-ec% %o less e$$ec%ive re#air.
2. A %o%al o$ 12 human genes involve) in %he re#air o$ ra)ia%ion )amage have been clone) an)0or
ma##e)= curren%ly %he mos% im#or%an% o$ %hese is %he gene (A)*+ %ha% )e%ermines %he ra)iosensi%ive an)
cancer #rone human )isor)er a%a4ia-%elangiec%asia.
8. ./A )ouble-s%ran) lesion re#air by ./A recombina%ion an) %he associa%e) ac%ivi%y o$ ./A en)-
bin)ing #ro%eins an) !inases are im#or%an% $or cellular ra)iobiological res#onse.
5. he s%u)y o$ in vi%ro cellular inac%iva%ion an) chromosomal ra)iosensi%ivi%y sho, a%a4ia-
%elangiec%asia an) /i-megen brea!age syn)rome )isor)ers %o have unambiguously eleva%e)
ra)iosensi%ivi%y. 1ess )rama%ic increases in cellular or chromosomal ra)iosensi%ivi%y are a##aren% $or a
20
range o$ human gene%ic )isor)ers an) con)i%ions inclu)ing some !no,n %o be associa%e) ,i%h %umour
su##ressor gene mu%a%ion such as 1i7:raumeni syn)rome an) re%inoblas%oma.
>. "enomic ins%abili%y ,i%hou% )rama%ic mani$es%a%ion o$ enhance) ra)iosensi%ivi%y in res#ec% o$
cellular inac%iva%ion is evi)en% in %he )isor)ers 1i7:raumeni syn)rome, :anconi anaemia, Bloom
syn)rome an) a%a4ia-%elangiec%asia he%ero<ygo%es. he cancer #rone gene%ic )isor)er, here)i%ary non-
#oly#osis colon cancer, has i%s basis in )e$iciency in ./A misma%ch re#air= %his is mani$es%e) by a
s#eci$ic $orm o$ ./A se9uence ins%abili%y in %umour cells. he relevance o$ ra)ia%ion-in)uce)
#ersis%en% genomic ins%abili%y %o neo#las%ic )evelo#men% remains %o be es%ablishe).
7. *vi)ence is )evelo#ing %ha% heri%able breas% cancer associa%e) ,i%h BRCA1 an) BRCA2 mu%a%ion
may also be associa%e) ,i%h ./A re#air )e$iciency.
,! Mechanisms and %enetics of solid tumours
he molecular gene%ic era o$ cancer research is no, $irmly es%ablishe) an) i% is clear %ha%, in mos%
ins%ances, cancers arise via a monoclonal mul%i-s%e# #rocess, involving mul%i#le gene%ic al%era%ions (e.g.
:earon an) Vogels%ein, 199;+. he i)en%i$ica%ion o$ %he )e%erminan%s o$ mul%i-s%e# neo#las%ic
)evelo#men% has le) %o %he realisa%ion %ha% a% leas% %hree ma-or classes o$ genes are involve)@
oncogenes, ,hose #ro%ein #ro)uc%s serve %o s%imula%e cell gro,%h an) survival= %umour su##ressor
genes, ,hose #ro)uc%s a##ear %o nega%ively regula%e gro,%h, #romo%e a#o#%osis, an) main%ain in vivo
homeos%a%ic gro,%h an) )i$$eren%ia%ion #o%en%ial= an) ./A re#air genes, )e$ec%s in ,hich lea) %o
increase) genomic ins%abili%y (3%anbri)ge, 199;= Bisho#, 1991= 1oeb, 1998+. As ,ill be seen, mu%a%ions
in a number o$ %hese genes re#resen% %he germ line )e%erminan%s o$ $amilial #re)is#osi%ion %o soli)
cancers o$ various %issues. his sec%ion #rovi)es a general )escri#%ion o$ %he genes involve) in cancer
ini%ia%ion an) #rogression an) see!s %o i)en%i$y gene%ic $ea%ures %ha% may be relevan% %o ra)ia%ion
carcinogenesis. Also inclu)e) is an ou%line o$ %he #rinci#al gene%ic )isor)ers associa%e) ,i%h a
#re)is#osi%ion %o soli) %umours an) in$orma%ion relevan% %o -u)gemen%s on %he con%ribu%ion o$ gene%ic
$ac%ors %o human cancer ris! a$%er ra)ia%ion ,hich ,ill be #rovi)e) la%er in %he )ocumen%.
,!1! nco%enes
he #le%hora o$ $unc%ions associa%e) ,i%h oncogenes is, a% $irs% glance, be,il)ering (able 2.1+.
6o,ever, recen% s%u)ies have in)ica%e) %ha% many oncogene #ro)uc%s in%erac% ,i%h each o%her in signal
%rans)uc%ion casca)es %ha% resul% in mi%ogenic signals %ha% )rive %he cells in%o a #roli$era%ive s%a%e an)
also have #leio%ro#ic e$$ec%s on cell mobili%y an) cy%os!ele%al archi%ec%ure (6un%er, 1991= Fhosravi-:ar
an) .er, 1998+. Cne o$ %he mos% in%ensively s%u)ie) grou# o$ oncogenes %ha% illus%ra%es %his signal
%rans)uc%ion ,ell is %he RA+ $amily. Ini%ially, i% ,as %hough% %ha% %he 'as #ro%ein signals %hrough a
single #a%h,ay, i.e. 'asN'a$NM*FNMAP !inase. I% is no, !no,n %ha% mul%i#le #a%h,ays o$
%rans)uc%ion occur, ,i%h bo%h in)e#en)en% an) in%erac%ing com#onen%s (Farin, 1995+ :ig. 2.1 )e#ic%s
%hese signal %rans)uc%ion casca)es, in)ica%ing %he #leio%ro#ic e$$ec%s on membrane ru$$ling an)
cy%os!ele%al archi%ec%ure, an) gene %ranscri#%ion lea)ing %o mi%ogenic signals. I% shoul) be a##recia%e)
%ha% cons%i%u%ive ac%iva%ion o$ %hese #a%h,ays resul%s in cons%an% mi%ogenic signalling an) %ha%
ac%iva%ion o$ any member o$ %he casca)e, as a conse9uence o$ mu%a%ion, ,ill resul% in ac%iva%ion o$
)o,ns%ream members accom#anie) by $ur%her enhancemen% o$ mi%ogenesis. hus, mu%a%ional
ac%iva%ion o$ any one member o$ %he casca)e is su$$icien% $or cons%i%u%ive mi%ogenic signalling, %hereby
crea%ing %he #o%en%ial $or #roli$era%ive a)van%age.
21
able 2.1. :unc%ions o$ oncogene #ro)uc%s
:ig. 2.1. 3chema%ic re#resen%a%ion o$ 'as-me)ia%e) signal %rans)uc%ion #a%h,ays.
22
C%her oncogenes #lay cri%ical roles in cell survival (e.g. BC32+ an) con%rol o$ %he cell cycle (e.g.
PRA#1 or cyclin .1+, $unc%ions ,hich again #lay #ivo%al roles in %umour )evelo#men% (6oc!enberry e%
al., 1992= 6un%er an) Pines, 1998+. In consi)ering %he role o$ oncogenes in neo#lasia, i% is im#or%an% %o
no%e %ha% #oin% mu%a%ions are only one mechanism ,hereby ac%iva%ion o$ oncogenes occurs. Cne may
also encoun%er am#li$ica%ion, over-e4#ression, ina##ro#ria%e e4#ression (%em#orally, )evelo#men%ally,
or %issue-s#eci$ic+, an) gene %ransloca%ion resul%ing in ac%iva%ion o$ gene e4#ression an)0or %he
genera%ion o$ $usion #ro)uc%s. he !ey role %ha% #ro%o-oncogenes #lay in )i$$eren%ia%ion can also be
seen $rom %he $ac% %ha% oncogene over-e4#ression may resul% in neo#las%ic %rans$orma%ion or in)uc%ion
o$ )i$$eren%ia%ion an)0or a#o#%osis (Bar-3agi an) :eramisco, 1985= "arri)o e% al., 1992= 6an e% al.,
199>+.
/umerous #ro%o-oncogenes have been sho,n %o be ac%iva%e) in human %umours. Ac%iva%ion by #oin%
mu%a%ion is seen in %he RA+ $amily, ,hich has been )e%ec%e) in a varie%y o$ human cancers. Poin%
mu%a%ions in cri%ical co)ons, i.e. co)ons 12, 12, or >1, can ac%iva%e %hese genes. In some %umours
mu%a%ion o$ %he RA+ gene can be $oun) even in #remalignan% s%ages o$ cancer )evelo#men%, $or
ins%ance in %he a)enoma%ous s%ages in %he )evelo#men% o$ colorec%al cancer, an) myelo)ys#las%ic
syn)rome in leu!aemia )evelo#men% (:earon an) Vogels%ein, 199;+.
"ene am#li$ica%ion is o$%en seen in %he *4C $amily. 3ome%imes, %he am#li$ie) ./A segmen%s
con%aining %he oncogene can be i)en%i$ie) as a homogeneously s%aining region (63'+ in "iemsa-
ban)e) chromosomes or e4%ra-chromosomal )ouble minu%es (.M+. "ene over-e4#ression in %he
absence o$ gene am#li$ica%ion also occurs in %he )evelo#men% o$ many human %umours (Bisho#, 1991+.
he am#li$ica%ion o$ oncogenes is usually associa%e) ,i%h %he la%e s%ages o$ %umour #rogression.
6o,ever, am#li$ie) 56R27n/u has been observe) in early clinical s%ages o$ breas% cancer (3lamon,
199;+.
"erm line mu%a%ions o$ a #ro%o-oncogene have been re#or%e) in %he R6) gene, ,hich #re)is#ose %o
mul%i#le en)ocrine neo#lasia, namely M*/2A an) M*/2B (&arlson e% al., 1998+. Mu%a%ions o$ '*
are also $oun) in s#ora)ic me)ullary %hyroi) carcinoma. his is one o$ %he $e, e4am#les o$ an inheri%e)
#ro%o-oncogene mu%a%ion in con%ras% %o %umour su##ressor genes, ,here many o$ %hose so $ar i)en%i$ie)
are $oun) as germline mu%a%ions in $amilial cancer syn)romes, as )iscusse) belo,.
here is some sugges%ive evi)ence in)ica%ing %ha% cer%ain rare alleles o$ #ro%o-oncogenes are associa%e)
,i%h %he susce#%ibili%y %o some %y#es o$ cancers (Fron%iris, e% al., 1992+. 6igh $re9uencies o$ s#eci$ic
alleles o$ 5RA+ have been re#or%e) in #a%ien%s ,i%h breas% cancer (1in)ereau e% al., 198>= 3aglio e% al.,
1988+, lung cancer (6eigh,ay e% al., 198>+, melanoma ('a)ice e% al., 1987+, colorec%al cancer (Eyllie
e% al., 1988+ an) EilmsI %umour (6ay,ar) e% al., 1988+. he issue o$ 5RA+1 allelic varia%ion is
)iscusse) in 3ec%ion 2.8.8. A rare allele o$ %he *8+ gene has also been sho,n %o be lin!e) %o %he
)evelo#men% o$ breas% cancer (1in)ereau e% al., 1985+. A s#eci$ic allele o$ 1*4C a##ears in high
$re9uency in bone an) so$%-%issue sarcomas (Fa%o e% al., 199;+ an) has been associa%e) ,i%h a %en)ency
%o )evelo# me%as%asis in lung an) !i)ney cancers (Fa,ashima e% al., 1988= Fa!ehi an) Joshi)a, 1989+.
he %rue signi$icance o$ %hese observa%ions is unclear a% %his %ime.
A rela%ionshi# be%,een oncogene e4#ression an) ra)ia%ion res#onse has been claime) by various
inves%iga%ors (e.g. &assoni, 1998+. here is rela%ively consis%en% evi)ence %ha% e4#ression o$ RA+
oncogenes increase cellular ra)ioresis%ance in some ro)en% cell lines bu% no% in normal human cells.
'a)ioresis%ance con$erre) by o%her ac%iva%e) oncogenes, e.g. *4C an) RA9, is rela%ively %enuous an)
ye% o%hers, e.g. *4B, 98+, an) 96+ have no measurable e$$ec%. he $iel) o$ in9uiry remains some,ha%
23
con$use) an) )irec% clear lin!s %o ra)ia%ion oncogenesis have ye% %o be es%ablishe). In s#i%e o$ %his, %he
#ivo%al role o$ some oncogenes in mi%ogenic signalling an) hence cell cycle con%rol (:ig. 2.1 an) 2.2+
#rovi)es a lin! ,i%h ./A )amage res#onse an) re#air (6ar%,ell an) Fas%an, 1998+.
:ig. 2.2. he cell cycle. /on-)ivi)ing cells en%er %he cell cycle $rom %he 9uiescen% "; #hase in%o %he "1
(ga#+ #hase. 1a%e in "1, a res%ric%ion #oin% e4is%s a% ,hich %he )ecision is ma)e %o #rogress %hrough %he
res% o$ %he cell cycle. Passage %hrough %he res%ric%ion is an absolu%e commi%men% %o syn%hesise ./A in 3
(syn%hesis+ #hase. A$%er 3 #hase, %he cell en%ers %he "2 #hase in ,hich %he mass o$ %he cell is increase)
an) necessary en<ymes are manu$ac%ure) %o allo, %he cell %o )ivi)e in%o %,o )augh%er cells in M
(mi%osis+ #hase. In M #hase, %he )u#lica%e) chromosomes %ha% ,ere syn%hesise) in 3 #hase are
se#ara%e) an) cy%o!inesis resul%s in %,o )augh%er cells. A% %he en) o$ M #hase, %he cell may ei%her re-
en%er %he cell cycle a% "1 or go in%o ";.
,!"! &umour suppressor %enes
Ehereas %he #ro%ein #ro)uc%s o$ many oncogenes are %hough% %o $unc%ion as #romo%ers o$ cell
#roli$era%ion an) cell survival, %umour su##ressor gene #ro)uc%s a##ear %o be involve) in nega%ive
regula%ion o$ cell gro,%h, in)uc%ion o$ )i$$eren%ia%ion an) #rogramme) cell )ea%h.
1oss o$ $unc%ion o$ %umour su##ressor (3+ genes is %he hallmar! even% in %he genesis o$ many cancers.
1oss o$ $unc%ion via )ele%ion, rearrangemen% or #oin% mu%a%ion, o$ bo%h alleles o$ a given au%osomal 3
gene is a common occurrence in %umour cells. hus, %hese 3 genes ,oul) seem %o be recessive,
al%hough %here are e4ce#%ions %o %his no%ion, e.g. %he :91 gene (1i e% al., 1992+. 1oss o$ $unc%ion o$
cer%ain 3 genes seems %o be rela%ively cell lineage-s#eci$ic, $or e4am#le, %he :92 gene in
meningioma, ,hereas )e$ec%s in o%her 3 genes are encoun%ere) in a ,i)er array o$ malignancies
(3%anbri)ge, 199;+.
I% shoul) be a##recia%e) %ha% ,hereas more %han 1;; oncogenes have been i)en%i$ie), only a rela%ively
small number o$ !no,n or can)i)a%e 3 genes have been re#or%e) (see able 2.2+. his arises
#rinci#ally because %here are no goo) $unc%ional screening assays $or 3 genes an) %he ma-ori%y o$
%hose i)en%i$ie) have been isola%e) by %he ar)uous #rocess o$ #osi%ional cloning, i.e. via %he screening
o$ ./A clones $rom %he !no,n chromosomal #osi%ion o$ %he gene o$ in%eres%. In%eres%ingly, %he
)e)uce) $unc%ions o$ 3 genes in many ins%ances mimic %hose o$ oncogenes. hese inclu)e
%ranscri#%ion $ac%ors, cell cycle regula%ors, sur$ace a)hesion molecules, an) " #ro%ein regula%ors.
24
6o,ever, %hese $unc%ions are an%agonis%ic %o oncogene $unc%ions. o illus%ra%e %his yin-yang e$$ec%, %,o
e4am#les are #rovi)e), namely, cell cycle regula%ion an) ./A )amage chec!#oin% con%rol.
able 2.2. 3ome !no,n or can)i)a%e %umour su##ressor genes
,!"!1! &umour suppressor %enes in the cell cycle
he charac%eris%ic #roli$era%ive #a%%ern o$ cell gro,%h an) )ivision has been )e$ine) as %he cell cycle
(:ig. 2.2+. he cell cycle is )ivi)e) in%o $our une9ual #ar%s or #hases $or )ivi)ing cells, %erme) "1, 3,
"2, an) M, an) one #hase $or non-)ivi)ing cells, %erme) ";. "1 is %he $irs% ga# in %he cell cycle )uring
,hich %he cell #re#ares $or ./A syn%hesis. he "1 chec!#oin% has been )elinea%e) by a #oin% in la%e
"1 %ha% occurs %,o %o $our hours #rior %o %he "103 boun)ary. his #oin% has been )e$ine) as %he
res%ric%ion #oin% a$%er ,hich %he cell is commi%%e) %o #rocee) in%o 3 #hase an) syn%hesise ./A.
&hromosome )u#lica%ion in %he $orm o$ ./A syn%hesis occurs )uring 3 (syn%hesis+ #hase. "2 is
)e$ine) as %he ga# be%,een 3 an) M #hases )uring ,hich %he cell #re#ares %he necessary en<ymes an)
me%abolic machinery %o en%er mi%osis. Mi%osis occurs in M #hase )uring ,hich %he )u#lica%e)
chromosomes are se#ara%e) via %he s#in)le a##ara%us, $ollo,e) by cy%o!inesis an) %he genera%ion o$
%,o )augh%er cells. A% %he en) o$ M #hase, %he %,o )augh%er cells may en%er ei%her "1 or ";. he ";
#hase is )e$ine) as a s%a%e o$ 9uiescence in ,hich %he cell e4i%s %he cell cycle an) s%o#s )ivi)ing. ";
cells may be res%imula%e) by gro,%h $ac%ors or mi%ogens %o en%er %he cell cycle a% %he "1 #hase. In %he
case o$ #os%-mi%o%ic s%em cells %he $a%e o$ %he %,o )augh%ers is usually )i$$eren%. Ehereas one )augh%er
may #rocee) %hrough $ur%her )ivision cycles in or)er %o #rovi)e a clonal #o#ula%ion o$ )i$$eren%ia%ing
cells, %he o%her ,ill re-en%er a 9uiescen% #hase. In %his ,ay s%em cell e9uilibrium is main%aine). he
cellular $ac%ors %ha% govern %his e9uilibrium are, $or mos% %issues, #oorly un)ers%oo).
25
:ig. 2.2. 3chema%ic re#resen%a%ion o$ $ac%ors regula%ing %he cell cycle= #15, #1>, #21, an) #27 are
nega%ive regula%ors.
he cyclic regula%ion o$ %he cell cycle is )e%ermine) by %he accumula%ion an) )egra)a%ion o$ #ro%eins
)uring %he s#eci$ic #hases o$ %he cell cycle. hese cyclically e4#resse) an) )egra)e) #ro%eins have been
%erme) cyclins. &yclins A an) B ,ere $irs% )iscovere) in molluscs base) on %he observe) accumula%ion
an) )egra)a%ion o$ %hese #ro%eins )uring %he cell cycle. his observa%ion ,as la%er %ie) in%o %he
observa%ion %ha% in yeas% %here is an absolu%e re9uiremen% $or %he #resence o$ 3 #hase an) M #hase
serine0%hreonine !inase ac%ivi%y $or %he cell %o #rocee) %o %he ne4% #hase o$ %he cell cycle. he !inase
,as i)en%i$ie) as c)c2 (cell )ivision cycle+, ,hich enco)es %he ca%aly%ic subuni%. In yeas%, c)c2
#er$orms bo%h o$ %hese regula%ory $unc%ions by com#le4ing ,i%h )i$$eren% cyclins, ,hich com#rise %he
regula%ory subuni%s, )uring )i$$eren% #hases o$ %he cell cycle. In mammals, %here is a com#le4 $amily o$
%hese serine0%hreonine !inases %ha% regula%e %he )i$$eren% #hases o$ %he cell cycle. hese serine0%hreonine
!inases have been %erme) cell cycle )e#en)en% !inases (c)!+, ,i%h c)!1 being e9uivalen% %o %he c)c2
homologue $rom yeas%.
he $ree c)! ca%aly%ic subuni% is inac%ive, )ue %o #hos#horyla%ion, un%il a cyclin molecule com#le4es
,i%h i% ,hich lea)s %o a )e#hos#horyla%ion o$ %he c)! an) hence ac%iva%ion. :ree c)!s are #resen% )uring
%he en%ire cell cycle. A% a s#eci$ic #oin% in %he cell cycle a s#eci$ic cyclin is e4#resse) an) $orms a
he%ero)imer ,i%h a c)! molecule. his s#eci$ic cyclin@c)! )imer is %hen ac%iva%e) an) #hos#hory7
#hos#horyla%es %he re9uire) subs%ra%es %o allo, %he cell %o #rogress %hrough a given #oin% o$ %he cell
26
cycle. he c)!0cyclin com#le4 is %hen inac%iva%e) by %he #rogramme) )egra)a%ion o$ %he cyclin
(Morgan, 1995+.
Malignan% cells lose %he abili%y %o correc%ly regula%e %he cell cycle= %his loss o$ con%rol o$ %he cell cycle
can come in %he general $orm o$ %,o signals. :irs%, %he increase o$ #osi%ive gro,%h signals $rom mu%an%
#ro%o-oncogenes may overri)e %he nega%ive regula%ory con%rol on %he cell cycle. 3econ), %he genes
enco)ing %he nega%ive gro,%h regula%ory #ro%eins (%umour su##ressor genes+ may be inac%iva%e) by
mu%a%ion, loss, or in %he case o$ 'b an) p53 onco#ro%eins, by com#le4ing ,i%h %he %rans$orming
#ro%eins o$ ./A %umour viruses. he summa%ion o$ %hese %,o #rocesses #ro$oun)ly com#romises
con%rol o$ %he cell cycle resul%ing in abnormal #a%%erns o$ cell #roli$era%ion.
he com#le4 na%ure o$ %hese #osi%ive an) nega%ive cell cycle regula%ory elemen%s is illus%ra%e) in :ig.
2.2. A number o$ %he #ro%eins involve) in cell cycle con%rol have recen%ly been sho,n %o be oncogene
#ro)uc%s or 3 gene #ro)uc%s. Cne o$ %he mos% in%ensively s%u)ie) #ro%eins is %he 'b #ro%ein, ,hich is
%he #ro)uc% o$ %he RB1 3 gene. I%s i)en%i$ica%ion an) #osi%ional cloning re#resen%s %he classic
me%ho)ology $or isola%ion o$ can)i)a%e 3 genes.
&y%ogene%ic an) res%ric%ion $ragmen% leng%h #olymor#hism (':1P+ analyses ma##e) %he #u%a%ive
re%inoblas%oma gene %o chromosome 12918. ':1P analysis $ur%her sho,e) %he loss o$ he%ero<ygosi%y
(1C6+ by ./A )ele%ion in %his region in %umour %issue ./A as com#are) %o normal cons%i%u%ional
%issue ./A (&avenee e% al., 1982+. his no, classic 1C6 allelo%y#ing has been use) %o ma# mul%i#le
can)i)a%e 3 gene loci (3%anbri)ge, 199;+. he RB1 gene ,as $inally clone) in 198> (:rien) e% al.,
198>+ an) e4hibi%e) loss o$ $unc%ion o$ bo%h alleles in %umour ./A, as #re)ic%e) by %he Fnu)son %,o
hi% %heory (Fnu)son, 1971= see also 3ec%ion 5+.
:unc%ional analyses o$ %he 'b #ro%ein have sho,n %ha% i% #lays an im#or%an% role in #rogression o$ %he
cell cycle an) $unc%ions as a ga%e!ee#er. 'b is a #hos#ho#ro%ein %ha% localises %o %he nucleus. he
#hos#horyla%e) s%a%e o$ %he #ro%ein is %he cri%ical )e%erminan% o$ i%s ac%ivi%y an) #hos#horyla%ion is
)e#en)en% on cyclin-)e#en)en% !inase (c)!+ ac%ivi%y. As cells %ransi% "1, %hey reach a res%ric%ion #oin%
,here %he me%abolic )ecision %o #rocee) %o 3 #hase or no% is ma)e. he oscilla%ion o$ 'b $rom %he
hy#o- %o %he hy#er#hos#horyla%e) s%a%e #rovi)es or relieves %his bloc!, res#ec%ively, i.e. %he
hy#o#hos#horyla%e) s%a%e is %he ac%ive $orm o$ 'b. In %his ac%ive s%a%e i% ac%s as a nega%ive regula%or o$
%he cell cycle an) inhibi%s #rogression %hrough "1 %o 3= %he cells may %hen en%er %he 9uiescen% "; s%a%e
%ha% may heral) in)uc%ion o$ )i$$eren%ia%ion or a#o#%osis.
Fey %o %he regula%ion o$ "1 #rogression in mammalian cells are .-%y#e cyclins (.1, .2, an) .2+
,hich in%erac% ,i%h %he cyclin )e#en)en% !inases (c)!s+ c)!8 an) c)!>, an) cyclin * ,hich in%erac%s
la%er in "1 ,i%h c)!2. he cri%ical role o$ cyclins . an) * is illus%ra%e) by %he $ac% %ha% over-e4#ression
o$ %hese cyclins resul%s in a shor%ening o$ %he "1 #erio) an) a re)uce) )e#en)ency o$ %he cell $or
gro,%h $ac%ors (3herr, 1998+. In %he con%inue) #resence o$ mi%ogens, %he .-%y#e cyclins #ersis% an) %hey
e4hibi% only mo)era%e oscilla%ions )uring %he cell cycle ,i%h #ea! levels near "103. 6o,ever, ,hen %he
mi%ogens are ,i%h)ra,n, %he .-%y#e cyclins are ra#i)ly )egra)e). I$ %his )egra)a%ion occurs in "1, %he
cells $ail %o en%er %he 3 #hase.
Anli!e %he .-%y#e cyclins, cyclin * is e4#resse) #erio)ically ,i%h a ma4imum level a% "103. As %he
cells en%er 3 #hase, cyclin * is ra#i)ly )egra)e) an) %he $ree) c)!2 %hen com#le4es ,i%h cyclin A. he
cyclin A7c)!2 com#le4 correla%es ,i%h ini%ia%ion o$ 3 #hase, an) cyclin A is )egra)e) la%e in "2.
27
&yclins B10B2 are also #erio)ic in %heir e4#ression. hey are e4#resse) )uring la%e "2 #hase an)
)egra)e) )uring la%e M #hase (Morgan, 1995+.
here is a )is%inc% $unc%ional associa%ion be%,een .-%y#e cyclins an) 'b #ro%ein. &yclin . bin)s
)irec%ly %o 'b an) %he cyclin .7c)!80c)!> com#le4 #hos#horyla%es 'b, %hereby inac%iva%ing i% an)
relieving 'b-me)ia%e) "1 inhibi%ion. he gro,%h su##ressive e$$ec%s o$ 'b are me)ia%e) in #ar% by %he
abili%y o$ hy#o#hos#horyla%e) 'b %o bin) %o *2: an) nega%ively regula%ing i%s %ranscri#%ional ac%iva%ion
o$ genes re9uire) $or ./A re#lica%ion (/evins, 1992+. 6y#er#hos#horyla%ion o$ 'b releases *2: an)
$rees i% %o ac%iva%e %he re9uisi%e genes (see 6un%er an) Pines, 1998+.
he connec%ion be%,een .-%y#e cyclins or 'b an) %umorigenesis is com#elling. Am#li$ica%ion an)
over-e4#ression o$ cyclin .1 are seen in many malignancies (6un%er an) Pines, 1998+. 1oss o$ $unc%ion
(via mu%a%ion or )ele%ion+ or loss o$ e4#ression o$ 'b are no%e) no% only in re%inoblas%omas an)
os%eosarcomas bu% also in a varie%y o$ haema%o#oie%ic an) soli) %umours. :ur%hermore, 'b #ro%ein bin)s
%o ./A %umour virus %rans$orming #ro%eins, e.g. 3V8; an%igen, 6PV*7 an) a)enovirus *1A
(/evins, 1992+. he 'b #ro%ein is inac%iva%e) as a conse9uence o$ bin)ing %o %he viral onco#ro%eins.
Je% o%her levels o$ con%rol o$ %he cell cycle have been recen%ly )iscovere) %ha% have signi$icance $or
%umour su##ression. Bo%h cyclin *-boun) c)!2 an) cyclin .-boun) c)!8 un)ergo #hos#horyla%ion on a
single %hreonine resi)ue, a mo)i$ica%ion nee)e) $or %heir ac%iva%ion. he en<yme res#onsible $or %his
ac%iva%ion is a c)!-ac%iva%ing !inase (&AF+ ,hich is i%sel$ a mul%i-subuni% en<yme com#ose) o$ a
ca%aly%ic subuni% (MC15 or c)!7+ an) a novel cyclin (cyclin 6+.
Ac%ive binary com#le4es o$ cyclins7c)!s are ca%aly%ically ac%ive. 6o,ever, o%her #ro%eins co-#uri$y
,i%h %hese binary com#le4es in e4%rac%s $rom normal cells (Oiong e% al., 1992+. Among %hese is a
21 !.a #ro%ein (#21&i#1+ ,hich is a universal c)! inhibi%or an) is ca#able o$ inhibi%ing %he ac%ivi%y o$
cyclin7c)! holoen<ymes %ha% have un)ergone &AF-me)ia%e) #hos#horyla%ion. p21 e4#ression is
regula%e) by %he p53 %umour su##ressor #ro%ein in res#onse %o ./A )amage (see belo,+. As illus%ra%e)
in :ig. 2.8 p21 is $oun) in a 9ua%ernary com#le4 %ha% inclu)es no% only cyclin an) c)! bu% also %he
#roli$era%ing cell nuclear an%igen (P&/A+, ,hich $unc%ions in bo%h ./A re#air an) re#lica%ion as a
subuni% o$ ./A #olymerase )el%a (Oiong e% al., 1992+.
:ig. 2.8. Pos%ula%e) 9ua%ernary com#le4 be%,een .-%y#e cyclins, &.Fs, #21, an) P&/A (a$%er Oiong
e% al., 1992+.
Ano%her regula%or o$ "1 #rogression is %he #ro%ein p27Fi#1 ,hich also inhibi%s %he ac%ivi%y o$ all c)!s
(Polya! e% al., 1998+. I% is %he rela%ive levels o$ cyclin .7c)! com#le4es an) p27 %ha% )e%ermine
inhibi%ion or #rogression %hrough "1 (Oiong e% al., 1992+.
28
Cne no%able "1 cyclin7c)! inhibi%or (&.I+ is p16I/F8. he p16 #ro%ein a##aren%ly inhibi%s c)!8 an)
c)!> by bin)ing in com#e%i%ion ,i%h cyclin .. here is a reci#roci%y be%,een %he levels o$ 'b an) p16
e4#ression in %umour cells. hose cells %ha% e4#ress ,il) %y#e 'b #ro%ein have lo, levels o$ p16 an)
cells lac!ing $unc%ional 'b e4#ression e4#ress high levels o$ p16. his sugges%s %ha% 'b may su##ress
p16 e4#ression, %he reci#rocal o$ 'b-s%imula%e) cyclin . e4#ression.
he p16 gene ma#s %o chromosome 9p21 in humans. Ano%her gene, p15, is in close #ro4imi%y. he p15
#ro%ein is also an inhibi%or o$ c)!8 an) c)!> an) shares s%rong se9uence i)en%i%y ,i%h p16 (6annon an)
Beach, 1998+. he p16 locus is )ele%e), rearrange), or mu%a%e) in %he ma-ori%y o$ %umour cell lines
(Famb e% al., 1998a+. his $in)ing le) %o %he sugges%ion %ha% p16 may be %he 3 gene (*)+1+ %ha% ma#s
%o %his region o$ chromosome 9 an) ,hose inac%iva%ion has been im#lica%e) in many malignancies,
inclu)ing s#ora)ic carcinomas an) $amilial melanomas (6ussussian e% al., 1998+. &on$irma%ion o$ %his
hy#o%hesis has been con%roversial, #ossibly )ue %o %he has%e in ,hich %he analyses ,ere #er$orme). :or
e4am#le, %he lin!age %o $amilial #re)is#osi%ion %o melanoma has bo%h i%s #ro#onen%s (6ussussian e% al.,
1998+ an) o##onen%s (Famb e% al., 1998b+. 'esolu%ion o$ %his con%roversy shoul) shor%ly be
$or%hcoming an) may have im#lica%ions $or ./A )amage re#air (see 3ec%ion 2.8.>+. I% is also #ossible,
o$ course, %ha% p15 may re#resen% a cri%ical 3 gene.
In summa%ion, i% is clear %ha% regula%ion o$ %he cell cycle is cri%ical $or %he )evelo#men% an)
main%enance o$ normal cell behaviour. .ysregula%ion serves as a #o,er$ul )riving $orce $or abnormal
#roli$era%ion. 3everal genes %ha% govern con%rol o$ %he "103 #rogression are !no,n %o be, or are
can)i)a%e, oncogenes (PRA#10cyclin .1+ or %umour su##ressor genes (p15, p16, p21, p27, RB, an)
p53+. Presumably, any o$ %he cri%ical cell cycle regula%ory genes are can)i)a%es an) %heir aberran%
$unc%ioning in cancers is being ac%ively inves%iga%e).
'ela%ively li%%le is !no,n abou% chec!#oin% con%rols in 3, "2, an) M #hases o$ %he cell cycle. An early
"2 chec!#oin% res#onse in normal human cells has been associa%e) ,i%h inhibi%ion o$ #28
&.&2
0cyclin B
!inase ac%ivi%y (Paules e% al., 1995+. here is also evi)ence $or a la%er "2 chec!#oin% closer %o %he "20M
boun)ary.
.es#i%e %he small amoun% o$ !no,le)ge available, %here are some in%riguing $in)ings. :or e4am#le,
cyclin * is %hough% %o be im#or%an% in %he ini%ia%ion o$ ./A re#lica%ion. &yclin * is over-e4#resse) in
many human %umour %y#es, inclu)ing breas% cancers (6un%er an) Pines, 1998+. *4#erimen%al evi)ence
$or an oncogenic ac%ivi%y $or cyclin * is, ho,ever, no% com#elling. he cyclin A gene (CC:A+ is %he
uni9ue inser%ion si%e o$ a he#a%i%is B virus (6BV+ in clonal he#a%oma. he in%egra%ion #ro)uce) a
chimeric $usion #ro%ein %ha% lac!e) %he so-calle) cyclin )es%ruc%ion bo4 (Eang e% al., 1992+, %hus %he
chimeric cyclin A #ro%ein ,as no% )egra)e) in mi%osis. 3ince cyclin A is re9uire) $or #rogression
%hrough 3 #hase an) "20M, i%s cons%i%u%ive e4#ression may con%ribu%e %o aberran% cell cycle con%rol
(6un%er an) Pines, 1998+.
Fno,le)ge on cell cycle con%rol con%inues %o )evelo# ra#i)ly an) a series o$ recen% revie,s #rovi)e
$ur%her insigh%s in%o %his cri%ical area o$ cellular #hysiology (see /asmy%h, 199>+.
,!"!"! &he p53 %ene in #$A dama%e chec)point control
.amage %o ./A can elici% %,o early cellular res#onses@ cell cycle arres% $ollo,e) by re#air, or
a#o#%osis (#rogramme) cell )ea%h+. 1oss o$ ei%her res#onse can lea) %o accumula%ion o$ mu%a%ions an)
genomic ins%abili%y, bo%h o$ ,hich may con%ribu%e %o neo#las%ic )evelo#men%.
29
A !ey regula%or o$ %he "103 chec!#oin% con%rol in %he cell cycle is %he #ro%ein #ro)uc% o$ %he p53 3
gene. p53 is %he mos% commonly mu%a%e) 3 gene $oun) in human cancers. he p53 #ro%ein ,as $irs%
i)en%i$ie) %hrough i%s abili%y %o $orm a s%able com#le4 ,i%h 3V8; large an%igen. he 3V8; an%igen
,as subse9uen%ly $oun) %o bloc! %he ac%ivi%y o$ ,il) %y#e p53, an im#or%an% com#onen% o$ %he
%rans$orming ac%ivi%y o$ 3V8; An%igen. p53 #ro%ein has been sho,n %o bin) %o ./A an) $unc%ion as a
%ranscri#%ional ac%iva%or (1ane, 1998+. I% also re#resses %he %ranscri#%ion o$ cer%ain genes (e.g. %he mul%i-
)rug resis%ance gene or *#R+ via #ro%ein@#ro%ein in%erac%ions.
he p53 #ro%ein has a very shor% hal$-li$e (a##ro4ima%ely 15 minu%es+ in normal cells. A#on e4#osure
o$ cells %o ./A-)amaging agen%s, e.g. AV ligh%, ionising ra)ia%ion an) ./A in%ercala%ion agen%s, %he
hal$-li$e o$ p53 #ro%ein increases signi$ican%ly (%o several hours+ an) %he cells arres% in "1 or un)ergo
a#o#%osis, )e#en)ing on cell %y#e. he mechanisms by ,hich p53 in)uces "103 chec!#oin% con%rol are
un!no,n. 6o,ever, i% has been sho,n %ha% p53 u#regula%es %he e4#ression o$ p21&IP10EA:1, %he c)!
inhibi%or %ha% $orms a 9ua%ernary com#le4 ,i%h cyclin ., c)! an) P&/A (:ig. 2.8+. his 9ua%ernary
com#le4 seems %o be re9uire) $or e$$icien% cell cycle con%rol (Oiong e% al., 1992+. I% is curren%ly %hough%
%ha% %he in)uc%ion o$ %he "103 chec!#oin% con%rol allo,s %he cell %o ei%her re#air %he ./A )amagePin
,hich case %he "103 bloc! is %em#oraryPor, i$ %he )amage is irre#arable, %he cell is #ermanen%ly
arres%e) or )iver%e) in%o %he #rogramme) cell )ea%h or a#o#%o%ic #a%h,ays. he sensi%ivi%y o$ %he ./A
)amage sensing by ,il) %y#e p53 is remar!able= Eahl an) colleagues have sugges%e) %ha% %he e4is%ence
o$ a single ./A )ouble s%ran) brea! in a cell migh% be su$$icien% %o ac%iva%e %he p53-me)ia%e) "103
arres% (6uang e% al., 199>+.
1oss o$ $unc%ion o$ %he p53 gene is a cri%ical even% in neo#las%ic #rogression. his may occur as a
conse9uence o$ )ele%ion o$ %he p53 gene or, more commonly, )ue %o missense or nonsense #oin%
mu%a%ions. he ma-ori%y o$ #oin% mu%a%ions are missense, %hereby #reserving %he o#en rea)ing $rame o$
%he gene. he gene is a##ro4ima%ely 2; !b in leng%h, %ranscribing a 2.8 !b m'/A ,hich is %ransla%e)
in%o a 292 amino aci) #ro%ein. he gene has 11 e4ons. he $unc%ional )omains o$ %he p53 #ro%ein are
illus%ra%e) in :ig. 2.5. here are $ive evolu%ionarily highly conserve) )omains ,hich corres#on) closely
%o %he regions mos% $re9uen%ly mu%a%e) in s#ora)ic cancers. .omains II7V corres#on) %o %he region o$
%he molecule res#onsible $or bin)ing %o se9uence-s#eci$ic ./A regions in p53-res#onsive #romo%ers.
he carbo4y %erminal )omain inclu)es %he nuclear localising signal an) %he oligomerisa%ion )omain.
he crys%al s%ruc%ure o$ p53 #re)ic%s a %e%rameric com#le4 bin)ing %o ./A (&ho e% al., 1998, De$$rey e%
al., 1995+. Missense mu%a%ions in p53 resul% in loss o$ bin)ing %o p53 consensus si%es in ./A an)0or
loss o$ %ranscri#%ional ac%iva%ion (Prives, 1998+.
:ig. 2.5. Mu%a%ional s#ec%rum ,i%hin conserve) )omains o$ #52 #ro%ein. &onserve) )omains I7V are
ha%che)= bars re#resen% rela%ive $re9uency o$ mu%a%ion, %he highes% being mu%a%ional ho%-s#o%s.
30
&ells %ha% lac! ,il) %y#e p53 $unc%ion $ail %o arres% a% %he "103 chec!#oin% %hereby increasing %he
li!elihoo) o$ )evelo#men% o$ gene%ic lesions crea%e) by re#lica%ion errors an) %heir subse9uen% $i4a%ion
in %he genome. &onse9uen%ial ./A )amage may inclu)e #oin% mu%a%ions, ./A )ele%ions, inser%ions
an) rearrangemen%s, an) gene am#li$ica%ion. In a))i%ion %o i%s "103 #hase roles, in some cell %y#es p53
#ro%ein may also #lay a role in chec!#oin% re#air in "20M (Bou$$ler e% al., 1995+. he im#or%ance o$
%his $or cellular ra)ia%ion res#onse an) %umorigenesis is )iscusse) 3ec%ion 5. here are also in)ica%ions
%ha% p53 may #lay a role in correc% main%enance o$ cen%rosome re#lica%ion. he cen%rosome #lays a
cri%ical role in mi%o%ic s%abili%y, ensuring %he es%ablishmen% o$ bi#olar s#in)les an) balance)
chromosome segrega%ion. he cen%rosome )u#lica%es only once )uring each cell cycle. :u!asa,a e% al.
(199>+ re#or% %ha% in mouse embryonic $ibroblas%s lac!ing %he p53 %umour su##ressor #ro%ein, mul%i#le
co#ies o$ $unc%ionally com#e%en% cen%rosomes are genera%e) )uring a single cell cycle. he #resence o$
mul%i#le co#ies o$ %he cen%rosome lea) %o une9ual chromosome segrega%ion an) conse9uen%
chromosomal aneu#loi)y.
*vi)ence %ha% loss o$ $unc%ion o$ %he p53 gene is a cri%ical even% in neo#las%ic )evelo#men% has come
$rom several sources. Cne o$ %he mos% com#elling is %ha% a germ-line mu%a%ion in p53 is %he heri%able
%rai% in %he 1i7:raumeni syn)rome, a rare au%osomal )ominan% con)i%ion %ha% is charac%erise) by %he
%en)ency %o )evelo# mul%i#le malignanciesP#ar%icularly so$% %issue sarcomas an) breas% carcinomasP
a% an early age (Mal!in e% al., 199;+. I% has no, been sho,n %ha% %umours arising in %hese in)ivi)uals
have su$$ere) )ele%ions or #oin% mu%a%ions in %he remaining ,il) %y#e p53 allele.
ransgenic mice have been #ro)uce) %ha% are ei%her he%ero<ygous or null $or p53. he p53
K0L

he%ero<ygous mice )evelo# normally an) a signi$ican% $rac%ion o$ %he animals )evelo# %umours a$%er
a##ro4ima%ely one year. In%eres%ingly, %he ma-ori%y o$ mice %ha% are p53 null also )evelo# normallyP
in)ica%ing %ha% p53 is no% essen%ial $or normal )evelo#men%Pbu% %he vas% ma-ori%y succumb %o
malignancy ,i%hin si4 mon%hs o$ bir%h (.oneho,er e% al., 1992+. his is in con%ras% %o RB1
nulli<ygosi%y ,hich in mice is an embryonic le%hal con)i%ion (1ee e% al., 1992+. he %umorigenic an)
cy%ogene%ic res#onses o$ p53-)e$icien% mice %o ra)ia%ion are )iscusse) in 3ec%ion 5.
I% shoul) be no%e) %ha% p53 inac%iva%ing mu%a%ions an) )ys$unc%ion o$ %he p53 #ro%ein are %he mos%
common al%era%ions observe) in human cancers. hey have been associa%e) ,i%h some $rac%ion o$
vir%ually every s#ora)ically occurring %y#e o$ malignancy ("reenbla%% e% al., 1998+. :or e4am#le, in
s#ora)ic colon carcinomaP%he $irs% malignancy ,here p53 loss o$ $unc%ion ,as im#lica%e)Ploss o$
he%ero<ygosi%y an) mu%a%ion o$ p53 is seen in more %han 7;5 o$ cases.
here is an increasing a##recia%ion %ha% %umours %ha% re%ain ,il) %y#e p53 alleles may also have
com#romise) p53 #ro%ein $unc%ion by in)irec% means. :or e4am#le, 6o,ley an) colleagues sho,e)
%ha% %he 6PV1> or 6PV18 *> %rans$orming #ro%ein com#le4es ,i%h p53 #ro%ein an) me)ia%es i%s ra#i)
)egra)a%ion via a ubi9uina%ion #a%h,ay (3che$$ner e% al., 199;+. hey $oun) %ha% cervical carcinomas
%ha% are 6PV-#osi%ive have ,il) %y#e p53 ,hereas %hose %ha% are 6PV-nega%ive have mu%an% or null p53
alleles. he obvious in$erence is %ha% %he e4#ression o$ %he *> #ro%ein ren)ers %he cell $unc%ionally null
$or p53 ac%ivi%y. 3imilarly, 1evine an) colleagues (Moman) e% al., 1992+ have $oun) %ha% %he m)m2
#ro%ein, o$%en over-e4#resse) in breas% carcinomas an) o%her malignancies, com#le4es ,i%h p53 #ro%ein
an) inhibi%s i%s %ranscri#%ion ac%iva%ion $unc%ion.
,!"!,! (omatic mutations of p53 in human tumours
31
he p53 %umour su##ressor gene has recen%ly receive) much a%%en%ion because o$ i%s $re9uen% mu%a%ion
in )iverse %y#es o$ human cancers. :re9uen%ly, %he ini%ial mu%a%ion in one allele is accom#anie) by a
loss o$ %he secon) allele. A )a%a base, consis%ing o$ #ublishe) p53 mu%a%ions, has been re#or%e) %ha%
#rovi)es a mu%a%ion s#ec%rum $or soma%ic mu%a%ions in %he p53 gene ("reenbla%% e% al., 1998+. All
classes o$ mu%a%ions occur@ single base subs%i%u%ions #re)omina%e an) cons%i%u%e more %han 8;5 o$ all
mu%a%ions. Among %hose, %he mos% common mu%a%ions are "@&NA@ an) A@N"@& %ransi%ions an)
"@&N@A %ransversions, an) more %han >;5 o$ base subs%i%u%ions are $oun) a% "@& base #airs (:ig.
2.>+. 6o,ever, %he mu%a%ion s#ec%ra )i$$er )e#en)ing on %umour %y#e, in)ica%ing %ha% %he origins o$
mu%a%ions are )is%inc% among )i$$eren% %umour %y#es.
:ig. 2.>. 3oma%ic an) germ-line mu%a%ion o$ %he human p53 gene ($rom "reenbla%% e% al., 1998+.
Mu%a%ions sca%%er over %he en%ire region o$ evolu%ionally conserve) )omains (co)ons 977292+. Ehile
mu%a%ional ho% s#o%s are no% evi)en% $or )ele%ion0inser%ion mu%a%ions an) nonsense base subs%i%u%ions,
%he missense base subs%i%u%ions %en) %o clus%er a% high $re9uency in co)ons 175, 285, 288, 289, 272, an)
282. &o)ons 175, 285, 288, 272, an) 282 con%ain &#" )inucleo%i)es. he #revalence o$ "@&NA@
%ransi%ions in %hese si%es sugges%s %he s#on%aneous )eamina%ion o$ 5-me%hylcy%osine (
5m%
&+ conver%ing
in%o uracil or %hymine. Ali#ha%ic al!yla%ion o$ guanine a% %he C> #osi%ion is also e4#ec%e) %o genera%e
"@&NA@ %ransi%ions by mis#airing ,i%h %hymine )uring ./A re#lica%ion. he bul!y a))uc%s #ro)uce
unins%ruc%ive lesions ,hich, along ,i%h abasic si%es, %en) %o be re#lica%e) by %he a))i%ion o$ a)enine
o##osi%e %he lesions (HA ruleI+. his HA ruleI accoun%s $or %he " %o an) A %o %ransversions.
Ehile %he %y#es an) si%es o$ mu%a%ions are %he )riving $orce o$ mu%a%ion an) selec%ion %hey also #rovi)e
e%iologic clues in some %umours. Pre)ominance o$ %he "@&NA@ %ransi%ion ,i%h $re9uen% involvemen%
o$ &#" si%es is evi)en% $or colon, brain, an) s%omach cancers, basal cell carcinoma o$ s!in an)
leu!aemia0lym#homa. In con%ras%, %he involvemen% o$ &#" si%es in & %o %ransi%ions is com#ara%ively
less $re9uen% $or lung an) liver cancers, ,here "@&N@A %ransversions #re)omina%e. In %hese organs,
%obacco smo!ing an) in%a!e o$ mu%agens $rom )ie% may be %he origin o$ mu%a%ion, $orming
unins%ruc%ive bases by mu%agen ac%ion. In breas% cancer, ,hile "@&NA@ %ransi%ions cons%i%u%e %he
ma-ori%y o$ mu%a%ions, ,i%h a high $re9uency a% &#" si%es, "@&N@A %ransversions are $re9uen% in
*uro#e an) America bu% very rare in Da#an, in)ica%ing )i$$eren% e%iological mechanisms among %hese
coun%ries. In s!in cancer, #ar%icularly s9uamous cell carcinoma o$ %he s!in, mu%a%ions in %he p53 gene
are highly AV s#eci$ic, i.e. && %o or & %o changes a% )i#yrimi)ine si%es (Brash e% al., 1991=
Giegler e% al., 1992= 3a%o e% al., 1992+. he %hymine moie%y inclu)e) in , &, an) & )imers is
e4#ec%e) %o #air ,i%h a)enine, resul%ing in res%ora%ion o$ %he original base se9uence. In liver cancer,
A"" %o A" change (or "@&N@A %ransversion a% %he 2r) #osi%ion+ in co)on 289 has been s#eci$ically
32
correla%e) ,i%h %he e4#osure %o a$la%o4in B1. hese lines o$ evi)ence, %oge%her ,i%h base-)irec%e)
mu%agenesis, sho, %ha% %he p53 mu%a%ions are highly %issue s#eci$ic an) agen% s#eci$ic, coming $rom
ei%her s#on%aneous )eamina%ion o$
5m%
& or mu%agen-in)uce) base )amage.
I% is no%e,or%hy %ha% %he AV-rela%e) && %o mu%a%ions in p53 gene have been also $oun) a% a high
$re9uency (785+ in normal s!in sam#les $rom sun-e4#ose) areas o$ %he s!in cancer #a%ien%s (/a!a<a,a
e% al., 1998+. 3imilarly, A"" %o A" mu%a%ions a% co)on 289 are also $oun) in non-malignan% sam#les
o$ liver $rom #a%ien%s in Qi)ong, &hina, an) Ees%ern coun%ries, an) are correla%e) ,i%h e4#osure %o
a$la%o4in B1 (Aguilar e% al., 1998+. In bla))er cancer mos% o$ %he mu%a%ions are "@& %o A@ %ransi%ions.
he involvemen% o$ %he &#" )ouble% is rela%ively high, bu% in smo!ers 801> (255+ o$ mu%an% p53 genes
sho,e) %an)em )ouble mu%a%ions (3#ruc! e% al., 1992+. 3uch mul%i#le mu%a%ions in one allele are also
$oun) in mu%agen-in)uce) cancers in ra%s (Ma!ino e% al., 1992+. Mul%i#le mu%a%ions in %he p53 gene
also have been $oun) in s!in %umours %ha% arose in #a%ien%s ,i%h 4ero)erma #igmen%osum, a gene%ic
)isease lac!ing e4cision re#air o$ AV-in)uce) ./A )amage (3a%o e% al., 1992+.
.a%a are no, available $or p53 mu%a%ions in some ra)ia%ion-associa%e) cancers (:ig. 2.7+. VRhR!angas
e% al. (1992+ s%u)ie) mu%a%ions in p53 genes in 19 cases o$ lung cancer %ha% )evelo#e) in uranium
miners an) i)en%i$ie) nine mu%a%ions, inclu)ing %,o )ele%ions, in seven o$ %he #a%ien%s. Among si4 base
subs%i%u%ion mu%a%ions, %hree ,ere "@&N@A %ransi%ions. More recen%ly, aylor e% al. (1998b+ re#or%e)
%ha% 1> o$ 52 lung cancers $rom uranium miners con%aine) A"" %o A" %ransversions a% co)on 289.
his si%e-s#eci$ic mu%a%ion, #ar%icularly " %o %ransversion a% %he 2n) #osi%ion o$ co)on 289, is a rare
even% in p53 mu%a%ions %ha% are $oun) in conven%ional lung cancers, an) %hey re#or%e) %ha% such
mu%a%ions migh% be a #o%en%ial mar!er $or ra)ia%ion-in)uce) lung cancer. his is, ho,ever, a
con%roversial $in)ing. a!eshima e% al. (1992+ s%u)ie) p53 mu%a%ions in lung cancers %ha% arose in nine
lo,-)ose a%omic bomb survivors ,ho ,ere nonsmo!ers an) i)en%i$ie) $our mu%a%ions. he $re9uencies
an) %y#es o$ mu%a%ions ,ere no% )i$$eren% $rom %hose in lung cancers o$ nonsmo!er con%rols, ,here
"@&NA@ %ransi%ions #re)omina%e), in con%ras% %o %he #re)ominance o$ "@&N@A %ransversions in
smo!ers. 'ecen%ly, Ch%suyama e% al. (1998+ s%u)ie) p53 mu%a%ions in mouse s!in %umours an)
os%eosarcomas, ,hich a##eare) a$%er -irra)ia%ion, an) $oun) %ha% %he ma-ori%y o$ mu%a%ions ,ere a%
&#" si%es. hus, no clear evi)ence is emerging $or ra)ia%ion-s#eci$ic mu%a%ions in ra)ia%ion-associa%e)
%umours, al%hough )a%a remain ra%her s#arse.
:ig. 2.7. p53 mu%a%ions in human lung cancer. .a%a on lung cancer in %he general #o#ula%ion %a!en $rom
"reenbla%% e% al. (1998+. 3ee %e4% $or re$erences on ra)ia%ion-associa%e) lung cancer.
33
In summary, %umour su##ressor genes may be seen %o occu#y a cen%ral #osi%ion in %he nega%ive
regula%ion o$ a range o$ cellular $unc%ions %ha% are relevan% %o neo#las%ic )evelo#men%. C$ #rinci#al
im#or%ance %o normal cell #hysiology are %he %umour su##ressor gene $unc%ions in signal %rans)uc%ion,
cellular in%erac%ions, cell cycle regula%ion an) %he main%enance o$ genomic s%abili%y. 1oss or mu%a%ion o$
such genes can ac% %o com#romise %hese cri%ical biochemical an) bio#hysical #a%h,ays, o$%en in a
$ashion %ha% im#lies a )egree o$ cell %y#e, an) %hereby %issue s#eci$ici%y. Mos% %umour su##ressor genes
are recessive in $unc%ion an) loss0mu%a%ion o$ bo%h au%osomally enco)e) co#ies ,ill be necessary $or
$ull #heno%y#ic e4#ression )uring neo#las%ic )evelo#men%. In some cases, ho,ever, single-co#y gene
mu%a%ion is su$$icien% $or %he genera%ion o$ #ar%ial #heno%y#ic e$$ec%s. Mu%an% %umour su##ressor genes
an) #ro%o-oncogenes a##ear %o o#era%e in a synergis%ic an) o$%en gene-s#eci$ic $ashion )uring
mul%is%age oncogenesis. he consis%ency o$ soma%ic %umour su##ressor gene mu%a%ions in many %umour
%y#es, %heir cri%ical involvemen% in $amilial %umours, an) in vi%ro e4#erimen%al evi)ence, %en) %o su##or%
%he vie, %ha% %hey are %he #rinci#al ra%e-limi%ing gene%ic com#onen% o$ human cancer.
,!,! #$A repair and replication %enes in solid tumours
Inheri%e) syn)romes %ha% are associa%e) ,i%h ./A re#air )e$iciencies, ra)ia%ion sensi%ivi%y, an)
increase) ris! o$ malignancies have been !no,n $or many years. An illus%ra%ion o$ such genes an) %he
)isor)ers %hey are associa%e) ,i%h are given in able 2.2. hese con)i%ions, an) %heir relevance %o
lym#hohaemo#oie%ic neo#lasia are )iscusse) in 3ec%ion 2 an) 3ec%ion 8 o$ %his )ocumen%.
able 2.2. &lone) ./A re#lica%ion an) re#air genes im#lica%e) in human carcinogenesis
A s#eci$ic se% o$ ./A re#air genes involve) in ./A misma%ch correc%ion have been recen%ly
im#lica%e) in %he genesis o$ soli) %umours. A varie%y o$ %umours have been $oun) %o harbour al%era%ions
in microsa%elli%e se9uences )is%ribu%e) %hroughou% %heir genome (Ionov e% al., 1992= Aal%onen e% al.,
1992+. his microsa%elli%e ins%abili%y in)ica%es mal$unc%ions(s+ in %he re#lica%ion or re#air o$ ./A
,hich #ersis% %hroughou% %he li$e s#an o$ %he %umour, cons%an%ly #rovi)ing a source o$ gene%ic
ins%abili%y. he molecular )e%erminan% o$ microsa%elli%e ins%abili%y ,as resolve) ,hen i% ,as $oun) %ha%
germ line mu%a%ions in a ./A misma%ch re#air gene, h*+52, %he homologue o$ %he #ro!aryo%ic -ut+
misma%ch re#air gene, charac%erise here)i%ary non#oly#osis colorec%al cancer (6/P&&+ #a%ien%s (:ishel
e% al., 1992= Parsons e% al., 1992+. 6/P&& (or 1ynch syn)rome+ is one o$ %he mos% common cancer-
#re)is#osing syn)romes (see 3ec%ion >+. &olonic %umours )erive) $rom h*+52 6/P&& in)ivi)uals
con%ain %he germline mu%a%ion in h*+52 #lus mu%a%ion or )ele%ion o$ %he remaining ,il) %y#e allele.
'ecen% e4#erimen%s have con$irme) %he recessive na%ure o$ %his gene (&asares e% al., 1995+.
34
/o% all 6/P&& #a%ien%s have a h*+52 germ line mu%a%ion. I% has no, been sho,n %ha% germ line
mu%a%ions in %hree o%her ./A misma%ch re#air genes, namely h*351 (a homologue o$ %he bac%erial
-ut3 gene+, hP*+1, an) hP*+2 (%,o o%her homologues o$ %he #ro!aryo%ic -ut3 gene+ are mu%a%e) in a
subse% o$ 6/P&& cases (able 2.8+ (Bronner e% al., 1998= /icolai)es e% al., 1998+. In %hese cases,
soma%ic mu%a%ions in %he res#ec%ive remaining ,il) %y#e allele are also $oun) in %umours ob%aine) $rom
%hese #a%ien%s.
able 2.8. "ene%ic )e%erminan%s o$ soli) %umours in )i$$eren% organs
35
Base) on %he high $re9uencies o$ chromosomal abnormali%ies an) mu%a%ions %ha% are $oun) in human
cancers, 1oeb hy#o%hesise) %ha% cancer is mani$es%e) by a mu%a%or #heno%y#e (1oeb, 1998+. Al%hough
a%%rac%ive, %his hy#o%hesis lac!e) e4#erimen%al su##or% un%il %he )iscovery o$ )e$ec%s in ./A re#air
genes. he re#lica%ion error ('*'+ #heno%y#e %ha% charac%erises microsa%elli%e ins%abili%y is also
associa%e) ,i%h an increase) in vi%ro soma%ic mu%a%ion ra%e (*schelman e% al., 1995+. 1oeb has
)evelo#e) a hy#o%he%ical scenario (:ig. 2.8+ %ha% #re)ic%s %ha% mu%a%ions in genomic s%abili%y genes
36
(inclu)ing ./A re#air an) re#lica%ion+ are early even%s in carcinogenesis. .e$ec%s in ./A re#air,
re#lica%ion, an) chromosomal segrega%ion are li!ely %o increase %he #robabili%y o$ )amage %o, or loss o$,
oncogenes an) %umour su##ressor genes %ha% are cri%ical $or %he $inal mani$es%a%ion o$ %he malignan%
#heno%y#e. *4#erimen%al evi)ence is no, accumula%ing %o su##or% %his con%en%ion. I% is no%e,or%hy %ha%
misma%ch re#air gene )e$ec%s are $oun) in s#ora)ic colorec%al cancers (an) o%her cancers+ ,i%h
microsa%elli%e ins%abili%y. :ur%hermore, a signi$ican% number o$ cancer cells %ha% e4hibi% %he '*'
#heno%y#e )o no% sho, )e$ec%s in %he $our !no,n misma%ch re#air genes (1iu e% al., 1995+. his is no% a
sur#rising $in)ing since i% is !no,n %ha% in %he bac%erium 6sch/richia coli, a##ro4ima%ely 1; gene
#ro)uc%s are involve) in misma%ch re#air. hus, %he '*' #heno%y#e in %hese cases may be )ue %o
)e$ec%s in o%her genes res#onsible $or ./A re#air or re#lica%ion.
:ig. 2.8. 3ources o$ mul%i#le mu%a%ions )uring cancer )evelo#men% (see 1oeb, 1998+.
In summary, mu%a%ion o$ ./A misma%ch re#air genes a##ears %o be an im#or%an% com#onen% o$
s#ora)ic an) $amilial soli) %umours ,i%h mu%an% gene e$$ec%s being mos% #ronounce) in %he in%es%inal
%rac%. *vi)ence %ha% has accumula%e) in %his ne, area o$ s%u)y has $ur%her highligh%e) %he cri%ical
im#or%ance o$ %he early ac9uisi%ion o$ genomic ins%abili%y $or neo#las%ic )evelo#men%. ,o $ur%her
a)vances in our un)ers%an)ing o$ ho, )e$ec%ive genes associa%e) ,i%h ./A re#lica%ion0re#air #lay a
role in neo#las%ic #rogression came ,i%h %he cloning an) charac%erisa%ion o$ %he A)* an) BloomIs
syn)rome genes. he A)* gene is mu%a%e) in #a%ien%s ,i%h %he cancer-#rone gene%ic )isor)er a%a4ia-
%elangiec%asia (3avi%s!y e% al., 1995+. I% enco)es a cell cycle chec!#oin% #ro%ein rela%e) %o %he yeas%
Ra3 gene, a member o$ %he #hos#ha%i)yl-2S subgrou# o$ !inases (Eal,or%h an) Bernar)s, 199>+.
C%her $unc%ions o$ %his large gene (%ranscri#% si<e o$ 12 !b+ are curren%ly un)er inves%iga%ion.
he BloomIs syn)rome gene, B3*, #lays an im#or%an% role in %he main%enance o$ genomic s%abili%y in
soma%ic cells. he B3* gene has recen%ly been clone) an) se9uence com#arison sho,s homology ,i%h
'ecQ helicases (*llis e% al., 1995+.
he relevance o$ %hese gene )e$ec%s, as ,ell as %hose res#onsible $or 4ero)erma #igmen%osum,
&oc!ayneIs syn)rome, an) EernerIs syn)rome, ,i%h res#ec% %o ra)iosensi%ivi%y an) #re)is#osi%ion %o
cancer, are a))resse) in 3ec%ion 2 an) also no%e) in 3ec%ion 5.
,!-! Genetic susceptibility to solid tumours
6aving es%ablishe) %he general role o$ oncogenes, %umour su##ressor an) ./A re#air genes in %he
genesis o$ human soli) %umours, an) having #rovi)e) illus%ra%ive e4am#les o$ %he cellular0molecular
mechanisms involve), i% becomes #ossible %o consi)er %he s#eci$ic germ line mu%a%ions %ha% #re)is#ose
37
%o cancer. 3uch #re)is#osi%ion has been %he sub-ec% o$ a number o$ revie,s (Fnu)son, 1992a an)
Fnu)son, 1992b= *ng an) Pon)er, 1992= 1an$rancone e% al., 1998= Far# an) Bro)er, 1995= *eles e% al.,
199>+ an) here ,e #rovi)e an ou%line o$ %his ra#i)ly )evelo#ing $iel) on %he basis o$ %he e4#ression o$
)isease in )i$$eren% organ sys%ems.
Al%hough in)ivi)uals ,i%h cancer-#re)is#osing germ line mu%a%ions carry a mu%an% gene in each an) all
o$ %heir soma%ic cells, %he subse9uen% age-rela%e) )evelo#men% o$ over% cancer is usually limi%e) %o a
$e, o$ %hese cells an) o$%en #resen%s as cancer in a subse% o$ %issues (see also 3ec%ion 5+. hus %he
mu%an% gene in 9ues%ion, al%hough no% assuring neo#las%ic %rans$orma%ion, mus% re)uce or by#ass a
given ra%e limi%ing s%e# in carcinogenic )evelo#men%. I% also $ollo,s %ha% %he rela%ive im#or%ance o$
such a mu%a%ion %o #hysiological con%rol )i$$ers be%,een cell %y#es.
hese $ea%ures may also un)erlie a##aren% )i$$erences in %he #ene%rance an) e4#ressivi%y o$ %he germ
line %umour genes o$ in%eres%. In %he con%e4% o$ %umour #re)is#osi%ion, %he %erm #ene%rance #rinci#ally
a##lies %o %he #robabili%y %ha% a given gene carrier ,ill e4#ress %he mu%an% geno%y#e as neo#las%ic
)isease. *4#ressivi%y is less ,ell )e$ine) bu% essen%ially a##lies %o %he na%ure o$ )isease in carriers, e.g.
%he age o$ onse% (,hich is usually a% an earlier age %han seen in %he normal #o#ula%ion+, %he
mani$es%a%ion o$ mul%i#le %umours a% %he same or )i$$eren% si%es, an) %he rela%ive numbers o$ benign an)
malignan% neo#lasms. hus, #ene%rance an) e4#ressivi%y are %he #rinci#al biological )e%erminan%s o$
cancer morbi)i%y an) mor%ali%y in %umour-#re)is#ose) in)ivi)uals.
he $ac%ors %ha% in$luence #ene%rance an) e4#ressivi%y o$ germ line %umour gene mu%a%ions are #oorly
un)ers%oo). 6o,ever, %hey seem %o inclu)e %he s#eci$ic na%ure o$ %he mu%a%ion in 9ues%ion, %he #resence
or absence o$ o%her genomic )e%erminan%s (so-calle) mo)i$ier genes+, e#igene%ic $ac%ors, such as
#aren%-o$-origin e$$ec%s on gene e4#ression, an) #erha#s, ,ha% is mos% im#or%an%, environmen%al $ac%ors
such as )ie%ary in%a!es an) e4#osure %o geno%o4ic agen%s. 3ome o$ %hese issues are )iscusse) in %his an)
o%her sec%ions o$ %he )ocumen%.
,!-!1! /eritable breast and ovarian cancer
"ene%ic lin!age s%u)ies have es%ablishe) %ha% a gene #re)is#osing %o breas% an) ovarian cancer (BRCA1+
accoun%s $or %he inheri%e) #re)is#osi%ion %o cancers in a high #ro#or%ion o$ $amilies ,i%h mul%i#le breas%
cancer an) ovarian cancers, an) a##ro4ima%ely hal$ o$ all early-onse% breas% cancer $amilies ,i%hou%
ovarian cancer (:or) e% al., 1998+. I% ,as es%ima%e) %ha% %he #ene%rance o$ %he gene is 875 by age 7;
(*as%on e% al., 1992+. 3igni$ican% e4cesses $or colon cancer an) #ros%a%e cancer ,ere also observe) in
some $amilies (:or) e% al., 1998+.
he BRCA1 gene is si%ua%e) on chromosome 17921 an) has been clone) (Mi!i e% al., 1998+. I% is
e4#resse) in numerous %issues, inclu)ing breas% an) ovary, an) enco)es a #re)ic%e) #ro%ein o$ 18>2
amino aci)s. he BRCA1 gene is large, com#rising 22 co)ing e4ons )is%ribu%e) over a##ro4ima%ely 1;;
!b o$ genomic ./A.
:ollo,-u# s%u)ies have con$irme) %he original $in)ing o$ germ line BRCA1 mu%a%ions in a signi$ican%
#ro#or%ion o$ breas%0ovarian cancer $amilies. hese have bo%h )ele%ion an) chain %ermina%ing mu%a%ions
as %he #rinci#al mu%a%ional even%s (:rie)man e% al., 1998= 3imar) e% al., 1998= &as%illa e% al., 1998=
&ollins, 199>+. 3uch #ro%ein-inac%iva%ing mu%a%ions are broa)ly consis%en% ,i%h a %umour-su##ressor
role $or BRCA1. In s#i%e o$ %his, soma%ic BRCA1 mu%a%ion a##ears no% %o be a #rinci#al $ea%ure o$
s#ora)ic breas% cancer (:u%real e% al., 1998+, ,hich migh% in)ica%e a s#eci$ic )evelo#men%al role $or %he
38
gene. he si<e an) com#le4i%y o$ BRCA1 may, ho,ever, be a con$oun)ing $ac%or in %hese analyses= an
al%erna%ive e4#lana%ion is %ha% %he BRCA1 #ro%ein may be ina##ro#ria%ely e4#resse) in %umours (see
Boy), 1995+. *$$or%s are curren%ly un)er,ay %o clari$y %hese #ossibili%ies (e.g. Fin<ler an) Vogels%ein,
199>= 3%eeg, 199>+.
*arly lin!age s%u)ies sugges%e) %ha% %he chromosome 17-lin!e) locus no, i)en%i$ie) as BRCA1 coul)
accoun% $or only a##ro4ima%ely hal$ o$ %he s%rongly e4#ressing heri%able breas% cancers. In accor) ,i%h
%his, a secon) gene BRCA2 has been ma##e) %o chromosome 129 12712 (Eoos%er e% al., 1998+ an) has
recen%ly been clone) (Eoos%er e% al., 1995+. Mu%a%ions in %he BRCA2 gene accoun% $or a##ro4ima%ely
one-%hir) o$ high-ris! $amilies. :unc%ionally, %he %,o !no,n BRCA genes may be )i$$eren% since, ,hile
mu%a%ion %o ei%her gene gives a similarly high ris! o$ breas% cancer, BRCA1 )e$ec%s are associa%e) ,i%h
a much higher ris! o$ ovarian )isease an) BRCA2, unli!e BRCA1, can e4#ress as breas% cancer in
males. :rien) (199>+ has summarise) recen% $in)ings in BRCA2 !in)re) ,hich con$irm %he rela%ively
high ris! o$ male breas% cancer an) %ha% o$ very early onse% )isease in some $emale carriers. hese
s%u)ies )o #rovi)e, ho,ever, evi)ence o$ %he variable #ene%rance o$ a single BRCA2 mu%a%ion in
Icelan)ic #o#ula%ions highligh%ing %he im#or%ance o$ gene%ic7gene%ic an) gene%ic7environmen%al
$ac%ors in %he e4#ression o$ heri%able cancer. he lin!age s%u)y o$ Eoos%er e% al. (1998+ also sho,s %ha%
mu%a%ion o$ BRCA1 or BRCA2 canno% accoun% $or all cases o$ heri%able breas% cancer. oge%her %hey
may e4#lain no more %han 55 o$ %o%al breas% cancer a% all ages in Ees%ern #o#ula%ions bu% amongs% %he
remain)er %here a##ear %o be $amilial cases %ha% may involve genes o$ lo,er #ene%rance. In %he case o$
BRCA1 su$$icien% breas% cancer cases are no, )e$ine) a% %he molecular level %o allo, commen% u#on
%he range o$ mu%a%ions in %he #o#ula%ion an) %heir li!ely con%ribu%ion %o #o#ula%ion ris! (see &ollins,
199> an) 3ec%ion >+. An im#or%an% $in)ing is %ha% a single mu%a%ion (185 )elA"+ #ro#aga%e) by
common )escen% ($oun)er e$$ec%+ con%ribu%es %o %he high BRCA1 con%ribu%ion o$ aroun) 285 o$ cases
?2; years in De,ish ,omen o$ Ash!ena<i origins. By con%ras%, %he %o%al BRCA1 con%ribu%ion %o breas%
cancer a% ?2; years in non-De,ish ,omen ,as aroun) 75. C$ e9ual im#or%ance ,as %he $in)ing o$
BRCA1 germ line mu%a%ions in cases ,i%hou% s%ri!ing $amily his%ories o$ breas% or o%her cancers.
here is gro,ing evi)ence %ha% %here can be varia%ion o$ ris! o$ breas% an) ovarian cancer ,i%h )i$$eren%
germ line mu%a%ions o$ BRCA1 an) BRCA2 bu% %ha% alleles o$ BRCA1 %ha% are common in %he
#o#ula%ion )o no% have obvious im#lica%ions $or ris! ("ay%her e% al., 1997= .unning e% al., 1997+.
Ei%h regar) %o %he s#eci$ic $unc%ions o$ breas% cancer-#re)is#osing genes evi)ence is no, emerging
%ha% BRCA1 an) BRCA2 #ro%eins may #lay a role in ./A me%abolism an) )amage res#onse. In %he case
o$ BRCA1 #ro%ein, bin)ing %o asyna#se) regions o$ meio%ic chromosomes has been )emons%ra%e)
(3cully e% al., 1997+ an) in%erac%ion ,i%h RA#51 seems li!ely. *9ually, s%u)ies ,i%h gene%ically
mani#ula%e) mice (3haran e% al., 1997+ sugges% %ha% BRCA2 #ro%ein may be a co-$ac%or in RA#51-
)e#en)en% re#air o$ ./A )ouble s%ran) brea!s %hereby ac%ing as a co-)e%erminan% o$ cellular
ra)iosensi%ivi%y.
In 3ec%ion 5 %he con%en%ion %ha% he%ero<ygous carriers o$ %he mu%a%ions associa%e) ,i%h %he 119-lin!e)
ra)iosensi%ive )isor)er, a%a4ia-%elangiec%asia (A-+ have an increase) ris! o$ s#on%aneous breas% cancer
is )iscusse) (see *as%on, 1998+. As sho,n in 3ec%ion >, such A- he%ero<ygo%es may be rela%ively
common in %he #o#ula%ion, having an es%ima%e) $re9uency o$ aroun) 1 in 2;;.
'ecen% )a%a regar)ing breas% cancer ris! in A- he%ero<ygo%es, i.e A)*
K0L
a##ear %o be more e9uivocal
%han %he earlier e#i)emiological s%u)ies revie,e) by *as%on (see Bisho# an) 6o##er, 1997= also
3ec%ion 5+. Ehile in a s%u)y o$ A- he%ero<ygous $emales ascer%aine) by molecular me%ho)s, A%hma e%
39
al. (199>+ es%ima%e) %ha% %he rela%ive ris! o$ breas% cancer ,as 2.8, :i%<geral) e% al. (1997+ $oun) no
evi)ence o$ such increase) ris! ,hen com#aring germ line A)* mu%a%ion inci)ence in 8;2 breas%
cancer cases )iagnose) be$ore age 8; years ,i%h %ha% o$ 2;2 con%rols. As no%e) by Bisho# an) 6o##er,
%hese %,o )a%a se%s are no% incom#a%ible an) $ur%her large-scale s%u)ies are re9uire) %o resolve %he issue.
:inally, a rela%ively high $re9uency o$ breas% cancer genes o$ lo, #ene%rance may accoun% $or %he
observa%ions o$ 3co%% e% al. (1998+. hese )a%a sho, %ha% aroun) 8;5 o$ unselec%e) breas% cancer
#a%ien%s e4hibi% signi$ican%ly eleva%e) chromosomal ra)iosensi%ivi%y in lym#hocy%es (3ec%ion 2+. A
gene%ic basis $or %his #heno%y#ic associa%ion has ye% %o be es%ablishe) bu% i% is alrea)y evi)en% %ha% such
ra)iosensi%ive #heno%y#es are #resen% in %he #o#ula%ion a% a $re9uency %ha% is %oo high %o be e4#laine)
by a combina%ion o$ BRCA1, BRCA2, an) A)*
K0L
geno%y#es. Al%hough %here is no )irec% in$orma%ion on
%he na%ure o$ lo, #ene%rance breas% cancer genes, 3!olnic! e% al. (199;+ have sho,n %ha% gene%ic
)e%erminan%s o$ neo#lasia-associa%e) #roli$era%ive breas% )isease may be rela%ively common in %he
#o#ula%ion. I% ,as sugges%e) %ha% %hese un)erlie a grea%er #ro#or%ion o$ breas% cancer a% all ages %han %he
more #ene%ran% genes no, i)en%i$ie) as BRCA1 an) BRCA2.
,!-!"! /eritable colon cancer
&linical, gene%ic, an) labora%ory s%u)ies in res#ec% o$ human susce#%ibili%y %o colon cancer have been
revie,e) ('us%gi, 1998= Bo)mer e% al., 1998+.
:amilial a)enoma%ous #oly#osis (:AP+ ,as %he $irs% gene%ic )isor)er %o be associa%e) ,i%h
#re)is#osi%ion %o in%es%inal %umours. he :AP )isor)er, ,hich has a #revalence o$ be%,een 1 in 5;;;
an) 1 in 1;,;;;, is #rinci#ally charac%erise) by %he )evelo#men% o$ u# %o %housan)s o$ neo#las%ic
a)enoma%ous #oly#s %hroughou% %he large in%es%ine. A##ro4ima%ely 8;5 o$ :AP #a%ien%s )evelo# early
onse% colorec%al cancer bu% neo#lasms a% o%her gas%roin%es%inal si%es are no% uncommon ('us%gi, 1998+.
A single locus res#onsible $or :AP ,as ma##e) %o chromosome 5921 an) subse9uen%ly clone) an)
charac%erise) as %he APC gene (Fin<ler e% al., 1991= /ishisho e% al., 1991+. APC sho,s %he #rimary
charac%eris%ics o$ a %umour su##ressor gene an) i%s $unc%ion ha) been lin!e) ,i%h %hose o$ ca%enin
#ro%eins ,i%h a #u%a%ive role in cellular cy%os!ele%on $unc%ion an) cell a)hesion (3u e% al., 1992+. More
recen%ly APC #ro%ein $unc%ion has been lin!e) ,i%h -ca%enin )egra)a%ion an) %ranscri#%ional con%rol o$
cellular #roli$era%ion (see /a!amura 1997+.
"ar)nerIs an) urco%Is syn)romes share some o$ %he clinical $ea%ures o$ :AP bu% have been regar)e) as
being clinically )is%inc%. here is, ho,ever, evi)ence %ha% %hese )isor)ers are rare gene%ic varian%s o$
:AP. he rare con)i%ions, Peu%<7DegherIs syn)rome, -uvenile #oly#osis, &o,)ens )isease an) Muir7
orre syn)rome, are #oorly un)ers%oo) gene%ic )isor)ers associa%e) ,i%h some )egree o$ #re)is#osi%ion
%o in%es%inal neo#lasia ('us%gi, 1998+.
6ere)i%ary non-#oly#osis colon cancer (6/P&&+ ,as originally sugges%e) %o have a $re9uency o$
aroun) 1 in 2;; %o 1 in 5;; in Ees%ern #o#ula%ions an) ,as claime) %o accoun% $or u# %o 155 o$ colon
cancers (1ynch e% al., 1992+. As such, i% is by $ar %he s%ronges% gene%ic )e%erminan% o$ such neo#lasms
(1ynch e% al., 1992+. 3uch es%ima%es remain, ho,ever, highly con%roversial an) )e#en) cri%ically on %he
cri%eria use) $or clinical an) $amilial ascer%ainmen%. he #revailing vie, is %ha% 6/P&& is subs%an%ially
less common %han originally believe) (:ishel an) Folo)ner, 1995= 1iu e% al., 1995+. Cn %he basis o$ %he
assum#%ion %ha% 6/P&& con%ribu%es only aroun) 25 o$ colon cancer an) has a #ene%rance o$ aroun)
>;5, using a li$e%ime cumula%ive colon cancer ra%e o$ 25 $or a A3A #o#ula%ion (Par!in e% al., 1992+ i%
40
may be #rovisionally es%ima%e) %ha% aroun) 1 in 2;;; in)ivi)uals carry %he gene%ic )e%erminan%s o$
6/P&&.
6/P&&, unli!e %he colon cancer #re)is#osing )isor)ers )e%ermine) by APC mu%a%ion, )oes no% involve
%he ,i)es#rea) )evelo#men% o$ mul%i#le colonic #oly#s. 6/P&& #oly#s are $e, an) largely con$ine)
%o %he #ro4imal colon, ,i%hin ,hich early onse% an) #oorly )i$$eren%ia%e) colon cancers subse9uen%ly
)evelo#. 3ome 6/P&& #a%ien%s also )evelo# neo#lasia a% o%her si%es, #rinci#ally %he en)ome%rium,
s%omach an) #ancreas, %he #ene%rance o$ mu%a%ions in 6/P&& !in)re) is lo,er %han %ha% o$ :AP an)
%en)s %o be some,ha% variable (1ynch e% al., 1992= 'us%gi, 1998+. 1i!e heri%able breas% cancer, 6/P&&
has been sub-ec% %o in%ense molecular gene%ic inves%iga%ion over %he las% $e, years an) evi)ence $or %he
s#eci$ic involvemen% o$ mu%an% ./A misma%ch re#air genes in %his )isor)er an) %he ensuing genomic
ins%abili%y o$ colonic %umours has alrea)y been )iscusse) (3ec%ion 2.2+.
,!-!,! /eritable renal cancer
he 2#2> gene, !53, o$ %he von 6i##el71in)au )isor)er is #rinci#ally res#onsible $or early-onse%
$amilial !i)ney cancer an), less $re9uen%ly, hemangioblas%oma an) #haeochromocy%oma (see "narra e%
al., 1998+. &harac%erisa%ion o$ %he germ line mu%a%ions involve), an) o$ loss o$ %he normal allele in %he
renal cancers o$ !53 #a%ien%s, is s%rongly sugges%ive o$ %umour su##ressor $unc%ions. his is also
consis%en% ,i%h %he $in)ing %ha% aroun) >55 o$ s#ora)ic renal %umours harbour soma%ic !53 mu%a%ions
("narra e% al., 1998+. 'ecen% s%u)ies #oin% %o,ar)s a role $or %he !53 gene in %he regula%ion o$
%ranscri#%ional elonga%ion (.uan e% al., 1995+.
Ehile !53 is clearly a cri%ical gene $or renal carcinogenesis, a secon) locus res#onsible $or here)i%ary
#a#illiary renal cell carcinoma has also been i)en%i$ie) (Gbar e% al., 1998= 3chmi)% e% al., 1997+. In
a))i%ion %o !53-)e%ermine) a)ul% !i)ney cancer, an embryonal !i)ney %umour (EilmsI %umour+ can
arise, o$%en bila%erally, in a clinically com#le4 chromosome 11# )isor)er %erme) EilmsI aniri)ia,
geni%ourinary mal$orma%ion an) men%al re%ar)a%ion (EA"'+ (6ousman e% al., 198>+. Ehile an 11#12
%umour su##ressor gene ;)1 enco)ing a %ranscri#%ional regula%or is occasionally inac%iva%e) in EilmsI
%umour cells, %his gene is no% %he sole )e%erminan% o$ EA"'. Mu%a%ion o$ ;)1 is seen in %he .enys7
.rash syn)rome ,hich is associa%e) ,i%h urogeni%al abnormali%ies an) !i)ney %umour susce#%ibili%y
(6as%ie, 1998+. he com#le4i%y o$ %he gene%ics o$ EilmsI %umour is $ur%her evi)ence) by %he $in)ing
%ha% a )is%inc% gene%ic en%i%y, %he Bec!,i%h7Eie)emann syn)rome (BE3+, %ha% ma#s %o 11#15,
#re)is#oses, amongs% o%hers, %o EilmsI %umour. Also e#igene%ic, #aren%-o$-origin e$$ec%s in$luence bo%h
%he e4#ression o$ BE3 an) loss o$ he%ero<ygosi%y $or ;)1 in %umours (e.g. 3%eenman e% al., 1998=
Bar%olomei, 1998= 3!use an) 1u)lo,, 1995+. Al%hough o$ grea% aca)emic in%eres% bo%h EA"' an)
BE3 are rare gene%ic )isor)ers an) )o no% im#ac% s%rongly on chil)hoo) !i)ney cancer inci)ence.
,!-!-! /eritable tumours of the nervous system
he %,o #rinci#al gene%ic )isor)ers #re)is#osing %o nervous sys%em %umours are neuro$ibroma%osis %y#e
1 (/:1+ an) %y#e 2 (/:2+.
/:1 or von 'ec!linghausen )isease is a rela%ively common ( 1 in 2;;;+ gene%ic )isor)er )e%ermine)
by mu%a%ion o$ a 17911 gene ,i%h %umour su##ressor $unc%ions (3!use e% al., 1989+. he :91 gene
#ro)uc%, neuro$ibromin, is believe) %o be a "Pase-ac%iva%ing #ro%ein ,hich may $unc%ion in cellular
signal %rans)uc%ion #a%h,ays. he #rinci#al neurological sys%em %umours in :91 #a%ien%s are
neuro$ibromas ('iccar)i an) *ichner, 198>+ bu% as no%e) in 3ec%ion 8 %here is also evi)ence $or
#re)is#osi%ion %o -uvenile myeloi) leu!aemia.
41
/:2 is less common %han /:1 an) #re)is#oses %o %umours o$ %he ves%ibular branch o$ %he 8%h cranial
nerve (sch,annomas+, meningiomas an) #eri#heral neuro$ibromas (Eer%elec!i e% al., 1988+. he :92
gene ma#s %o 22912 an) sho,s %he #rimary $ea%ures o$ a %umour su##ressor gene. I%s gene #ro)uc%,
%erme) merlin, has been #ro#ose) %o ac% %o lin! elemen%s o$ %he cell membrane ,i%h %hose o$ %he
cy%os!ele%on (ro$a%%er e% al., 1992+.
he %hir) gene%ic en%i%y %o be brie$ly consi)ere) here is /evoi) basal cell carcinoma syn)rome
(/B&&3+. he #re)is#osing gene (P)C+ has recen%ly been clone) (see 3ec%ion 2.8.>+. Ehile mul%i#le
basal cell carcinoma is %he #rinci#al neo#lasm in /B&&3 a signi$ican% number o$ #a%ien%s )evelo#
me)ulloblas%oma (Bale e% al., 1998+. Pre)is#osi%ion %o cen%ral nervous sys%em %umours, albei% no% as %he
#re)ominan% neo#las%ic mani$es%a%ion, has also been associa%e) ,i%h %he 1i7:raumeni syn)rome,
%uberous sclerosis, $amilial #oly#osis an) von 6i##el71in)au )isease (see Bon)y e% al., 1992+.
,!-!.! /eritable prostate and testicular cancer
Pros%a%e cancer is increasingly recognise) as a common neo#lasm in Ees%ern #o#ula%ions. &urren%
es%ima%es sugges% %ha% 571;5 o$ all #ros%a%e cancer, an) aroun) 8;5 o$ %he early onse% varie%y in males
?55 years, is inheri%e) in a Men)elian $ashion (&ar%er e% al., 1992+. An associa%ion be%,een $amilial
#ros%a%e an) breas% cancer is su##or%e) by %he $in)ing o$ e4cess early #ros%a%e cancer in %he male
rela%ives o$ ,omen ,i%h BRCA1 mu%a%ions. I% is clear, ho,ever, %ha% BRCA1 is no% %he #rinci#al gene%ic
)e%erminan% o$ #ros%a%e cancer. C%her can)i)a%e genes $or #ros%a%e cancer #re)is#osi%ion have been
)iscusse) by &annon-Albrigh% an) *eles (1995+ an), more recen%ly %hrough %he analysis o$ high-ris!
$amilies, a ma-or )ominan%ly e4#ressing susce#%ibili%y locus, 5PC1, has been ma##e) %o chromosome
1 (1928725+. 3#eci$ic can)i)a%e genes $rom %his region have ye% %o be re#or%e) on bu% i% has been
es%ima%e) %ha% 5PC1 may accoun% $or a signi$ican% $rac%ion o$ here)i%ary #ros%a%e cancer an) %ha%
mu%an% alleles are carrie) by u# %o 1 in 5;; in)ivi)uals in %he A3A (3mi%h e% al., 199>+. A heri%able
com#onen% %o %es%icular cancer is also su##or%e) by %,in an) $amily s%u)ies (:orman e% al., 1992+ bu%,
as ye%, %he un)erlying gene%ics remains obscure.
,!-!1! /eritable s)in cancer
he clinical an) gene%ic as#ec%s o$ heri%able s!in %umours have recen%ly been revie,e) by 6auc! an)
Man)ers (1998+ an) *#s%ein (199>+. An I&'P as! "rou# has re#or%e) in Publication 5< u#on some o$
%he im#lica%ions $or ra)iological #ro%ec%ion (I&'P, 1991+.
,o o$ %he mos% im#or%an% gene%ic )e%erminan%s o$ heri%able s!in cancer, namely s!in #igmen%a%ion
geno%y#es (e.g. albinism+ an) ./A #ho%o#ro)uc% re#air )isor)ers (e.g. 4ero)erma #igmen%osum+, ,hile
having clear im#lica%ions $or #ho%o-carcinogenesis, are o$ less )irec% relevance %o ionising ra)ia%ion
e4#osures. 6auc! an) Man)ers (1998+ an) *#s%ein (199>+ have also no%e) %ha% e4cess s!in %umours
may be associa%e) ,i%h a range o$ gene%ic )isor)ers, inclu)ing &o,)enIs )isease, "ar)nerIs syn)rome,
neuro$ibroma%osis, %uberous sclerosis, an) $amilial cylin)roma%osis. 6ere ,e $ocus on %,o o%her
)isor)ers, $amilial melanoma an) nevoi) basal cell carcinoma syn)rome (/B&&3+, %he la%%er being o$
#ar%icular relevance %o subse9uen% -u)gemen%s on %he )egree o$ ra)iosensi%ivi%y %ha% may accom#any
gene%ic #re)is#osi%ion %o cancer (see 3ec%ion 5+.
:amilial melanoma is an au%osomal )ominan%, bu% gene%ically he%ero<ygous, )isease ,hich may
accoun% $or 571;5 o$ all cases arising in %he #o#ula%ion (Eain,righ%, 1998+. Pene%rance o$ %he )isease
is largely incom#le%e an) %he e4#ression is highly variable. ,o #rinci#al loci, enco)e) on chromosome
9# (*3*1+ an) 1# (*3*2+, have been associa%e) ,i%h $amilial melanoma an) mos% a%%en%ion has been
42
given %o %he i)en%i$ica%ion o$ %he *3*1 gene, ,hich may accoun% $or 5;5 o$ $amilial cases. Al%hough
con%en%ious, %here is evi)ence (Eain,righ%, 1998= 'ana)e e% al., 1995+ %ha% %he *3*1 locus may be
i)en%ical ,i%h %he p16
=:&>
gene (%he *)+1 %umour su##ressor+, %he $unc%ion o$ ,hich has alrea)y been
)iscusse) (3ec%ion 2.2.2+. :ur%her su##or% $or %his no%ion has come $rom %he $unc%ional analysis o$
mu%a%ions in %he p16 gene %ha% have been sho,n %o segrega%e ,i%h $amilial #re)is#osi%ion %o malignan%
melanoma (Parry an) Pe%ers, 199>+.
he secon) con)i%ion (consi)ere) $ur%her in 3ec%ion 5+, /B&&3, is also an au%osomal )ominan%
)isor)er ,i%h variable e4#ression bu%, unli!e $amilial melanoma, is charac%erise) by mul%i#le basal cell
carcinomas (B&&+ o$ %he s!in, me)ulloblas%oma, -a, cys%s, an) )iverse )evelo#men%al abnormali%ies
(Bale e% al., 1998= "orlin, 1995+. /B&&3 is a rare )isor)er in ,hich %here a##ears %o be a sur#risingly
high con%ribu%ion $rom )e novo mu%a%ions an) evi)ence o$ unusual #a%%erns o$ e4#ression.
"ene%ic lin!age o$ /B&&3 ,i%h a locus enco)e) in an 2cM in%erval o$ chromosome 99 22.2721 has
been es%ablishe) an) %he gene has recen%ly been i)en%i$ie) (Dohnson e% al., 199>+. Mu%a%ions have been
$oun) in %he gene in %he germline o$ /B&&3 #a%ien%s an) in cases o$ s#ora)ic B&&. he gene sho,s
se9uence homology %o %he #rosophila ($rui% $ly+ patch/ (ptc+ gene. he ptc gene enco)es a
%ransmembrane #ro%ein %ha% in #rosophila ac%s in o##osi%ion %o %he 6rinac/us (he)gehog+ signalling
#ro%ein, con%rolling cell $a%es, #a%%erning, an) gro,%h in numerous %issues (Dohnson e% al., 199>+. hus,
%he human P)C gene a##ears %o be crucial $or bo%h embryonic )evelo#men% an) con%rol o$ cellular
#roli$era%ion.
,!-!7! /eritable cancers of the endocrine system
6eri%able #re)is#osi%ion %o &-cell me)ullary %hyroi) carcinomas (M&+ is %he #rinci#al mani$es%a%ion
o$ %he mul%i#le en)ocrine neo#lasia syn)romes M*/2A an) M*/2B= M& is also charac%eris%ic o$ a
%hir) gene%ic en%i%y, $amilial M& (:M&+. 6o,ever, ,hereas M*/2A an) M*/2B share an
a))i%ional #re)is#osi%ion %o a)renal #haeochromocy%oma, M*/2A, bu% no% 2B, is associa%e) ,i%h
#ara%hyroi) hy#er#lasia, an) in M*/2B %here are accom#anying )evelo#men%al abnormali%ies. In
con%ras%, M& is %he sole mani$es%a%ion o$ )isease in :M& (3chim!e, 1988+. In s#i%e o$ %his clinical
com#le4i%y M*/2A, M*/2B, an) :M& all ma# %o a s#eci$ic region o$ chromosome 1;911.2
("ar)ner e% al., 1992+. 'ecen% s%u)ies have cas% ligh% on %he gene%ic basis o$ %hese )iseases an) sho,
%ha% a high #ro#or%ion o$ M*/2A an) 2B #a%ien%s carry germ line R6) #ro%o-oncogene mu%a%ions an)
%ha% %here is a s%rong correla%ion be%,een %he #heno%y#ic e4#ression o$ )isease an) %he na%ure an)
)is%ribu%ion o$ R6) mu%a%ion. '* mu%a%ions have also been $oun) in some cases o$ :M& (3asa!i,
199>+.
R6) mu%a%ions analyse) in M*/2A an) :M& #a%ien%s ,ere $oun) %o be #oin% mu%a%ions in one o$ $ive
cys%eines o$ %he e4%racellular )omain. Mu%a%ions a% cys%eine >28 are %he mos% common an) have been
$oun) in 875 o$ M*/2 cases. he )e novo mu%a%ions sho, a s%rong bias %o,ar)s %he #a%ernal allele.
.ele%ion mu%a%ions o$ %he ,hole gene cause 6irschs#rung )isease, an au%osomal recessive )isease o$
%he en%eric nervous sys%em. Cverall, germ line R6) mu%a%ion #rovi)es an e4cellen% e4am#le o$ ho,
sub%le )i$$erences in s#eci$ic gene mu%a%ion can have #ro$oun) e$$ec%s on %he %issue s#eci$ici%y o$
ensuing )isease (see also 'omeo an) McFusic!, 1998+.
,!-!2! Genes associated 3ith cancer at multiple sites
he %umour susce#%ibili%y loci so $ar consi)ere) e4hibi% a subs%an%ial )egree o$ %issue s#eci$ici%y
sugges%ive o$ )i$$eren% ra%e-limi%ing %umorigenic #rocesses in )i$$eren% organ %y#es. here are, ho,ever,
43
many e4ce#%ions %o %his %issue s#eci$ici%y, e.g. %he e4cess o$ me)ulloblas%oma in /B&&3, -uvenile AM1
in :91 an) #ros%a%e cancer in BRCA1 !in)re). here is an e4#ec%a%ion, %here$ore, %ha% in cer%ain gene%ic
)isor)ers %umour #re)is#osi%ion ,ill e4#ress as %umours a% mul%i#le si%es in )evelo#men%ally unrela%e)
%issues. he mos% ,ell charac%erise) o$ %hese are %he 1i7:raumeni syn)rome an) %uberous sclerosis, bu%
accumula%ing )a%a sho, %ha% re%inoblas%oma also $alls in%o %his ca%egory.
1i7:raumeni syn)rome (1:3+, al%hough gene%ically he%erogenous, is, in a #ro#or%ion o$ #a%ien%s,
associa%e) ,i%h mu%a%ion %o %he ,ell charac%erise) an) soma%ically ubi9ui%ous 17912-enco)e) p53
%umour su##ressor gene (Mal!in e% al., 199;= Birch e% al., 1998+. A broa) range o$ %umours are $oun) in
e4cess in 1:3 !in)re). /eo#las%ic e4#ression in 1:3 is, ho,ever, #ar%icularly evi)en% as so$% %issue an)
bone sarcomas, breas%, brain, an) a)renocor%ical carcinomas, %oge%her ,i%h lym#hocy%ic an) myeloi)
leu!aemia. &ancer ris! in 1:3 is high@ 5;5 by age 2; an) 9;5 by age 7; bu%, $or%una%ely, i% is a
rare con)i%ion ,i%h an inci)ence %ha% a##ears %o be less %han 1 in 5;,;;;. he $unc%ional as#ec%s o$ p53
mu%a%ion relevan% %o carcinogenesis have alrea)y been )iscusse) (3ec%ion 2.2.2 an) 2.2.2+ bu% %he o%her
gene%ic )e%erminan%s o$ 1:3 remain obscure. umorigenic ra)iosensi%ivi%y in p53-)e$icien% geno%y#es
is )iscusse) in 3ec%ion 5.
uberous sclerosis (3&+ is a gene%ic con)i%ion charac%erise) by neo#las%ic lesions, %erme)
hamar%omas, #rinci#ally o$ s!in, nervous %issue, hear%, an) !i)ney, e.g. as%rocy%omas, renal
angiomyoli#omas, an) car)iac rhab)omyomas ("ome<, 1991+. In some res#ec%s &3 resembles /:1,
bu% %en)s %o be some,ha% less %issue s#eci$ic. he #revalence o$ %he )isease is es%ima%e) %o be aroun) 1
in 1;,;;; ,i%h a high #ro#or%ion o$ cases re#resen%ing )e novo mu%a%ion. 6e%erogenei%y in &3 is
evi)en%, no% only in %erms o$ neo#las%ic )evelo#men% bu% also in res#ec% o$ neurological mani$es%a%ions
("ome<, 1991+. "ene%ic he%erogenei%y in 3& has also been reveale) by %he i)en%i$ica%ion o$ %,o
#rinci#al unlin!e) 3& loci, enco)e) on chromosome 9928 ()+C1+ an) 1>#12 ()+C2+. 1oss o$
he%ero<ygosi%y $or %he 1>#12 locus in %he %umours o$ )+C2 #a%ien%s is s%rongly sugges%ive o$ a %umour
su##ressor role ("reen e% al., 1998+ bu% %he s#eci$ic $unc%ion o$ %he gene remains %o be resolve).
'a)ia%ion res#onse in )sc2-)e$icien% ra%s is )iscusse) in 3ec%ion 5.
'e%inoblas%oma is an ocular embryonic %umour o$ chil)ren, aroun) 8;5 o$ ,hich is bila%eral or
mul%i$ocal an) re#resen%s %he heri%able $orm o$ %he )isease (Fnu)son, 1971+. he inci)ence o$ heri%able
re%inoblas%oma ('B+ is es%ima%e) %o be 1 in 25,;;; %o 1 in 5;,;;; an) only a minori%y o$ 'B #a%ien%s
$ail %o )evelo# re%inal neo#lasia.
Increasing survival ra%es in 'B #a%ien%s have allo,e) long-%erm $ollo,-u# s%u)ies %o be con)uc%e) an)
%hese sho, %ha% a% la%er ages %he increase) mor%ali%y ra%e in 'B is associa%e) ,i%h e4cess bone an) so$%
%issue sarcomas, %umours o$ %he brain an) meninges an) melanoma. Benign %umours are also seen in
e4cess in %hese #a%ien%s (see *ng e% al., 1992+. In a))i%ion %here is also in$orma%ion, albei% limi%e), in
res#ec% o$ ra)io%hera#y rela%e) secon) %umours in 'B= %hese ,ill be )iscusse) in 3ec%ion 5 o$ %he re#or%.
.isease mani$es%a%ion in 'B an) %he gene%ics o$ %he )isor)er #rovi)e) %he basis o$ %he %,o-hi%
hy#o%hesis o$ Fnu)son (Fnu)son, 1971= see also 3ec%ion 5+. Pre)ic%ably, %he res#onsible gene, RB1,
,as %he $irs% %umour su##ressor gene %o be isola%e) an) charac%erise).
An im#or%an% message %ha% emerges $rom 'B s%u)ies is %ha% ,hile cancer #re)is#osi%ion associa%e) ,i%h
a given germ line lesion migh% a% $irs% sigh% be regar)e) as having a high )egree o$ %issue s#eci$ici%y,
in%ensive s%u)y an) long-%erm $ollo,-u# o$ #a%ien%s may o$%en reveal more ,i)es#rea) an) age-rela%e)
e$$ec%s.
44
:inally, a large case con%rol s%u)y cou#le) ,i%h me%a-analysis o$ 22 smaller inves%iga%ions has #rovi)e)
some evi)ence %ha% %here is an associa%ion o$ uncommon germ line 5RA+1 minisa%elli%e alleles ,i%h
cancer a% mul%i#le si%es (Fron%iris e% al., 1992+. In %he &aucasian #o#ula%ion 985 carry combina%ions o$
$our common alleles ,hile %he remain)er (>5+ have rare )eriva%ive alleles. he )a%a #resen%e) sugges%
%ha% %he rela%ive ris! o$ cancer in carriers o$ one uncommon allele ,as 1.85 ,hile %ha% $or homo<ygo%es
$or %hese alleles ,as 8.>2. Al%hough %hese rela%ive ris!s are mo)es% an) ,oul) no% reveal as $amilial
cancer, $rom %he #revalence o$ uncommon alleles i% ,as #re)ic%e) %ha% #erha#s 1 in 11 cancers o$ %he
breas%, colon, an) bla))er migh% be a%%ribu%able %o 5RA+1 allelic varia%ion. Fron%iris e% al. (1992+
)iscuss a #ossible mechanism o$ %ranscri#%ional )ysregula%ion involving %he 5RA+1 minisa%elli%e ,hich
,oul) im#ly %ha% %he se9uence migh% ac% as a lo, #ene%rance mo)i$ier o$ ris!. Al%hough some su##or%
$or %his no%ion has come $rom s%u)ies o$ 5RA+1 alleles an) ovarian cancer ris! in BRCA1 carriers
(Phelan e% al., 199>+ %he %rue im#ac% regar)ing cancer in %he ,hole #o#ula%ion remains some,ha%
con%roversial.
,!.! &he ori%in of mutations in tumour'associated %enes
here is a ra#i)ly e4#an)ing li%era%ure on %he $re9uency o$ soma%ic an)0or germline mu%a%ions in
s#ora)ic an)0or $amilial cancers. Analyses o$ soma%ic mu%a%ions have reveale) %ha% #re)ic%e)
environmen%al e4#osures resul% in %he corres#on)ing %y#es o$ mu%a%ion, un)erscoring %he cri%icali%y o$
environmen%al in$luences. :ur%hermore, #aren%al origin o$ %he mu%a%ions in cer%ain malignancies is
sugges%ive o$ e#igene%ic e$$ec%s )ue %o some $orm o$ genomic im#rin%ing. :inally, mu%a%ional
mosaicism may #lay an im#or%an% role in %he )evelo#men% o$ cer%ain malignancies. hese issues are
brie$ly )iscusse) belo,.
,!.!1! Germline mutations of tumour'suppressor %enes
able 2.5 illus%ra%es re#resen%a%ive mu%a%ions o$ a number o$ germ line %umour su##ressor genes.
*4ce#% $or %he p53 an) R6) genes, $rameshi$% mu%a%ions by )ele%ion or inser%ion, or nonsense mu%a%ions
resul%ing in #rema%ure %ermina%ion o$ %ransla%ion, #re)omina%e. In con%ras%, mu%a%ions in p53 an) R6)
genes are mainly o$ %he missense %y#e, resul%ing in %he subs%i%u%ion o$ amino aci)s. hese )i$$erences in
%he mu%a%ion s#ec%ra #robably re$lec% #heno%y#ic selec%ion o$ %hose mu%a%ions %ha% #rovi)e $or gene-
s#eci$ic #roli$era%ive a)van%age in res#ec% o$ neo#las%ic )evelo#men% an)0or %hose %ha% are mos%
com#a%ible ,i%h cell viabili%y an) embryonic0neona%al )evelo#men%.
able 2.5. "ermline mu%a%ions in some %umour-su##ressor genes
45
In %he germinal mu%a%ions o$ %he base subs%i%u%ion %y#e, "@&NA@ %ransi%ion #re)omina%es. Moreover,
more %han 5;5 o$ "@&NA@ %ransi%ions are $oun) a% &#" si%es, in)ica%ing s#on%aneous )eamina%ion o$
5-me%hyl cy%osine resi)ues (
5m%
&+, resul%ing in %hymine. his is sur#rising given %ha% less %han 15 o$ %he
bases o$ human ./A are
5m%
& (Bir), 1978+, an) %ha% cells have a shor% #a%ch re#air #rocess $or "@
misma%ches (1oeb, 1998+. Cnly 2755 o$ %he cy%osine resi)ues are me%hyla%e) an) more %han 9;5 o$
%he
5m%
& are $oun) in %he
5m%
&#" )inucleo%i)es. his im#lies a high s#on%aneous mu%a%ion ra%e a%
5m%
&#"
si%es resul%ing $rom cy%osine )eamina%ion.
he $re9uency o$ loss-o$-$unc%ion mu%a%ions by )ele%ions an) inser%ions is rela%ively high com#are) %o
%ha% seen in soma%ic mu%a%ions. Micro)ele%ions o$ one or a $e, base #airs #re)ominan%ly occur in runs
o$ single base-#air re#ea%s. Mos% o$ %he )ele%ions o$ longer s%re%ches o$ base #airs are charac%erise) by
%he #resence o$ )irec% shor% re#ea%s a% %he -unc%ions (&anning an) .ry-a, 1989+, an) sli##age or
misalignmen% )uring ./A re#lica%ion is a li!ely mechanism $or %heir genera%ion. hese )a%a im#ly %ha%
%he ma-ori%y o$ germ line mu%a%ions in %umour-associa%e) genes arise via en)ogenous me%abolic
#rocesses.
,!.!"! Preferential involvement of parental alleles in tumour %ene mutations
here is a gro,ing lis% o$ %he #aren%al origin $or human )e novo mu%a%ions inclu)ing chromosome
s%ruc%ural rearrangemen%s (Clson an) Magenis, 1988+. hese are summarise) in able 2.>. As seen in
%he %able, a s%rong bias e4is%s %o,ar)s a #a%ernal origin $or )e novo s%ruc%ural rearrangemen%s an)
germinal mu%a%ions, inclu)ing loss-o$-$unc%ion mu%a%ions o$ %umour su##ressor genes. he s%rong bias
%o,ar) #a%ernal origin o$ ne, germ line mu%a%ions o$ %umour su##ressor genes migh% in)ica%e
)i$$eren%ial e4#ression o$ %he gene o$ in%eres%, )e#en)ing on %he #aren%al origin o$ %he chromosome on
,hich i% is enco)e). 3uch bias migh% resul% $rom %he o#era%ion o$ a #oorly un)ers%oo) #rocess %erme)
genomic im#rin%ing, ,hereby a subse% o$ genes in %he genome is sub-ec% %o germ line me)ia%e) non-
mu%a%ional (e#igene%ic+ mo)i$ica%ion o$ e4#ression ,hich is )e#en)en% u#on ,he%her %he genes in
9ues%ion are inheri%e) $rom %he mo%her or %he $a%her (e.g. Bar%olomei, 1998+. issue-s#eci$ic im#rin%ing
o$ cer%ain genes has been )emons%ra%e), #ar%icularly in %he mouse. ./A me%hyla%ion changes resul%ing
in %he #aren%ally )e#en)en% mo)i$ica%ion o$ gene %ranscri#%ion re#resen%s one mechanism $or %he
im#osi%ion o$ %hese gene e4#ression changes.
In s#i%e o$ early in)ica%ions o$ #aren%-o$-origin e$$ec%s on %he genesis o$ re%inoblas%oma, %here is no
evi)ence $or %he %ranscri#%ional im#rin%ing o$ %he RB1 gene i%sel$. In $amilial re%inoblas%oma %he
e4#ressivi%y is no% )i$$eren% ,he%her %he mu%a%e) RB1 gene is %ransmi%%e) $rom $a%her or mo%her. :or %he
;)1 gene, ma%ernally an) #a%ernally )erive) alleles are e9ually e4#resse) in %he $oe%al !i)ney (1i%%le e%
al., 1992+. he #aren%al origin o$ mu%a%ion in %hese cases has been )e%ermine) by 1C6, ,hich sugges%s
%ha% %he re%aine) chromosome may harbour %he ini%ial germ line mu%a%ion. he #re$eren%ial re%en%ion o$
%he #aren%al allele o$ in%eres% coul) be )ue %o chromosomal )omain e$$ec%s, e.g. a re$lec%ion o$ %he loss
o$ $lan!ing chromosome regions ,hich are %ranscri#%ionally im#rin%e) (Blan9ue% e% al., 1991= Ghang e%
al., 1992+. Ano%her #ossibili%y is %ha% #aren%-o$-origin e$$ec%s are a re$lec%ion o$ %he )i$$erence in %he
number o$ cell )ivisions involve) in %he #ro)uc%ion o$ germ cells be%,een males an) $emales (.ry-a e%
al., 1989+. his hy#o%hesis ,oul) #re)ic% %ha% ol)er males migh% have more chance %o $a%her )e novo
bila%eral re%inoblas%oma #a%ien%s. 6o,ever, %he mean #a%ernal age a% %he %ime o$ bir%h o$ such bila%eral
re%inoblas%oma #a%ien%s )oes no% )i$$er $rom %hose cases o$ s#ora)ic unila%eral re%inoblas%oma an) %hose
in %he general #o#ula%ion (Ma%sunaga e% al., 199;+. he lac! o$ #a%ernal age e$$ec% sugges%s %ha% %he
#os%-meio%ic s%ages or %he $er%ilise) eggs are %he cri%ical s%age o$ mu%agenesis, an) )i$$eren%ial allelic
mu%abili%y by #aren%-o$-origin e$$ec%s remains as a #ossible e4#lana%ion.
46
he unila%eral $orm o$ chil)hoo) cancer is assume) %o arise $rom soma%ic mu%a%ions. here are some
in)ica%ions %ha% %he ini%ial soma%ic mu%a%ions o$ cer%ain %umour su##ressor genes also #re$eren%ially
occur on %he #a%ernally )erive) alleles in some %umours. In a s%u)y o$ s#ora)ic unila%eral EilmsI
%umours, 11 ou% o$ 12 %umours re%aine) %he #a%ernally )erive) co#y o$ 11#12, sugges%ing im#rin%ing o$
%he #a%ernally )erive) co#y o$ %he ;)1 gene. A similar si%ua%ion also hol)s $or rhab)omyosarcoma, an)
%he RB1 gene in s#ora)ic os%eosarcoma (see :einberg, 1992+.
Cbserva%ions on %he involvemen% o$ %he RB1 #aren% o$ origin e$$ec%s in s#ora)ic unila%eral
re%inoblas%oma are con%roversial. 1each e% al. (199;+ sho,e) a #re$eren%ial involvemen% o$ %he
#a%ernally )erive) RB1 allele ,hile o%hers sho,e) more e9ual involvemen% o$ #a%ernal an) ma%ernal
alleles in %he ini%ial loss-o$-$unc%ion mu%a%ions. 6o,ever, %hese observa%ions are base) on 1C6 o$
chromosomal region 12918. In %he soma%ic mu%a%ion cases, %he ini%ial mu%a%ion can be large )ele%ions,
,hich by %hemselves give rise %o 1C6. hus, %he re%aine) co#y o$ RB1 )oes no% necessarily re#resen%
%he chromosome segmen% ,hich harbours %he ini%ial mu%a%ion. he soma%ic role o$ me%hyla%ion-
)e#en)en% e$$ec%s in carcinogenesis has been )iscusse) recen%ly by 1i%%le an) Eain,righ% (1995+.
,!.!,! 4vidence for mutational mosaicism
Mu%a%ional mosaicism is ano%her as#ec% o$ %he na%ure o$ mu%a%ions ,hich is relevan% %o human heal%h
e$$ec%s, inclu)ing %he )evelo#men% o$ neo#lasia (A/3&*A', 1992+. 3oma%ic mosaicism has long been
!no,n $or chromosome mu%a%ions (6all, 1988+. :irm evi)ence $or %he e4is%ence o$ soma%ic or germinal
mosaicism has recen%ly been #resen%e) $or o%her gene%ic )iseases such as os%eogenesis im#er$ec%a
(Byers e% al., 1988= &ohn e% al., 199;= *),ar)s e% al., 1992+, .uchenne muscular )ys%ro#hy (.arras e%
al., 1988= Ba!!er e% al., 1989+, 6emo#hilia A (1evinson e% al., 199;= BrTc!er-Vrien)s e% al., 199;+,
re%inoblas%oma ("reger e% al., 199;+, EilmsI %umour (&hao e% al., 1992+, 1i7:raumeni syn)rome
(Fovar e% al., 1992+, an) neuro$ibroma%osis (%y#e I+ (1U<aro e% al., 1998+. Mu%a%ional mosaicism is no%
al,ays rea)ily recognisable an) %he $rac%ion o$ soma%ic cells carrying %he mu%a%ion o$ in%eres% varies
be%,een %issues an) in)ivi)uals. Accor)ingly, %he e4%en% o$ mu%a%ional mosaicism curren%ly observe)
may be a subs%an%ial un)eres%ima%e o$ %his $ea%ure, ,hich may ma!e a signi$ican% bu% ill )e$ine)
con%ribu%ion %o cancer ris!.
Mosaicism mos% li!ely arises by soma%ic mu%a%ion )uring early )evelo#men% an) subse9uen% bi-clonal
#roli$era%ion in )evelo#ing %issues. he origin o$ germ cell-me)ia%e) mosaicism is, ho,ever, a ma%%er
o$ some )eba%e. .elaye) mu%a%ion o$ %he Auerbach %y#e is )is%inc% since %he hy#o%hesise) #remu%a%ion
,oul) be e4#ec%e) %o be #rogressively mo)i$ie) over one or more genera%ions ra%her %han being )ilu%e)
by mosaicism. In %his con%e4%, &arlson an) .esnic! (1979+ have #ro#ose) %ha% some s#ora)ic
re%inoblas%oma may be e4#laine) by )elaye) mu%a%ion, i.e. $i4a%ion o$ RB1 #remu%a%ion in %he early
s%age o$ )evelo#men% giving rise %o here)i%ary bila%eral %umours an) $i4a%ion in a la%er s%age resul%ing in
unila%eral %umours ,i%h varying )egrees o$ gona)al mosaicism.
3ugges%ive evi)ence $or gona)al mosaicism )ue %o $i4a%ion o$ #remu%a%ion has been re#or%e) by "reger
e% al. (199;+. ,o sibs ,i%h bila%eral re%inoblas%oma ha) )i$$eren% in%ragenic RB1 )ele%ions ,hich
share) %he same brea!#oin%. In e4#lana%ion o$ %his, %he $a%her migh% have carrie) a #remu%a%ion an) %he
%,o %y#es o$ germ line )ele%ion have emerge) $rom %his even%, %hus resul%ing in gona)al mosaicisms. In
re%inoblas%oma #a%ien%s, abou% one-$our%h o$ cons%i%u%ional chromosome )ele%ions o$ )e novo origin
involving %he RB1 gene are recognise) as mosaics. Ehile %hese are %hough% %o arise $rom soma%ic
mu%a%ions a$%er $er%ilisa%ion, ye% again %he )ele%ions occur #re$eren%ially on #a%ernally )erive)
chromosomes (3asa!i an) 3himi<u, 1998+.
47
In summary, evi)ence is accumula%ing %ha% )is%inc% #a%%erns o$ germ line mu%a%ion may )is%inguish
)i$$eren% genes associa%e) ,i%h human #re)is#osi%ion %o cancer. In some cases %hese mu%a%ional
varia%ions ,ill in$luence %he )egree %o ,hich such genes )e%ermine cancer )evelo#men% in )i$$eren%
in)ivi)uals an) in)ee) )i$$eren% %issues. he origin, inheri%ance an) e4#ression o$ some cancer
#re)is#osing mu%a%ions may be sub-ec% %o e#igene%ic #rocesses ,hich are %erme) #aren%-o$-origin
e$$ec%s. In a))i%ion, some cancer-#re)is#ose) in)ivi)uals may be mosaics, carrying a H#a%ch,or!I o$
normal an) %umour gene-mu%a%e) cells in %heir soma%ic an) germinal %issues.
he origin, mechanisms an) im#ac% o$ #aren%-o$-origin e$$ec%s an) mosaicism in in)ivi)uals have ye% %o
be a)e9ua%ely )escribe) bu% %here is reason %o believe %ha%, in some cases, %hey ,ill be signi$ican%
)e%erminan%s o$ cancer ris!. hese #rocesses, %oge%her ,i%h mu%a%ional varia%ion an) environmen%al
$ac%ors, may serve %o mo)i$y %he #ene%rance an) e4#ressivi%y o$ a signi$ican% #ro#or%ion o$ germ line
)e%erminan%s o$ neo#lasia. hrough such com#le4 in%erac%ions normal Men)elian #a%%erns o$
inheri%ance may be obscure).
able 2.>. Paren%al origin o$ )e novo mu%a%ions
48
,!1! &he %enetic component of solid tumours
In s#i%e o$ %he $ac% %ha% gene%ic in$luences on %he )evelo#men% o$ mos% %y#es o$ soli) %umours have been
i)en%i$ie) i% remains )i$$icul% %o con$i)en%ly -u)ge an overall gene%ic con%ribu%ion. he #rinci#al source
o$ #roblems in ma!ing such a -u)gemen% is %ha% $amilial ascer%ainmen% o$ heri%able cancer is limi%e) in
i%s #o,er an) %en)s only %o clearly i)en%i$y %hose !in)re) carrying highly #ene%ran% germ line mu%a%ions
(3orensen, 1995= 6ouls%on an) Pe%o, 199>+. In illus%ra%ion o$ %his i% has been calcula%e) %ha% $or a
)ominan% cancer #re)is#osing gene ,i%h a $re9uency o$ ;.7 in %he #o#ula%ion %he rela%ive ris! o$ all
$orms o$ cancer in a chil) o$ a carrier canno% e4cee) 1.;2 (Pe%o, 198;+. In or)er %o resolve such cancer
#re)is#osi%ion i% is necessary %o consi)er o%her clinical $ac%ors such as %issue a% ris!, his%o#a%hological
%y#e an) age o$ onse%. hus, ,hile i% seems %ha% gene%ic e$$ec%s are mos% obvious $or neo#lasms o$ %he
breas% an) colon, ,here highly #ene%ran% an) s#eci$ically e4#resse) mu%a%ions may accoun% $or aroun)
2755 o$ #o#ula%ion ris!, a larger overall con%ribu%ion %o ris! a% all si%es $rom a range o$ less #ene%ran%
or less s#eci$ically e4#resse) mu%a%ions canno% be )iscoun%e). his )i$$icul% issue, an) i%s im#lica%ions
$or -u)gemen%s on gene%ic con%ribu%ions %o ra)ia%ion ris!, are )iscusse) la%er in %his re#or%. Ei%h regar)
%o $amilial cancer ,hich by )e$ini%ion ,ill largely involve germ line )e%erminan%s o$ rela%ively high
#ene%rance i% is -u)ge) %ha% #revalence in %he #o#ula%ion is li!ely %o be less %han 15 (see also 3ec%ion
>+.
,!7! (ummary
1. Mu%a%ions o$ #ro%o-oncogenes, ./A re#air genes an) %umour su##ressor genes con%ribu%e %o
neo#las%ic )evelo#men%. 1oss o$ $unc%ion o$ %umour su##ressor genes %hrough mu%a%ion or )ele%ion is
%he #re)ominan% even% in %he genesis o$ soli) %umours.
2. Pro%o-oncogene an) %umour su##ressor gene #ro)uc%s are cen%ral %o regula%ion o$ cell7cell
communica%ion an) )i$$eren%ia%ion, signal %rans)uc%ion an) %ranscri#%ion. hese #rocesses con%ribu%e
signi$ican%ly %o cell survival, cell )ea%h an) con%rol o$ %he cell cycle.
2. 'are $amilial gene%ic )e%erminan%s o$ neo#lasia in mos% human %issues have been i)en%i$ie) an) in
some cases isola%e) an) charac%erise). Mos% o$ %hese )e%erminan%s are mu%a%ions %o %umour su##ressor
genes= some involve ./A re#air genes bu% $e, involve #ro%o-oncogenes. Many such mu%a%ions are
e4#ec%e) %o im#ac% on %he regula%ion o$ #roli$era%ion an) on %he 9uali%y o$ ./A re#lica%ion an) re#air.
8. Mu%an% genes #re)is#osing %o breas% an) colon cancer have receive) grea%es% a%%en%ion because %hey
a##ear %o be more common %han o%her ca%egories.
5. here is much in$orma%ion accumula%ing on %he s#eci$ic na%ure o$ germ line ./A se9uence
mu%a%ions in cancer #re)is#osing genes= mos% are ./A base #air changes or in%ragenic )ele%ions.
>. Pre)is#osing germ line mu%a%ions e4#ressing as $amilial cancer are -u)ge) %o con%ribu%e no more %han
55 o$ all soli) cancers. here is insu$$icien% evi)ence %o -u)ge %he con%ribu%ion $rom mu%a%ions o$ lo,er
#ene%rance %ha% )o no% e4#ress as $amilial cancer.
7. Poorly un)ers%oo) e#igene%ic #rocesses can im#ac% on %he e4#ression o$ %umour-associa%e)
mu%a%ions= %here is also evi)ence %ha% mosaicism $or cancer-#re)is#osing mu%a%ions can occur. he %rue
e4%en% o$ %he in$luence o$ %hese #rocesses on cancer in %he #o#ula%ion canno% ho,ever be -u)ge).
49
-! Mechanisms and %enetics of lympho'haemopoietic neoplasia
:rom ae%iological an) clinical vie,#oin%s, neo#lasia o$ %he lym#ho-haemo#oie%ic sys%em )i$$ers
subs%an%ially $rom %ha% o$ o%her organs o$ %he bo)y. :or %hese reasons, %he leu!aemias an) lym#homas
%ha% com#rise %his ca%egory o$ neo#lasms have been %ra)i%ionally regar)e) in clinical, e#i)emiological
an) labora%ory s%u)ies as a #ar%icularly )is%inc% grou# o$ malignancies.
In %his sec%ion o$ %he re#or%, %he cellular an) molecular mechanisms un)erlying %he )evelo#men% o$
lym#ho-haemo#oie%ic neo#lasia are ou%line) $ollo,ing ,hich %he )a%a rela%ing %o gene%ic susce#%ibili%y
%o %hese malignancies is a))resse). In %hese res#ec%s, #oin%s o$ con%ras% are ma)e be%,een %he
mechanisms an) gene%ics o$ lym#ho-haemo#oie%ic neo#lasia an) %hose o$ soli) %umours.
In %he conclu)ing #aragra#hs, a general vie, o$ %he li!ely e4%en% o$ %he gene%ic com#onen% o$ human
lym#ho-haemo#oie%ic neo#lasia is #rovi)e) in or)er %o es%ablish a basis $or -u)gemen%s on %he
con%ribu%ion o$ gene%ic $ac%ors %o %he ris! o$ leu!aemia an) lym#homa in irra)ia%e) human #o#ula%ions
%o be #rovi)e) la%er in %he )ocumen%.
-!1! Mechanisms of induction of lympho'haemopoietic neoplasia
A broa) range o$ lym#ho-haemo#oie%ic neo#lasms (leu!aemias an) lym#homas+ have been i)en%i$ie)
in man an) e4#erimen%al animals. hese arise in bloo) $orming an) lym#ha%ic %issues an) have been
%he sub-ec% o$ in%ensive s%u)y #ar%icularly ,i%h regar) %o %he involvemen% o$ s#eci$ic chromosomal
even%s in )i$$eren% neo#las%ic sub-%y#es. he $ollo,ing #aragra#hs ou%line %he s%ruc%ure an) $unc%ion o$
%he lym#ho-haemo#oie%ic sys%em an) summarise in$orma%ion available on cy%ogene%ic an) molecular
mechanisms %ha% un)erlie %he )evelo#men% o$ neo#lasia.
-!1!1! (tructure and function of the lympho'haemopoietic system
he lym#ho-haemo#oie%ic (bloo)-$orming+ sys%em is com#ose) o$ a com#le4 arrangemen% o$ cell
lineage hierarchies ,i%h mul%i#le o#%ions $or cellular )i$$eren%ia%ion an) clonal am#li$ica%ion in or)er %o
genera%e ma%ure haemo#oie%ic e$$ec%or cells (:ig. 8.1+. hus %he #luri#o%en% s%em cell com#ar%men% in
bone marro, is able %o su##ly u#on )eman) an increase) %ransi% #o#ula%ion o$ lineage-res%ric%e)
#recursor cells o$ %he myeloi) an) lym#hoi) %y#es. hese #recursors subse9uen%ly am#li$y %hrough a
lineage commi%%e) com#ar%men% an), on subse9uen% en%ry in%o a ma%ura%ion com#ar%men%, conver% %o
%he ma%ure e$$ec%or cells o$ %he bloo) an) lym#ha%ic sys%em. his com#le4 #o#ula%ion o$ ma%ure cells
essen%ially com#rises granulocy%es an) monocy%es0macro#hages ,hich ac% %o scavenge microbes,
#arasi%es an) en)ogenous cellular )ebris= ery%hrocy%es ,hich %rans#or% o4ygen= #la%ele%s $or ,oun)
re#air= #lasma (B+ cells $or an%ibo)y secre%ion= su##ressor (+ cells $or cellular %o4ici%y an) hel#er (+
cells $or immune regula%ion ("reaves, 1991= 6en)erson e% al., 199>+.
50
:ig. 8.1. 6aemo#oie%ic cell lineages an) %heir $unc%ions ($rom "reaves, 1991+.
he genera%ion o$ %hese ma%ure cell lineages an) %he sel$-rene,al o$ %he #luri#o%en% s%em cells is sub-ec%
%o com#ar%men%alise) con%rol, no% only be%,een bone marro,, lym#h no)es, %hymus, an) s#leen bu%
also ,i%hin %hese %issues. :or e4am#le, s%em cells are largely res%ric%e) %o bone marro, ,here %hey are
organise) ,i%hin a %hree-)imensional s%romal ma%ri4, ,hile ,i%hin lym#h no)es an) s#leen %here is
some )egree o$ %o#ological cons%rain% on an) B cell #o#ula%ions ("reaves, 1991= 6en)erson e% al.,
199>+.
he con%rol o$ lym#ho-haemo#oie%ic cell #roli$era%ion an) )i$$eren%ia%ion is a highly com#le4 #rocess
(Me%cal$, 1988= 'obinson an) Queensberry, 199;= Me%cal$, 1991= /ess an) *ngel, 1998= Cr!in, 199>+,
%he )e%ail o$ ,hich is ou%si)e %he sco#e o$ %his revie,. In brie$, in associa%ion ,i%h %o#ological
cons%rain%s %he various cellular com#ar%men%s o$ %he sys%em are sub-ec% %o bo%h long- an) shor%-range
con%rol me)ia%e) by gro,%h an) ma%ura%ion $ac%ors. In mos% ins%ances %hese $ac%ors are s#eci$ic %o %he
lym#ho-haemo#oie%ic sys%em an) %heir ac%ion is o$%en me)ia%e) by or cou#le) %o %he in%erac%ion o$ %he
s%em an) commi%%e) #rogeni%ors ,i%h cells %ha% ma!e u# %he s%romal elemen%s. 3uch in%erac%ions ,oul)
inclu)e %hose me)ia%e) by some o$ %he cy%o!ine #ro%eins o$ %he in%erleu!in (I1+ $amily, granulocy%e7
macro#hage colony s%imula%ion $ac%or ("M-&3:+, granulocy%e colony s%imula%ing $ac%or ("-&3:+,
macro#hage colony s%imula%ing $ac%or (M-&3:+ an) s%em cell $ac%or (3&:+. Ac%ing in concer% an) in
associa%ion ,i%h a##ro#ria%e membrane-boun) rece#%ors an) in%racellular %ranscri#%ion $ac%ors, %hese
cy%o!ines #rovi)e %he $ine con%rol $or lym#ho-haemo#oie%ic )evelo#men%, main%enance, an) $unc%ion.
C%her long-range con%rolling $ac%ors circula%e more $reely in bloo) an) lym#ha%ic sys%ems an) ei%her
%arge% cells )irec%ly or e4#ress %heir e$$ec%s via %he s%romal elemen%s. 3uch long-range $ac%ors inclu)e
e#i)ermal gro,%h $ac%or (*":+, #la%ele% )erive) gro,%h $ac%or (P.":+, insulin, an) various s%eroi)s.
he con%rol o$ lym#ho-haemo#oie%ic )evelo#men% an) main%enance shoul) no% ho,ever be vie,e)
sim#ly as a ma%%er o$ regula%ing cellular #roli$era%ion an) $unc%ional )i$$eren%ia%ion. he overall si<e o$
cell com#ar%men%s an) %he in)ivi)ual clonal con%ribu%ions ,i%hin %hese are also regula%e) by #ro%ein
51
$ac%ors in%erac%ing ,i%h o%her cy%o!ines %ha% ei%her s%imula%e or bloc! an ac%ive #rocess o$ #rogramme)
cell )ea%h %erme) a#o#%osis (&ohen, 1991= 'a$$, 1992= Forsmeyer, 1992+. A#o#%osis is a crucial
elemen% in %he con%rol o$ normal lym#ho-haemo#oiesis an) may be vie,e) as a mos% im#or%an%
mechanism $or %he clonal res%ric%ion or elimina%ion o$ )egenera%e or aberran% cells.
In recen% years much has been learne) o$ %he gene%ics an) biochemis%ry o$ lym#ho-haemo#oie%ic
regula%ion, largely as a resul% o$ %he molecular cloning o$ %he genes involve) an) %he in vi%ro analysis o$
%heir mul%i$ace%e) $unc%ions (Me%cal$, 1991= Me%cal$, 1992= /ess an) *ngel, 1998= Cr!in, 199>+. In %he
main, )i$$eren%ia%ion o$ cell lineages is )e#en)en% u#on se9uen%ial ac%iva%ion or su##ression o$ s#eci$ic
genes, a #rocess %ha% is me)ia%e) by an array o$ %ranscri#%ion regula%ors. Ma%uring - an) B-cell
sub%y#es are ho,ever sub-ec% %o ,ha% is curren%ly un)ers%oo) %o be a uni9ue #rocess o$ clonal ./A
se9uence-s#eci$ic rearrangemen% in or)er %o s#eci$y novel #ro%eins %ha% subse9uen%ly me)ia%e immune
reac%ions agains% non-sel$ #ro%ein an%igens (onega,a, 1982+. In brie$, -cell an%igen rece#%or ()CR+
an) B-cell immunoglobulin (=?+ genes in a##ro#ria%e #recursor cells are na%urally rearrange) a% s#eci$ic
recombinogenic si%es in %hese genes. hese con%rolle) rearrangemen%s occur be%,een s#eci$ic gene
segmen%s an) are ca%alyse) by a com#le4 sys%em o$ recombina%ion an) hy#ermu%a%ion en<ymes
(1ieber, 1992= Eiller$or) e% al., 199>+. he ne% ou%come o$ %hese #rocesses is %he #o%en%ial $or clonal
e4#ression in lym#hocy%e subse%s o$ a vas% array o$ an%igen-s#eci$ic #ro%eins ,hich, in -cells, $unc%ion
as membrane-boun) recogni%ion molecules $or cell-me)ia%e) immune res#onse an), in B-cells, as
secre%e) an%ibo)ies $or humoral immuni%y.
In conclusion, al%hough %he cellular an) molecular biology o$ lym#ho-haemo#oie%ic )evelo#men% is
#robably be%%er un)ers%oo) %han %ha% o$ any o%her mammalian %issue, much remains %o be learne).
/ever%heless, as ,ill be seen, %he curren% un)ers%an)ing is su$$icien%ly goo) %o allo, s#eci$ic commen%
on %he role o$ s#eci$ic genes in neo#las%ic #rocesses.
-!1!"! 5ympho'haemopoietic neoplasia
/eo#lasms o$ %he lym#ho-haemo#oie%ic sys%em may be broa)ly )ivi)e) in%o %hose o$ %he myeloi) an)
lym#hoi) cell lineages. hese %,o ma-or ca%egories may be $ur%her sub)ivi)e) in%o sub-%y#es on %he
basis o$ clinical, haema%ological, an) his%o#a%hological cri%eria an) inclu)es #re-leu!aemic, chronic,
an) acu%e mani$es%a%ions o$ neo#lasia ("reaves, 1991 an) "reaves, 1992= 6en)erson e% al., 199>+.
1ym#ho-haemo#oie%ic neo#lasia accoun%s $or aroun) 55 o$ all cancer in Ees%ern #o#ula%ions bu% %here
are increases in %his con%ribu%ion %ha% )e#en) u#on age, e%hnici%y, an) )emogra#hy (Magra%h e% al.,
1988+. C$ #ar%icular no%e is %he rela%ively high con%ribu%ion (V2;5+ %ha% leu!aemia an) lym#homa
ma!es %o neo#lasia a% ages belo, 15 years (3%iller e% al., 1991+. Viruses, chemical carcinogens, an)
ionising ra)ia%ion have been im#lica%e) in %he a##earance o$ lym#ho-haemo#oie%ic neo#lasia in a
number o$ human grou#s an), in %he con%e4% o$ %his re#or%, a mos% im#or%an% )a%a base is %ha%
concerning %he e4cess neo#las%ic )isease in irra)ia%e) human #o#ula%ions. hese )a%a are )iscusse) in
)e%ail else,here (A/3&*A', 1998+.
1ym#ho-haemo#oie%ic neo#lasia #resen%s as %he clonal )ominance o$ aberran% cells e4#ressing myeloi)
or lym#hoi) charac%eris%ics. 1eu!aemia is charac%erise) by e4cess o$ ,hi%e cells in bloo) ,hich, in %he
acu%e $orm, may be accom#anie) by )is%urbances in bone marro, $unc%ion, e.g. anaemia an) in$ec%ion=
in)olen% (chronic an) #releu!aemic+ $orms have also been charac%erise). 1ym#homas mos% usually
#resen% as %he accumula%ion o$ neo#las%ic cells in lym#ha%ic %issues= many o$ %hese con)i%ions have an
in)olen% #hase. In)olen% $orms o$ lym#ho-haemo#oie%ic neo#lasia may, ,i%h %ime, conver% %o an acu%e
52
$orm %hrough %he evolu%ion o$ a more aggressive cellular #heno%y#e an) such %ransi%ions #rovi)e
clinical evi)ence o$ %he mul%i-s%age na%ure o$ )isease ("reaves, 1991= 6en)erson e% al., 199>+.
&y%ogene%ic, molecular, an) biochemical s%u)ies have been use) %o e4#lore %he cellular origin o$
leu!aemia0lym#homa an) ,i%h %he #ossible e4ce#%ion o$ )isease in some bone marro, %rans#lan% an)
ac9uire) immuno)e$iciency )isease (AI.3+ #a%ien%s, %hese s%u)ies #rovi)e com#elling evi)ence o$ %he
monoclonal (single cell+ origin o$ neo#lasia (Eoo)ru$$, 1988= 1ieber, 1992= "reaves, 1992+.
here is also evi)ence %ha% %he %arge% cell #o#ula%ion $or %he vas% ma-ori%y o$ leu!aemias an)
lym#homas is one %ha% is rela%ively un)i$$eren%ia%e) an) %ha% %he subse9uen% ma%ura%ion o$ #o%en%ially
neo#las%ic cells is no% synchronous ,i%h %ha% o$ %he res#ec%ive normal cell lineage. &onsis%en% ,i%h %his,
"reaves (198>+= "reaves (1991+ an) "reaves (1992+ has )escribe) a mo)el o$ leu!aemogenesis ,here
%he cri%ical cellular even% resul%s in changes %o %he )i$$eren%ia%ion #rogramme such %ha% %he #robabili%y
o$ sel$-rene,al o$ leu!aemia-ini%ia%e) cells e4cee)s %ha% o$ ma%ura%ion an) clonal e4%inc%ion. In %his
,ay a clone o$ rela%ively imma%ure cells %ha% ,oul) normally have only a %ransi%ory #resence in a given
ma%ura%ion com#ar%men% (see :ig. 8.1+ may accumula%e. Accor)ing %o %he mo)el, %he )egree o$
uncou#ling o$ #roli$era%ion an) ma%ura%ion #rovi)es $or %he #heno%y#ic he%erogenei%y %ha% charac%erises
many lym#ho-haemo#oie%ic neo#lasms. hus, %he monoclonal e4#ansion o$ #re-leu!aemic cells
#re)ic%e) by %he mo)el can accoun% $or in)olen% $orms o$ )isease an) also allo,s $or %he accumula%ion
o$ $ur%her mu%a%ional even%s ,i%hin %he ma%ura%ion-arres%e) clone. hese mu%a%ions ,ill be sub-ec% %o
#heno%y#ic selec%ion an) ,ill resul% $inally in %he blas% crisis %ha% is %he hallmar! o$ %he acu%e #hase o$
)isease.
In general, la%ency #erio)s $or %he )evelo#men% o$ haemo#oie%ic neo#lasia %en) %o be shor%er %han $or
soli) %umours (A/3&*A', 1998+ illus%ra%ing %he na%ural age-rela%e) #rocess o$ oncogenesis an)
im#lying, #erha#s, a re9uiremen% $or ra%her $e,er genomic changes $or %he )evelo#men% o$ malignancy.
Ehile s%ill some,ha% uncer%ain, %his con%en%ion receives some su##or% $rom %he cy%ogene%ic an)
molecular s%u)ies on leu!aemia an) lym#homa ou%line) in %his sec%ion.
-!1!,! Cyto%enetic and molecular mechanisms of lympho'haemopoietic neoplasia
he mos% consis%en% $ea%ure o$ human leu!aemias an) lym#homas is %he #resence o$ #rimary, non-
ran)om clonal chromosomal rearrangemen%s %ha% are charac%eris%ic o$ leu!aemia sub-%y#es (Mi%elman,
1991= 3an)berg, 1992+. In some cases a single chromosomal even% is #resen% ,i%hin an essen%ially
)i#loi) chromosome com#lemen%, in o%hers %he !aryo%y#e is more com#le4 ,i%h mul%i#le changes,
some o$ ,hich canno% be cy%ogene%ically )e$ine). Al%hough %here is some !no,le)ge o$ %he #rinci#al
chromosome s#eci$ic %ransloca%ions in leu!aemia an) lym#homas many such even%s remain obscure
an) %here is also uncer%ain%y on %he chromosome )ele%ions, numerical chromosomal changes, ./A
am#li$ica%ions, #oin% mu%a%ions an) genomic ins%abili%ies %ha% charac%erise many o$ %hese neo#lasms.
hese )a%a have been e4%ensively revie,e) (Mi%elman, 1991= 3a,yers e% al., 1991= 3an)berg, 1992=
&line, 1998= Joung, 1998= 'abbi%%s, 1998+ an) here ,e see! only %o summarise %he curren% #osi%ion.
-!1!,!1! Chromosome translocations
Aroun) 5; gene-s#eci$ic chromosome %ransloca%ions have been charac%erise) a% %he molecular level in
human lym#ho-haemo#oie%ic neo#lasms= %hese $all in%o %,o broa) ca%egories.
@/n/ /r/?ulation throu?h translocation. able 8.1 an) able 8.2 summarise %he %ransloca%ions %ha%
resul% in %he )eregula%ion o$ genes, %he ou%come o$ ,hich is %o change %he #roli$era%ion an)0or
53
ma%ura%ion o$ haemo#oie%ic #recursors. All o$ %hese even%s may be regar)e) as gain-o$-$unc%ion
mu%a%ions an) as such %he %arge% genes $or )eregula%ion can be classi$ie) as #ro%o-oncogenes (&line,
1998= Joung, 1998= 'abbi%%s, 1998+. ,o sub-classes o$ %hese even%s may be $ur%her )e$ine) on %he
basis o$ %he cell-o$-origin $or #ro%o-oncogene )eregula%ion an) %he #ar%ner ./A se9uence %ha% ac%s %o
e$$ec% %his.
able 8.1. Pro%o-oncogenes -u4%a#ose) %o -cell rece#%or genes in lym#ho-haemo#oie%ic neo#lasia
able 8.2. Pro%o-oncogenes -u4%a#ose) %o immunoglobulin loci in lym#ho-haemo#oie%ic neo#lasia
In -cell neo#lasia, gene )eregula%ing %ransloca%ion has %o )a%e been sho,n %o )e#en) u#on %he
-u4%a#osi%ion o$ enhancer or con%rolling se9uences o$ %he lineage-s#eci$ic )CR genes ,i%h cer%ain
#ro%o-oncogenes. )CRA, an) B se9uences are !no,n %o me)ia%e such even%s an) %he !no,n #ro%o-
oncogene %arge%s are %he genes )C31, )C35, 3C&, )A32, )A:1, 58X11, 3431 *4C, RB:)1, an)
RB:)2 (able 8.1+.
54
In B-cell neo#lasia gene )eregula%ing %ransloca%ion )e#en)s u#on similar gene -u4%a#osi%ion bu%, in
%hese cases, involving con%rolling elemen%s o$ )i$$eren% =? genes, i.e =?5, =?&, an) =?l. he !no,n
%arge% #ro%o-oncogenes $or %hese B-cell %ransloca%ions are *4C, R63, =33, BC31, BC32, BC33, an)
BC36 an), as in %he case o$ -cell neo#lasms, %here is some )egree o$ s#eci$ici%y in %erms o$ bo%h gene
#ar%nershi# an) neo#las%ic sub-%y#e (able 8.2+.
I% is im#or%an% %o recognise %ha% #ro%o-oncogene %ransloca%ions in - an) B-cell neo#lasms are no% %he
resul% o$ com#le%ely ran)om ./A e4change. As no%e) earlier, )CR an) =? se9uences are uni9uely
sub-ec% %o lineage-)e#en)en% recombina%ion, a #rocess %ha% is me)ia%e) by ./A #rocessing machinery
,hich recognises s#eci$ic ./A mo%i$s in %he normal immune se9uences (1ieber, 1992+. Molecular
s%u)ies have #rovi)e) com#elling evi)ence %ha% i% is loss o$ $i)eli%y o$ %his recombina%ion sys%em %ha%
)rives )CR0=?-#ro%o-oncogene %ransloca%ions by aberran%ly ca%alysing in%er-locus recombina%ion
be%,een %arge% se9uences. &ou#le) %o %his, %arge% se9uences may also be sub-ec% %o ./A se9uence
a))i%ions, losses, an) )u#lica%ions. his loss o$ $i)eli%y o$ ./A #rocessing im#lies a close rela%ionshi#
be%,een leu!aemogenesis an) ./A )amage re#air0recombina%ional #rocesses= %his issue is )iscusse)
$ur%her in 3ec%ion 2 o$ %he #resen% re#or%.
I% may be seen, %here$ore, %ha% a cri%ical even% in - an) B-cell neo#lasia is %he e4#ression o$ lineage-
)irec%e) genes %ha% are #lace) ina##ro#ria%ely un)er %he con%rol o$ ac%ive )CR an) =? se9uences %ha% are
s#eci$ically e4#resse) in - an) B-cell #recursors res#ec%ively. Al%hough %he s#eci$ic $unc%ions o$ %he
ac%ive oncogenes crea%e) by %hese %ransloca%ions may )i$$er, %hey %en) %o share %he general #ro#er%y o$
having %he #o%en%ial %o in%er$ere ,i%h %he normal #a%%erns o$ gene %ranscri#%ion %ha% me)ia%e cellular
)i$$eren%ia%ion. In illus%ra%ion o$ %his *4C, )C35, 3431, an) 58X11 have ei%her been )irec%ly
im#lica%e) as nuclear %ranscri#%ion $ac%ors or have $ea%ures o$ ./A se9uence %ha% are s%rongly
sugges%ive o$ %his, i.e heli47loo#7heli4, homeobo4 or 1IM )omains (Joung, 1998= 'abbi%%s, 1998+.
hus, ina##ro#ria%e %ransac%iva%ion o$ %he genes %arge%e) by %hese %ranscri#%ion $ac%ors may be vie,e)
as a means o$ esca#e $rom normal cellular cons%rain%s on gro,%h an) )evelo#men%.
6o,ever, genes ,i%h some,ha% )i$$eren% $unc%ions may also be sub-ec% %o %his class o$ leu!aemogenic
even%. he )a%a o$ able 8.2 sho, %ha% BC31, a cell cycle con%rol gene= =33, a gro,%h $ac%or gene an)
BC32, a gene s#eci$ying mi%ochon)rial #ro%ein may be ac%iva%e) in some B-cell neo#lasms. In %he case
o$ BC32 %he ou%come o$ such ac%iva%ion is %o bloc! a normal a#o#%o%ic mechanism me)ia%e) by
o4i)a%ive me%abolism, %hereby $acili%a%ing clonal e4#ansion ('abbi%%s, 1998+.
@/n/ Cusion throu?h translocation. Ehereas gene )eregula%ion %hrough )CR or =? se9uence
%ransloca%ion is res%ric%e) %o - an) B-cells res#ec%ively, a gene $usion mechanism a##ears %o have %he
#o%en%ial %o )rive leu!aemogenesis in bo%h lym#hoi) an) myeloi) lineages (&line, 1998= Joung, 1998=
'abbi%%s, 1998+.
"ene $usion can be ini%ia%e) ,hen chromosome brea!age occurs ,i%hin %he in%rons o$ %,o #hysically
unlin!e) %arge% genes. I$ reunion o$ %hese brea!s occurs (i.e a %ransloca%ion+ such %ha% %he $lan!ing
e4ons o$ %he %,o genes are in #hase %hen a correc%ly s#lice) hybri) m'/A can be %ranscribe) $rom %he
novel $usion gene. he #ro%ein syn%hesise) $rom %his message is a chimera o$ %he %,o normal #ro%eins
an) ,oul) be e4#ec%e) %o have a mi4e) bu% )e$ec%ive $unc%ion. In any such reci#rocal %ransloca%ion
%here is %he e4#ec%a%ion o$ %,o such $usion #ro)uc%s. hus, a carrier cell ,oul) be e4#ec%e) %o e4#ress
%hese %oge%her ,i%h %he normal gene #ro)uc%s $rom %he %,o remaining normal (un$use)+ gene co#ies o$
%he $usion #ar%ners.
55
able 8.2 summarises %he chromosome %ransloca%ions curren%ly !no,n %o be associa%e) ,i%h s#eci$ic
gene $usions. I% is no%able %ha%, ,i%h %he sole e4ce#%ion o$ )CRA(=?5 $usion in chromosome 18
inversion, %he genes involve) all )i$$er $rom %hose seen in gene-)eregula%ing %ransloca%ions o$ - an) B-
cells (able 8.1 an) able 8.2+.
Cn %he basis o$ curren% !no,le)ge i% a##ears %ha% %here is a high )egree o$ s#eci$ici%y in %he ma-ori%y o$
%he gene #ar%nershi#s in $usion even%s an) also neo#las%ic sub-%y#e s#eci$ici%y in res#ec% %o %he genes
involve). his is cer%ainly %he case $or %he BCR(AB3 $usion $or ,hich %here is only one !no,n
subs%i%u%e AB3-rela%e) !inase gene (&line, 1998= Joung, 1998= 'abbi%%s, 1998+. he ma-or e4ce#%ion %o
%his is %he *331 gene enco)e) in %he 11922 region o$ %he genome ,hich is ca#able o$ #ro)uc%ion
$usion ,i%h a% leas% si4 )i$$eren% #ar%ners an), albei% in )i$$eren% combina%ions, con%ribu%es %o neo#lasia
in -cell, B-cell an) myeloi) lineages. I% seems li!ely %here$ore %ha% ,hereas mos% $usion onco#ro%eins
#rinci#ally %arge% lineage-res%ric%e) haemo#oie%ic #rogeni%ors, *331 $usion #ro)uc%ions can e4er%
#heno%y#ic e$$ec%s in #luri#o%en% or early mul%i#o%en%ial cells ('abbi%%s, 1998+.
*331 involvemen% in haemo#oie%ic neo#lasia also sho,s s%rong age-)e#en)ence. ransloca%ions
involving 11922 are by $ar %he mos% common even%s in chil)hoo) acu%e leu!aemia an) *331 $usion
coul) un)erly u# %o 7;5 o$ all cases o$ in$an% AM1 an) A11 (hirman e% al., 1992+. 'elevan% %o %his
are s%u)ies on %he leu!aemias o$ i)en%ical %,ins no%e) la%er in %his sec%ion (3ec%ion 8.2.2+= %hese sho,
%ha% *331 %ransloca%ion may be $avoure) )uring in u%ero )evelo#men% o$ %he haemo#oie%ic sys%em
,hen, #erha#s, #luri#o%en% s%em cell ac%ivi%y is ma4imal.
In %he absence o$ a re9uiremen% $or %he recombinogenic mo%i$s seen in - an) B-cell neo#lasms %he
grea%es% cons%rain% on %he $orma%ion o$ #ro)uc%ive gene $usions is %he nee) %o encom#ass %he cri%ical
)omains $rom each o$ %he #ar%ner genes. his is cer%ainly evi)ence) in %he close brea!#oin% clus%ering
,i%hin %he 5)RX gene. In %he case o$ BCR(AB3 %here is, ho,ever, consi)erable varia%ion in BCR
brea!#oin%s an), al%hough some,ha% con%en%ious, some in)ica%ions %ha% %his may have #heno%y#ic
conse9uences (&line, 1998= Joung, 1998+.
he cellular )ys$unc%ions in)uce) by %he syn%hesis o$ leu!aemia-associa%e) $usion #ro%eins remain
uncer%ain an) i% is no% clear in all cases ,hich o$ %he %,o #o%en%ial chimeric #ro)uc%s has %he )ominan%
e$$ec%. *vi)ence is ho,ever emerging %ha% %hese #ro%eins may be involve) in %he nuclear signalling
#a%h,ays %ha% regula%e %he )i$$eren%ia%ion an) survival o$ haemo#oie%ic cell lineages. he normal genes
o$ many o$ %he $usion #ar%ners enco)e heli47loo#7heli4 an) <inc-$inger #ro%ein )omains associa%e)
,i%h %ranscri#%ional con%rol (able 8.2+= in a chimeric $orm such )omains may be e4#ec%e) %o )is%urb
%he normal #a%%erns o$ gene %ranscri#%ion (&line, 1998= Joung, 1998= 'abbi%%s, 1998+.
able 8.2. "ene $usions in lym#ho-haemo#oie%ic neo#lasia
56
In su##or% o$ %his %he P*3(RARA $usion #ro%ein has been sho,n %o in%erac% in a com#le4 $ashion ,i%h
%he normal #ar%ner #ro%ein #ro)uc%s an), %hrough %his, is able %o bloc! myeloi) )i$$eren%ia%ion (Earrell
e% al., 1992+. &om#le4 biochemical in%erac%ions also charac%erise %he 62A(PBX $usion #ro%ein ,hich is
seemingly able %o )ysregula%e %he #roli$era%ion an) survival o$ lym#hoi) cells (Joung, 1998= 'abbi%%s,
1998+. *vi)ence sugges%s %ha% %he e4#ression o$ %he BCR(AB3 $usion #ro%ein #lays a role in %he
inhibi%ion o$ a#o#%osis.
,o #ossible mechanisms o$ %ranscri#%ional )ysregula%ion by $usion onco#ro%eins may be sugges%e).
:irs%, %he chimeric $usion #ro)uc% may have enhance) ac%ivi%y or al%ere) s#eci$ici%y in res#ec% o$
%ransac%iva%ion o$ genes= %here is some evi)ence in su##or% o$ %his $or bo%h B&'-AB1 an) PM1-'A'A
$usion #ro%eins ('abbi%%s, 1998+. 3econ), by in%er$erence ,i%h cri%ical #ro%ein7#ro%ein in%erac%ions,
$usion #ro)uc%s coul) in%er$ere ,i%h normal %ranscri#%ion in a )ominan% nega%ive $ashion %ha% #arallels
%ha% o$ mu%an% p53 (1an$rancone e% al., 1998+= %he #a%%ern o$ *331 gene %runca%ion as a conse9uence o$
%ransloca%ion ('abbi%%s, 1998+ coul) in #rinci#le #rovi)e $or %his.
Ehile %here remain ma-or uncer%ain%ies on %he $unc%ional as#ec%s o$ $usion onco#ro%eins in
haemo#oie%ic neo#lasia i% is becoming increasingly clear %ha% overall %hey #lay an im#or%an% role in %he
)evelo#men% o$ %hese )iseases. 3uch %ransloca%ions have also been i)en%i$ie) in cer%ain soli) %umours
('abbi%%s, 1998+ an) a recen%ly #ublishe) ca%alogue o$ chromosomal even%s in human neo#lasia
#rovi)es $ur%her e4am#les o$ s#eci$ic %ransloca%ions in bo%h lym#ho-haemo#oie%ic an) soli) cancers
(see Mi%elman e% al., 1997+.
-!1!,!"! Chromosome deletions and numerical chan%es
57
A varie%y o$ non-ran)om chromosomal )ele%ions an) numerical changes have been observe) in
haemo#oie%ic neo#lasias bu% in %he main %hese have no% been resolve) a% %he molecular level (Mi%elman,
1991= 3an)berg, 1992= Dohansson e% al., 1992= .ohner e% al., 1992= Joung, 1998= Mi%elman e% al.,
1997+. C$ #ar%icular no%e ho,ever are %he )ele%ions an) losses o$ chromosomes 5 an) 7 in acu%e
myeloi) leu!aemias (AM1+ an) rela%e) myelo)ys#las%ic syn)romes (M.3+ (Van )en Berghe e% al.,
1985+= in some cases %hese neo#lasms have been associa%e) ,i%h occu#a%ional or me)ical e4#osure %o
./A )amaging agen%s inclu)ing ionising ra)ia%ion. 3uch loss even%s may signal %he #resence o$
%umour su##ressor genes in cri%ical )ele%e) chromosome segmen%s an) in #ursui% o$ %his much a%%en%ion
has been $ocuse) on %he 59 )ele%ions in AM1 an) M.3.
*4%ensive cy%ogene%ic analysis o$ %hese neo#lasms has i)en%i$ie) %he 5921 segmen% as %he cri%ical region
$or gene loss (1eBeau e% al., 1992= Eillman e% al., 1992+. Molecular analysis o$ %his region has recen%ly
reveale) %he #resence o$ %,o can)i)a%e %umour su##ressor genes, 6@R1 an) =R91. Bo%h %hese genes
have been sho,n %o be los% in many o$ %he 59 neo#lasms so $ar inves%iga%e), an) ei%her coul) be %he
cri%ical gene. I% remains ho,ever #ossible %ha% %here is a clus%er o$ su##ressor-%y#e genes in %his
chromosome region an) %ha% o%her can)i)a%es may come %o ligh%.
A%%en%ion has also been given %o 12918 )ele%ions an) %ransloca%ions in B-cell chronic lym#hocy%ic
leu!aemia an) molecular s%u)ies have recen%ly i)en%i$ie) a #u%a%ive su##ressor locus, #B*, ,hich is
loca%e) a% leas% 52;!b %elomeric %o RB1 (Bro,n e% al., 1992+. &hromosome 11922 )ele%ions have also
been observe) in haemo#oie%ic neo#lasia ('abbi%%s, 1998+= %hese are #robably associa%e) ,i%h *331
gene e$$ec%s no%e) earlier.
Many more ./A )ele%ions have ho,ever been charac%erise) a% %he cy%ogene%ic level. hese )a%a ,hich
have been summarise) an) analyse) by Mi%elman e% al. (1997+ give %he im#ression %ha% ./A loss
even%s are more $re9uen% in neo#lasms o$ myeloi) origin %han in o%her lym#ho-haemo#oie%ic sub%y#es.
/on-ran)om chromosome )ele%ions charac%erise cer%ain haemo#oie%ic neo#lasms o$ e4#erimen%al
animals an) in %he case o$ ra)ia%ion-in)uce) murine AM1 %here is some in$orma%ion on %he molecular
mechanisms involve) (see 3ec%ion 8.1.2.8+.
Cverall, in s#i%e o$ %he numerous e4am#les o$ non-ran)om chromosome )ele%ion even%s in human
haemo#oie%ic neo#lasms, i% is only recen%ly %ha% signi$ican% #rogress has been ma)e in %he eluci)a%ion
o$ %he %umour-su##ressor-%y#e gene losses %ha% are #re)ic%e) %o be involve). his is an area ,here much
remains %o be learne) o$ %he leu!aemogenic #rocess.
-!1!,!,! ther proto'onco%ene and tumour suppressor mutations
In a))i%ion %o %he many )isease-s#eci$ic chromosomal mu%a%ions i)en%i$ie) in haemo#oie%ic neo#lasms
%here is also some in$orma%ion on %he involvemen% o$ #ro%o-oncogene an) %umour su##ressor gene
mu%a%ions. In con%ras% %o chromosomal even%s i% is evi)en% %ha% %hese gene mu%a%ions )o no% arise in a
s%ric% cell lineage )e#en)en% manner (&line, 1998= Joung, 1998+.
In brie$ RA+ #ro%o-oncogene mu%a%ion is common in chronic myelomonocy%ic leu!aemia an) acu%e
myeloi) leu!aemia bu% ra%her less so in B-cell neo#lasms. *4C #ro%o-oncogene mu%a%ion has been
recor)e) in B- an) -cell neo#lasms an) in some myeloi) leu!aemias an) 9*+ mu%a%ion is no%
uncommon in myeloi) leu!aemia. C$ %he %umour su##ressor genes, p53 an) RB1 mu%a%ions have been
charac%erise) in a range o$ haemo#oie%ic neo#lasms, #ar%icularly %hose o$ an acu%e $orm, an) %here is
also some evi)ence o$ ;)1 involvemen% in a #ro#or%ion o$ acu%e myeloi) leu!aemias. 6omo<ygous
58
)ele%ions o$ %he A in%er$eron gene has been recor)e) more consis%en%ly in a range o$ leu!aemias (&line,
1998= Joung, 1998+.
Pro%o-oncogene an) %umour su##ressor gene mu%a%ions have also been i)en%i$ie) in s#on%aneously
arising an) chemically an) ra)ia%ion-in)uce) leu!aemias an) lym#homas in e4#erimen%al animals
(A/3&*A', 1992+. C$ #ar%icular no%e are recen% s%u)ies ,i%h mice he%ero<ygous $or p53 sho,ing %ha%
%he remaining ,il) %y#e p53 allele can be a )irec% %arge% $or %he ini%ia%ion o$ lym#ho-haemo#oie%ic
neo#lasia (Fem# e% al., 1998= see also 3ec%ion 5+.
&hromosomal an) gene am#li$ica%ions have been recor)e) in a $e, lym#ho-haemo#oie%ic neo#lasms
bu% %he s#eci$ic con%ribu%ion o$ %hese %o neo#las%ic )evelo#men% has ye% %o be )e%ermine) (Mi%elman,
1991= 3an)berg, 1992+= ne, molecular cy%ogene%ic %echni9ues (Pin!el, 1998+ a##ear %o have %he #o,er
o$ resolu%ion %o a))ress %his #roblem.
he overall im#ression %ha% may be gaine) $rom %hese s%u)ies is %ha% #ro%o-oncogene, %umour
su##ressor, an) gene am#li$ica%ion mu%a%ions e4er% %heir #rinci#al e$$ec%s )uring %he #rogression o$
haemo#oie%ic neo#lasia an) are, in many ins%ances, secon)ary %o lineage-s#eci$ic chromosomal even%s.
-!1!,!-! Genomic instability in haemopoietic neoplasia
he #rinci#al lin! be%,een genomic ins%abili%y an) lym#ho-haemo#oie%ic neo#lasia has been
es%ablishe) by %he $in)ing %ha% %he human gene%ic )isor)ers a%a4ia-%elangiec%asia an) :anconi anaemia
(see 3ec%ion 8.2.8+, associa%e) ,i%h )e$ec%s in ./A #rocessing an) a%%en)an% chromosomal ins%abili%y,
are also charac%erise) by #re)is#osi%ion %o cer%ain lym#ho-haemo#oie%ic neo#lasms. his $in)ing is
broa)ly consis%en% ,i%h %he vie, gaine) $rom cy%ogene%ic an) molecular s%u)ies %ha% %he #rinci#al
mechanisms $or %he ini%ia%ion o$ lym#ho-haemo#oie%ic neo#lasia cen%res on gene-s#eci$ic chromosome
%ransloca%ion or segmen%al chromosome loss.
In a))i%ion %o %his %here has been much )eba%e on %he role o$ so calle) $ragile chromosomal si%es (9RA+
in %he )evelo#men% o$ leu!aemia an) lym#homa. Analyses o$ %he rela%ionshi#s be%,een common
human 9RA an) neo#lasia-s#eci$ic chromosome brea!#oin%s sugges% %ha% such associa%ions are a% bes%
,ea! bu% %here is evi)ence %ha% rare heri%able 9RA may sho, a some,ha% s%ronger rela%ionshi# ,i%h %he
#osi%ion o$ chromosomal brea!#oin%s in some haemo#oie%ic neo#lasms (see 3ec%ion 8.2.8+. In %he
absence o$ $irm molecular )a%a on %he s%ruc%ure an) loca%ion o$ #o%en%ially in$orma%ive human 9RA %he
s%a%is%ical analyses so $ar #resen%e) an) )iscusse) )o no% allo, $or any $irm conclusions on %heir role in
%he )evelo#men% o$ haemo#oie%ic neo#lasia. /ever%heless, chromosome 59 brea!#oin%s in %he )ele%ions
charac%erising myelo)ys#lasia are believe) %o be non-ran)om (Mi%elman e% al., 198>+ bu% e9ually, )o
no% clearly corres#on) %o !no,n 9RA loci.
Albei% res%ric%e) %o a rela%ively small number o$ cases, genomic ins%abili%y in some haemo#oie%ic
neo#lasms has been more convincingly lin!e) a% %he cy%ogene%ic level ,i%h %elomere-associa%e)
chromosomal rearrangemen% (3hi##ey e% al., 199;+. In %hese cases neo#las%ic chromosome
%ransloca%ions involving %he non-reci#rocal e4change be%,een an in%ers%i%ial an) %erminal (%elomeric+
si%e a##ears %o crea%e a chromosomal reunion %ha% is highly uns%able an) is able %o un)ergo secon)ary
e4change or loss even%s. 3uch observa%ions lea) %o %he hy#o%hesis %ha% some human 9RA migh% be
re#resen%e) by %elomere-li!e re#ea% (1'+ se9uences (6as%ie an) Allshire, 1989+. 3ome su##or% $or %his
an) $or %he rela%ionshi# be%,een %elomeric se9uences an) leu!aemogenic chromosomal rearrangemen%
has been #rovi)e) by recen% animal s%u)ies no%e) belo,.
59
In cer%ain mouse s%rains ra)ia%ion-in)uce) AM1 is s%rongly associa%e) ,i%h in%ers%i%ial
)ele%ion0rearrangemen% o$ chromosome 2 an) %here is evi)ence %ha% such gross changes may re#resen%
ini%ia%ing even%s $or %his neo#lasm. Ehile molecular )a%a im#lica%ing s#eci$ic chromosome 2 enco)e)
genes in %his #rocess are no% com#elling, %here are some,ha% more convincing )a%a rela%ing %o %he
involvemen% o$ s#eci$ic recombinogenic 1' se9uences a% %he leu!aemia-associa%e) chromosome 2
brea!#oin%s (Bou$$ler e% al., 1991= Mei-ne e% al., 199>= &lar! e% al., 199>+. Ehe%her %hese 1' loci
re#resen% murine Cra an) %he #ossibili%y %ha% murine Cra ac% as gene%ic )e%erminan%s o$ leu!aemia
susce#%ibili%y remains, ho,ever, s#ecula%ive (see 3ec%ion 8.2.8+. In s#i%e o$ %his uncer%ain%y, recen%
a)vances in %elomere biology (Blac!burn, 1991= Fim e% al., 1998= Ga!ian, 1995+ )o sugges% %ha% %hese
re#ea% se9uences #lay a crucial role in chromosome s%abilisa%ion an) may be involve) in %he #rocesses
o$ cell senescence an) neo#las%ic %rans$orma%ion (see 3ec%ion 2+.
-!"! Genetic susceptibility to lympho'haemopoietic neoplasia
*vi)ence rela%ing %o %he heri%able com#onen% o$ leu!aemia an) lym#homa comes $rom a varie%y o$
sources. 3uch evi)ence %ha% %here is has been consi)ere) over a #erio) o$ some 2; years (Geul<er an)
&o4, 19>9= "un<, 1978= 1ine%, 1985= aylor an) Birch, 199>+.
he #rinci#al sources o$ in$orma%ion )erive $rom s%u)ies on neo#lasia in@ $amilies, mono<ygo%ic an)
)i<ygo%ic %,ins, cancer-$amily syn)romes, chromosome ins%abili%y syn)romes, chromosomal an)
)evelo#men%al abnormali%ies, an) immunological )e$iciencies. 6ere ,e #rovi)e a brie$ summary o$ %he
available )a%a ,i%h an em#hasis on %he )egree o$ uncer%ain%y %ha% surroun)s any -u)gemen% on %he
gene%ic com#onen% o$ human lym#ho-haemo#oie%ic neo#lasia.
-!"!1! 6amily studies
Ehile $amilial leu!aemia an) lym#homa is uncommon %here are a number o$ re#or%s ,hich su##or% %he
con%en%ion %ha%, in rare ins%ances, a %en)ency %o,ar)s haemo#oie%ic neo#lasia is heri%able (Geul<er an)
&o4, 19>9= "un<, 1978= 1ine%, 1985= aylor an) Birch, 199>+. In mos% o$ %hese $amilies a clear
Men)elian #a%%ern o$ inheri%ance has no% been es%ablishe) bu% as no%e) by 1ynch e% al. (1985+ %he e4%en%
o$ #e)igree analysis is cri%ical $or ascer%ainmen% o$ heri%able #re)is#osi%ion %o neo#lasia= %his is
#ar%icularly %he case $or mu%a%ions o$ lo, #ene%rance.
Acce#%ing %hese uncer%ain%ies %here is li%%le )oub% %ha% in rare ins%ances heri%able $ac%ors un)erly
mul%i#le cases o$ leu!aemia0lym#homa ,i%hin $amily #e)igrees ("un< e% al., 1975= 1ine% e% al., 1989=
Fnu)son, 1992a an) Fnu)son, 1992b+. :or e4am#le, in his revie, "un< (1978+ no%e) one $amily ,i%h
12 cases o$ leu!aemia in 292 $amily members over %hree genera%ions= 1i e% al. (1979+ re#or%e) on eigh%
males ,i%h leu!aemia0#re-leu!aemia over $our genera%ions sugges%ive o$ O-lin!e) inheri%ance an)
"un< e% al. (1975+ in an e4%ensive s%u)y no%e) a %hree-$ol) increase in ris! o$ leu!aemia among $irs%-
)egree rela%ives o$ #a%ien%s ,i%h all sub-%y#es o$ haemo#oie%ic neo#lasia. .ominan%ly inheri%e) $amilial
#re)is#osi%ion %o acu%e myeloi) leu!aemia has also been re#or%e) recen%ly (6e e% al., 1998+. In %heir
revie, aylor an) Birch, (199>+ #rovi)es $ur%her in$orma%ion on $amilial clus%ering o$, no% only
leu!aemia, bu% also o$ 6o)g!ins an) non-6o)g!ins lym#homa.
A no%able $ea%ure o$ %he available )a%a is %he $in)ing o$ increase) ris! an) concor)ance $or $amilial &11
bu% %he absence o$ %his $or &M1 (Geul<er an) &o4, 19>9= "un<, 1978= "un< e% al., 1975= 1ine% e% al.,
1989+. 3uch $amilial concor)ance $or leu!aemic sub-%y#e a))s a))i%ional cre)ibili%y %o a gene%ic basis
$or a small #ro#or%ion o$ haemo#oie%ic neo#lasia. 3ome o$ %he leu!aemia $amilies no%e) in %he revie,s
60
ci%e) here #robably $all in%o %he gene%ic ca%egories )iscusse) la%er in %his sec%ion bu% in %he main %hey
have ye% %o #rovi)e in$orma%ion on %he s#eci$ic na%ure o$ %he un)erlying gene%ic basis o$ haemo#oie%ic
)isease.
"ene%ic con%ribu%ions %o )isease may also be -u)ge) in sub #o#ula%ions ,here %here is a signi$ican%
)egree o$ inbree)ing (consanguini%y+ (*),ar)s, 19>9= Vogel an) Mo%uls!y, 198>+. *arly s%u)ies
sugges%e) %ha% consanguini%y among leu!aemia cases ,as no% $re9uen% (Geul<er an) &o4, 19>9=
3%einberg, 19>;+ bu% i% has been re#or%e) %ha% 1;029 Da#anese $amilies ,i%h %,o or more cases ,ere
consanguinous (Furi%a e% al., 1978+. In a))i%ion, %here are re#or%s o$ increase) $re9uency o$ leu!aemia
in inbre) De,ish an) 6u%%eri%e communi%ies in %he A3A (:el)man e% al., 197>= Mar%in e% al., 198;+ an)
consanguini%y has been no%e) in leu!aemia-#rone a%a4ia-%elangiec%asia (3,i$% e% al., 198>+ an) :anconi
anaemia (3chroe)er e% al., 197>+ $amilies (see also 3ec%ion 8.2.8+. C$ #ar%icular relevance %o chil)hoo)
leu!aemia, mor%ali%y ra%es, an) %he e$$ec%s o$ inbree)ing are %he recen% s%u)ies o$ uncbile! an) Foch
(1998+ an) Bi%%les an) /eel (1998+. As -u)ge) by %hese )a%a, %he con%ribu%ion o$ consanguini%y %o
leu!aemia ris! a##ears %o be lo,.
-!"!"! (tudies 3ith t3ins
In #rinci#le %he gene%ic com#onen% o$ lym#ho-haemo#oie%ic neo#lasia may be -u)ge) $rom %he
increase) )egree %o ,hich %here is concor)ance $or )isease in i)en%ical, mono<ygo%ic (MG+ %,ins over
%ha% seen in %he non-i)en%ical, )i<ygo%ic (.G+ %y#e (:alconer, 199;+. In brie$, i$ neo#lasia ,ere %o be
)ue %o a monogenic )ominan% mu%a%ion %hen concor)ance ra%es shoul) e4cee) 5;5 in MG an) i$ )ue %o
recessive mu%a%ion %his concor)ance shoul) e4cee) 255 ,i%h %he s#eci$ic )egree o$ concor)ance
)e#en)en% #erha#s on %he role o$ non-gene%ic $ac%ors. *arly re#or%s (Fei%h e% al., 1975= Furi%a e% al.,
1978+ sugges%ive o$ high concor)ance ra%es $or leu!aemia in MG %,ins an), by im#lica%ion, a
signi$ican% gene%ic com#onen% %o %he )isease nee) %o be in%er#re%e) ,i%h grea% cau%ion, no% only because
neo#lasia overall has been sho,n %o be )iscor)an% in such s%u)ies (6rubec an) /eel, 1982+ bu% also
because o$ a con$oun)ing mechanism %ha% a##lies s#eci$ically %o leu!aemia.
:ollo,ing %he original hy#o%hesis by &lar!son an) Boyse (1971+ i% has been unambiguously sho,n by
cy%ogene%ic an) molecular s%u)ies (&hagan%i e% al., 1979= :or) e% al., 1992+ %ha% in many ins%ances %he
concor)ance o$ leu!aemia in MG %,ins is no% )ue %o gene%ic $ac%ors bu% ra%her %o in u%ero
%rans#lan%a%ion o$ #re-malignan% cells be%,een MG $oe%uses having share) bloo) circula%ion. hus,
leu!aemia in MG %,ins is mos% $re9uen%ly monoclonal in origin ,i%h, in %hese cases, bo%h %,ins having
%he same brea!#oin% in %he *331 gene o$ chromosome 11922= )i$$eren% *331 brea!#oin%s are seen in
leu!aemia in .G %,ins.
:ur%her sources o$ con$oun)ing $or %he es%ima%ion o$ gene%ic com#onen%s o$ leu!aemia $rom %,in
s%u)ies have been i)en%i$ie) (Philli#s, 1992= &W%X an) "y$%o)imou, 1991= aylor an) Birch, 199>+ an)
inclu)e $e%al loss )ue %o leu!aemogenesis, non-gene%ic $ac%ors such as bir%h,eigh% variabili%y be%,een
%,in #airs an) %he #ossible role o$ early mi%o%ic even%s in %he %,inning #rocess lea)ing %o gene%ic
imbalance. An associa%ion be%,een %he #rocesses involve) in %,inning an) mal$orma%ion has also been
sugges%e) ("arabe)ian an) :raser, 1998+.
here are isola%e) re#or%s o$ a)ul% MG %,ins ,i%h leu!aemias having )i$$eren% cy%ogene%ic
abnormali%ies an)0or immune gene se9uence rearrangemen%s. hese #rovi)e evi)ence o$ #os%-<ygo%ic
genomic changes lea)ing %o leu!aemia bu% )o no% allo, commen% on ,he%her %he common gene%ic
61
bac!groun) or similar environmen%al $ea%ures o$ early li$e are %he causal elemen%s (6ech% e% al., 1988=
Bro!-3imoni e% al., 1987+.
In s#i%e o$ %hese uncer%ain%ies %here is increasing evi)ence $or %he role o$ inheri%e) $ac%ors in 6o)g!ins
)isease (6.+, a monoclonal in$lamma%ory con)i%ion associa%e) ,i%h lym#homagenesis. C$ #ar%icular
im#or%ance is a recen% s%u)y o$ concor)ance $or %he early a)ul% $orm (?5; years+ o$ 6. in a large s%u)y
o$ MG an) .G %,ins (Mac! e% al., 1995+. Ehereas none o$ %he 187 #airs o$ .G %,ins became
concor)an% $or 6., in 179 #airs o$ MG %,ins %here ,ere 1; ins%ances o$ concor)ance= %he me)ian age
o$ )iagnosis o$ 6. ,as 2> years. he e4#ec%e) inci)ence o$ 6. in each o$ %hese %,in grou#s ,as ;.1,
%hus #rovi)ing no evi)ence o$ e4cess ris! in .G %,ins bu% a grea%ly eleva%e) ris! in %he MG grou#
(s%an)ar)ise) inci)ence ra%io o$ 99, &I 887182+. A gene%ic basis $or concor)ance $or 6. in MG %,ins
,as $ur%her su##or%e) by %he $in)ing o$ a consis%en% #a%%ern o$ 6. his%ology (no)ular sclerosis sub-
%y#e+ in mos% o$ %he #airs. here ,as ho,ever no evi)ence o$ )is#ari%y be%,een MG an) .G %,in #airs
in res#ec% o$ o%her cancers. hese )a%a are )iscusse) by 1ynch an) Marcus (1995+ ,i%h em#hasis on %he
#ossible role o$ inheri%e) immunological )e$ec%s in %he ae%iology o$ 6..
-!"!,! Cancer family syndromes
1ym#ho-haemo#oie%ic neo#lasia is no% %he #rinci#al )isease in any o$ %he 2; or so cancer $amily
syn)romes having mu%an% genes %ha% are clone) or ma##e) on %he human genome (Fnu)son, 1992a an)
Fnu)son, 1992b= *ng an) Pon)er, 1992+. hus, al%hough %here are a $e, re#or%s o$ leu!aemia in, $or
e4am#le, heri%able re%inoblas%oma (.erFin)eren e% al., 1988+, i% seems %ha%, in %he main, %he ,ell
charac%erise) germ line %umour gene mu%a%ions #re)is#osing %o soli) cancers (3ec%ion 2+ )o no% im#ac%
signi$ican%ly on leu!aemia or lym#homa. he %,o e4ce#%ions %o %his rela%e %o %y#e 1 neuro$ibroma%osis
(/:1+ an) 1i7:raumeni syn)rome (1:3+.
here are con$lic%ing re#or%s concerning leu!aemia in /:1 #a%ien%s. Ehereas 3ei<inger (1992+ sugges%s
%ha% %here is no associa%ion o$ myelo)ys#lasia (M.3+ or acu%e myeloi) leu!aemia (AM1+ ,i%h /:1,
o%her au%hors ci%e )a%a in)ica%ive o$ a #osi%ive associa%ion (*ng an) Pon)er, 1992= Bro)eur, 1998=
3hannon e% al., 1992= 3%iller e% al., 1998+. In su##or% o$ %his associa%ion is %he recen% observa%ion %ha%
mice )e$icien% in %he :91 gene are #rone %o acu%e myeloi) leu!aemia (Dac!s e% al., 1998+.
Perha#s more universally acce#%e) is %he associa%ion be%,een 1:3 an) acu%e leu!aemia occurring
be$ore age 85 (*ng an) Pon)er, 1992= Mal!in, 1992= Birch e% al., 1998+. In a s%u)y o$ 82 1:3 $amilies
Mal!in (1992+ re#or%e) on 221 neo#lasms o$ ,hich 18 ,ere leu!aemias, an) since germ line p53 gene
mu%a%ion is no% a ,holly consis%en% $in)ing in 1:3, i% is im#or%an% %o consi)er %he #ossibili%y %ha%
leu!aemia #re)is#osi%ion is no% homogeneous amongs% 1:3 !in)re).
here are also s%u)ies in p53-)e$icien% mice %ha% allo, commen% u#on %he role o$ %his gene in heri%able
susce#%ibili%y %o lym#ho-haemo#oie%ic neo#lasia. Mice he%ero<ygous $or p53 (analogous %o 1:3+ have
been sho,n %o )evelo# os%eosarcoma, so$% %issue sarcoma, an) lym#homa a% a high $re9uency
(.oneho,er e% al., 1992= Fem# e% al., 1998+ an) also sho, increase) %umorigenic ra)iosensi%ivi%y
(Fem# e% al., 1998+. he mechanisms o$ %his eleva%e) sensi%ivi%y %o haemo#oie%ic neo#lasia a##ear %o
cen%re on increases in chromosome re#lica%ion errors an) #ar%icularly in %he case o$ ra)ia%ion
lym#homagenesis chromosome loss0gain even%s associa%e) ,i%h p53 )e$iciency (Bou$$ler e% al., 1995=
see also 3ec%ion 5+.
62
:inally, %here are #reliminary in)ica%ions %ha% $amilies carrying ;)1 (Eilms %umour+ mu%a%ions may
have an increase) inci)ence o$ haemo#oie%ic neo#lasia (6ar%ley e% al., 1998+.
-!"!-! Chromosome instability syndromes
he #rinci#al chromosome ins%abili%y syn)romes in man having associa%ions ,i%h lym#ho-
haemo#oie%ic neo#lasia are a%a4ia-%elangiec%asia (A-+, Bloom syn)rome (B3+, an) :anconi anaemia
(:A+ ("erman, 1982= Murnane an) Fa##, 1992+. hese )isor)ers are au%osomal recessive an) %he
cellular cy%ogene%ic an) molecular )a%a %ha% #rovi)e clues on associa%e) ./A #rocessing )e$ec%s are
ou%line) in 3ec%ion 2. 6ere ,e $ocus on %he #a%%ern o$ neo#lasia in %hese )iseases.
-!"!-!1! Ata0ia'telan%iectasia
A%a4ia-%elangiec%asia, al%hough )escribe) earlier, ,as more com#le%ely charac%erise) by Bo)er an)
3e)ge,ic! (1958+ as having com#le4 clinical $ea%ures %ha% inclu)e early onse% cerebellar a%a4ia,
%elangiec%asia, immuno)e$iciency, increase) ris! o$ sino-#ulmonary in$ec%ion an) haemo#oie%ic
neo#lasia (Bo)er, 1975= Bri)ges an) 6arn)en, 1982= Bun)ey, 1998+. he clinical $ea%ures o$ A- an)
%heir #ossible rela%ionshi#s ,i%h %he gene%ics, cy%ogene%ics, an) molecular biology o$ %he )isor)er are
,ell )escribe) in a series o$ monogra#hs an) mee%ing re#or%s covering %he #erio) 1982798 (Bri)ges
an) 6arn)en, 1982= "a%%i an) 3,i$%, 1985= aylor e% al., 1998b+.
he cancer ris! in A- ,i%h a li$es#an %ha% rarely e4cee)s 2; years has been es%ima%e) %o be be%,een 5
an) 2;5 (&ohen an) 1evy, 1989= Bun)ey, 1998+ ,i%h %he ris! o$ lym#ho-haemo#oie%ic neo#lasia being
u# %o 25;-$ol) grea%er %han %ha% in %he general #o#ula%ion= %here is also an increase) ris! o$ s%omach
cancer in some A- $amilies (3#ec%or e% al., 1982+. C$ #ar%icular no%e is %he rela%ive absence o$ an
e4cess o$ common soli) %umours an) myeloi) )iseases in A-, con%ras%ing ,i%h %he clear e4cess o$ -
an) %o a lesser e4%en% B-cell neo#lasms. his #re)is#osi%ion %o s#eci$ic sub-%y#es o$ haemo#oie%ic
neo#lasia broa)ly accor)s ,i%h cy%ogene%ic, molecular an) immunological $in)ings in)ica%ing %ha%
ma-or se9uelae o$ %he #u%a%ive ./A #rocessing )e$ec%(s+ in A- cen%re on recombina%ion errors in
res#ec% o$ immune gene se9uences (see 3ec%ion 8.1.2.1 an) 2+.
issue ra)iosensi%ivi%y in A- $ollo,ing ra)io%hera#y is ,ell )ocumen%e) (see 3ec%ion 5+ an) accor)s
,i%h %he $in)ings $rom in vi%ro cellular s%u)ies (3ec%ion 2+= %here are ho,ever no )a%a on ,hich %o -u)ge
leu!aemogenic ris! in A- homo<ygo%es a$%er ra)ia%ion. he con%en%ion %ha% in)ivi)uals he%ero<ygous
$or A- mu%an% genes sho, increase) in vi%ro ra)iosensi%ivi%y an) are also #rone %o neo#lasia is
)iscusse) in 3ec%ion 2 an) 3ec%ion 5. 6ere i% is su$$icien% %o say %ha% %here is no evi)ence %ha% %hese A-
gene carriers are #rone %o lym#ho-haemo#oie%ic neo#lasia.
Al%hough %he gene%ics o$ A- may be rela%ively s%raigh%$or,ar) (see 3ec%ion 2+, a varian% $orm, %he
/i-megen brea!age syn)rome (/B3+ has been )escribe) (Eeemaes e% al., 1981= Eeemaes e% al., 1998+.
*igh% lym#homas an) a single glioma have been re#or%e) amongs% 19 /B3 #a%ien%s an) i% is no%able
%ha%, unli!e HclassicalI A-, /B3 has ye% %o be associa%e) ,i%h -cell leu!aemia.
-!"!-!"! 7loom syndrome
Ini%ially )escribe) by Bloom (1958+, Bloom syn)rome (B3+ is very rare an) #rinci#ally charac%erise)
by ery%hema, sun sensi%ivi%y, gro,%h an) men%al re%ar)a%ion, an) #re)is#osi%ion %o neo#lasia ("erman,
19>9= "erman, 1982 an) "erman, 1992+. A regis%ry o$ B3 #a%ien%s ("erman, 1992+ #rovi)es )a%a on
neo#lasms in 122 cases an) sugges%s %ha% %he %umour s#ec%rum is more broa) %han in a%a4ia-
63
%elangiec%asia an) :anconi anaemia an) inclu)es no% only leu!aemias an) lym#homas bu% also a range
o$ common soli) %umours. &ancer ris! in B3 #a%ien%s a##ears %o e4cee) 2;5 bu% he%ero<ygo%es $or %he
B3 gene sho, no evi)ence o$ increase) malignancy.
he s#eci$ic na%ure o$ %he )e$ec% %ha% may lin! B3 ,i%h genomic ins%abili%y an) %umour #re)is#osi%ion
has ye% %o be uncovere) bu% $ollo,ing %he recen% cloning o$ %he B3 gene (B3*+ some $orm o$ ./A
helicase-)e$iciency seems li!ely (see Forn an) 'am!isson, 1995+.
-!"!-!,! 6anconi anaemia
:ollo,ing %he original )escri#%ion o$ :anconi anaemia (:A+ as a )isor)er associa%e) ,i%h a chil)hoo)
)e$ec% in bone marro, )evelo#men% (3chroe)er e% al., 197>= Al%er, 1987+, %he )isease has also been
sho,n %o inclu)e s!ele%al, neurological, s!in, an) renal abnormali%ies ("erman, 1982+. Various re#or%s
also highligh% %he chromosomal ins%abili%y an) abnormal ./A )amage res#onse o$ :A cells in vi%ro
(3ec%ion 2+ an) recen% s%u)ies have con$irme) %he gene%ic he%erogenei%y o$ %he )isor)er (see Buch,al),
1995+.
Anli!e A-, myeloi) ra%her %han lym#hocy%ic leu!aemia )omina%es amongs% haemo#oie%ic neo#lasms
in :A an) %he ra%e o$ leu!aemia in :A a##ears %o be aroun) 1;5 ,i%h an increase) inci)ence o$ myeloi)
)isease #erha#s 15,;;;-$ol) grea%er %han in %he normal #o#ula%ion (Al%er, 1987= Auerbach an) Allen,
1991+. he 9ues%ion o$ neo#las%ic ris! in :A he%ero<ygo%es has been a))resse) an) al%hough an early
re#or% (3,i$%, 1971+ ,as sugges%ive o$ increase) ris!, %his has no% been con$irme) (3,i$% e% al., 198;=
Po%%er e% al., 1982+.
aylor an) Birch (199>+ have grou#e) :A along ,i%h o%her $amilial )isor)ers sho,ing, amongs% o%her
$ea%ures, abnormali%ies o$ bone marro, )evelo#men% %oge%her ,i%h some )egree o$ #re)is#osi%ion %o
leu!aemia. his grou# o$ )iseases inclu)e %he E, IVI&, 3ch,achman7.iamon) an) Fos%mann
syn)romes, a%a4ia-#ancy%o#aenia, $amilial monosomy 7, )ys!era%osis congeni%a, amega!aryocy%ic
%hrombocy%o#aenia, an) Blac!$an7.iamon) anaemia.
hese are all rare )isor)ers an) ,i%h %he e4ce#%ion o$ Blac!$an7.iamon) anaemia (Is!an)ar e% al.,
198;+ li%%le is !no,n o$ %heir chromosomal res#onses %o ra)ia%ion. 6o,ever even in %he absence o$
chromosomal ins%abili%y i% may be reasonable %o assume %ha% %he associa%e) bone marro, )e$ec% may in
some circums%ances increase %he ris! o$ lym#ho-haemo#oie%ic neo#lasia as an in)irec% conse9uence o$
cellular #roli$era%ive s%ress #lace) u#on %ha% organ.
-!"!-!-! /eritable chromosomal fra%ile sites
3ince si%e-s#eci$ic chromosomal rearrangemen% is an im#or%an% soma%ic hallmar! o$ lym#ho-
haemo#oie%ic neo#lasia i% is $easible %ha% inheri%e) #re)is#osi%ion %o si%e-s#eci$ic chromosomal $ragili%y
can be a gene%ic )e%erminan% o$ %hese malignancies. In e4cess o$ 1;; rare an) common chromosomal
$ragile si%es have been i)en%i$ie) an) al%hough inheri%ance o$ many o$ %he rare si%es has been
)emons%ra%e) (Eenger, 1992+, only $our such loci, 9RAXA, 9RAX6, 9RAX9, an) 9RA16B have been
resolve) a% %he molecular level, in %hese cases as e4#an)e) %rinucleo%i)e re#ea%s in ./A (Eillems,
1998+. /one o$ %hese re#ea% se9uence si%es have been s#eci$ically im#lica%e) in malignancy= a
%rinucleo%i)e re#ea% has ho,ever been re#or%e) in %he A9< gene ,hich can #ar%ner *331 in
leu!aemogenic gene $usions (able 8.2+ (/a!amura e% al., 1992+ an) %he 9RA11B locus has been sho,n
%o involve a re#ea% e4#ansion in %he CB32 #ro%o-oncogene (Dones e% al., 1995a an) Dones e% al.
(1995b++.
64
he rela%ionshi# be%,een heri%able $ragile si%e e4#ression an) leu!aemogenesis in man have been
)eba%e) $or many years (3u%herlan) an) 3immers, 1988= 1eBeau, 1988+ an) ,hile i% remains #ossible
%ha% such associa%ions e4is% in rare $amilies ()e Brae!eleer e% al., 1985= 1eBeau, 1988= 6ori e% al.,
1988+, no s#eci$ic su##or% $or %he hy#o%hesis has come $rom molecular s%u)ies. Also, a survey o$ cancer
in %he !in)re)s o$ leu!aemia #a%ien%s ,i%h chromosomal rearrangemen%s a% #u%a%ive heri%able $ragile
si%es $aile) %o )emons%ra%e an increase) ris! o$ heri%able leu!aemia bu% )i) sugges% %he #ossibili%y o$
e4cess lung cancer in cer%ain $amilies (Mules e% al., 1989+.
*4#erimen%al s%u)ies in %he &BA mouse have also #rovi)e) ambiguous resul%s in res#ec% %o an
associa%ion be%,een heri%able varia%ion in %elomere-li!e se9uences, chromosome $ragili%y an) ra)ia%ion-
myeloi) leu!aemogenesis (3ilver an) &o4, 1992= Mei-ne e% al., 199>+. /ever%heless, i% may be relevan%
%ha% heri%abili%y o$ %erminal %elomeric leng%h in man has been sho,n %o be high (3lagboom e% al., 1998+.
-!"!.! Chromosomal and developmental abnormalities
-!"!.!1! Chromosomal abnormalities
he soma%ic chromosomal e4changes %ha% charac%erise many sub-%y#es o$ haemo#oie%ic neo#lasia have
no% been re#or%e) in %he germ line o$ #a%ien%s im#lying %ha%, as s#eci$ic en%i%ies, %hey #lay li%%le or no
role in germ line #re)is#osi%ion %o )isease. Al%hough s%u)ies ,i%h animals %ransgenic $or cer%ain
leu!aemia-associa%e) oncogenes (A)ams an) &ory, 1991+ sho, %ha% in cer%ain circums%ances (i.e
genomic con%e4%+ such gene ac%iva%ion or $usion even%s (able 5.1--5.2+ are com#a%ible ,i%h murine
embryogenesis, i% may be conclu)e) %ha%, in man, such even%s in %heir normal genomic con%e4% are
ei%her embryo-le%hal or e4%remely rare. I% is also no%able %ha% animal s%u)ies using gene H!noc!-ou%I
%echni9ues have no% reveale) a correla%ion be%,een genes con%ribu%ing %o leu!aemia an) a role $or %hese
in normal haemo#oiesis (Varmus an) 1o,ell, 1998+.
able 5.1. 3#on%aneous an) ra)ia%ion-in)uce) numerical chromosomal aberra%ions in bone marro,
cells o$ ,il)-%y#e an) p53-)e$icien% mice
a
($rom Bou$$ler e% al., 1995+
able 5.2. 'a)ia%ion )ose-res#onse $or renal %umour in)uc%ion in *!er ra%s ($rom 6ino e% al., 1992b+
65
able 5.2. Mor%ali%y $rom %umours o%her %han re%inoblas%oma in #a%ien%s ,ho ha) been one year
survivors o$ re%inoblas%oma by la%erali%y an) irra)ia%ion s%a%us ($rom *ng e% al., 1992+
In con%ras% %o %his, %here is evi)ence %ha%, in a less s#eci$ic $ashion, cer%ain germ line chromosomal
imbalances can #re)is#ose %o haemo#oie%ic neo#lasia. he mos% im#or%an% an) common o$ %hese is
%risomy $or chromosome 21, .o,n syn)rome (.3+ having charac%eris%ic mongoloi) $ea%ures, ,here
%here is an es%ima%e) 18-$ol) increase) ris! o$ leu!aemia (:ong an) Bro)eur, 1987+. he overall
s%reng%h o$ %he associa%ion be%,een cons%i%u%ional chromosomal abnormali%ies an) leu!aemia is more
)i$$icul% %o -u)ge. aylor an) Birch (199>+ lis% nine cases $rom %he li%era%ure ,here such associa%ions
have been $oun)= %hese inclu)e %risomy, monosomy, 'ober%sonian %ransloca%ion, balance) %ransloca%ion,
)ele%ion, inser%ion, an) $ragile si%e e4#ression. 1arger surveys o$ #a%ien%s are ho,ever more ins%ruc%ive.
In a s%u)y o$ 18;; #a%ien%s ,i%h haemo#oie%ic neo#lasia Alimena e% al. (1985+ no%e) %en cases o$
%risomy 21, $ive %ransloca%ions, an) si4 se4 chromosomal abnormali%ies ,hile Beni%e< e% al. (1987+
re#or%e) on 718 #a%ien%s an) no%e) nine cases o$ cons%i%u%ional chromosome abnormali%y.
3ince %hese chromosomal $re9uencies are signi$ican%ly higher %han seen in %he normal #o#ula%ion, i%
may be conclu)e) %ha% a general bu% rela%ively ,ea! associa%ion be%,een chromosomal abnormali%y
an) haemo#oie%ic neo#lasia )oes e4is% an) %ha% %his, as e4#ec%e), %en)s %o be )omina%e) by .3 ,hich
has by $ar %he highes% bir%h inci)ence a% aroun) 1 in 7;; (*#s%ein, 198>+.
Al%hough %he gene%ic basis o$ %he chromosomal associa%ions )escribe) above remains obscure, %hree
#ossible mechanisms may be rehearse). :irs%, %ha% as a conse9uence o$ some un)erlying )e$ec%
in$luencing bo%h meio%ic an) mi%o%ic #rocesses, %here may be $amilial %en)encies %o,ar)s germ line
chromosomal abnormali%y an) %he soma%ic genera%ion o$ leu!aemia-associa%e) chromosomal even%s in
haemo#oie%ic cells. 3econ), in a ra%her non-s#eci$ic $ashion, %he #resence o$ germ line chromosomal
imbalance i%sel$ #re)is#oses %o soma%ic chromosomal ins%abili%y an) hence %o haemo#oie%ic neo#lasia.
66
hir), %here is %he a))i%ional #ossibili%y %ha% %here is a more s#eci$ic associa%ion be%,een %risomy 21
an) )ysregula%ion o$ haemo#oiesis ,hich may be e4#resse) as H%ransien%I or over% leu!aemia ('osner
an) 1ee, 1972+. I% seems li!ely %ha% many genes con%ribu%e %o %he )iverse #heno%y#ic mani$es%a%ions in
.3 an) a curren% vie, is %ha% gene )osage e$$ec%s are mos% cri%ical. As ye% no s#eci$ic region o$
chromosome 21 has been associa%e) ,i%h leu!aemia )evelo#men% (Forenberg, 1995+.
-!"!.!"! #evelopmental abnormalities
here are con$lic%ing re#or%s on ,he%her %here is or is no% an associa%ion be%,een bir%h )e$ec%s overall
an) %he ris! o$ haemo#oie%ic neo#lasia (Mann e% al., 1992= Mili e% al., 1992+. I$ such ris! e4is%s i% ,oul)
a##ear %o be small an) i% is only $or a $e, rare congeni%al )isor)ers )iscusse) by 1i an) Ba)er (1987+
,here %here is any subs%an%ial evi)ence $or %his.
-!"!1! Immunolo%ical deficiencies
"ene%ically )e%ermine) immuno)e$iciency )isease resul%s #rinci#ally in )e$ec%s in %he )evelo#men% an)
$unc%ion o$ e$$ec%or - an) B-cell subse%s in %he haemo#oie%ic sys%em= )e$iciency o$ na%ural !iller (/F+
cells has also been no%e) in some o$ %hese )isor)ers ('ober%son an) 'i%<, 199;+. hese com#rise a rare
se% o$ )isor)ers ,here %here is no% only a high ris! o$ chil)hoo) mor%ali%y $rom microbial in$ec%ion bu%
also a 1;7255 ris! o$ malignancy ,i%h, overall, non-6o)g!in lym#homa as %he )ominan% neo#lasm
(:ili#ovich e% al., 1998+. Inclu)e) in %his grou# o$ )isor)ers are@ severe combine) immuno)e$iciency
(3&I.+, O-lin!e) hy#ogammaglobulinaemia (O 3&I.+, O-lin!e) hy#er-IgM (6IM+, #urine nucleosi)e
#hos#horylase (P/P+ )e$iciency, Eis!o%%7Al)rich syn)rome (EA3+ an) O-lin!e) lym#ho#roli$era%ive
)isease (O1P+ (aylor an) Birch, 199>+. he Immuno)e$iciency &ancer 'egis%ry (:ili#ovich e% al.,
1998= :ili#ovich e% al., 1992+ recor)s )a%a $rom many such #a%ien%s an) inclu)es a%a4ia-%elangiec%asia
(A-+ in i%s lis%ing. he highes% cancer ra%es occur in A- an) EA3 ,i%h EA3 sho,ing aroun) 18;-
$ol) increase) ris! o$ malignancy. A can)i)a%e gene $or EA3 has been isola%e) (.erry e% al., 1998+ an)
subse9uen%ly also sho,n %o un)erlie O-lin!e) %hrombocy%o#enia (Villa e% al., 1995+. he mechanism o$
ac%ion o$ %he EA3 gene is believe) %o be com#le4 (:ea%hers%one, 1997+.
Im#or%an%ly, %he mechanisms %ha% un)erlie leu!aemia0lym#homa #re)is#osi%ion in %hese )isor)ers may
no% al,ays be a )irec% conse9uence o$ a lac! o$ cellular surveillance. Al%hough %he no%able e4cess o$ B-
cell neo#lasia may #rinci#ally rela%e %o *#s%ein7Barr virus (*BV+ in$ec%ion (Flein, 1998+ %he
associa%ion seems no% %o be en%irely secure (:ili#ovich e% al., 1998= "rassmann e% al., 1998+. he role o$
in$ec%ive agen%s in chil)hoo) leu!aemia an) o$ viral involvemen% in human an) animal lym#ho-
haemo#oie%ic neo#lasia in general has been )iscusse) ,i)ely ("reaves, 1988= Gur 6ausen, 1991=
Abou), 1992+ bu% ,i%h %he e4ce#%ion o$ %he *BV associa%ion no%e) above, %here is no s%rong evi)ence
$or %he in%erac%ion o$ s#eci$ic gene%ic an) viral $ac%ors in human susce#%ibili%y %o haemo#oie%ic
neo#lasia.
In cer%ain immuno)e$iciency gene%ic )isor)ers a subs%an%ially )i$$eren% ae%iology may a##ly since in A-
, 3&I., an) o%her isola%e) cases %he immuno)e$iciency an) leu!aemia #re)is#osi%ion may no% be
conse9uen%ial bu% ins%ea) %o share a common roo% ,hich is believe) %o cen%re on an un)erlying gene%ic
)e$ec% in ./A recombina%ion an)0or re#air (see 3ec%ion 2+. Associa%ions be%,een lym#ho-
haemo#oie%ic neo#lasia an) varia%ion in immune-involve) his%ocom#a%ibili%y (61A+ genes have also
been consi)ere) (aylor an) Birch, 199>+. In %he mouse such associa%ions, ,hich may be s%rong in
some s%rains, a##ear %o arise as a conse9uence o$ 61A-me)ia%e) susce#%ibili%y0 resis%ance %o
lym#homagenic virus. In man %hese lin!s are much ,ea!er ,i%h con$lic%ing re#or%s in %he li%era%ure
even in %he case o$ %he rare leu!aemia sub%y#e (A1+ !no,n %o be associa%e) ,i%h 61V-1 virus
67
in$ec%ion ,here, on %he basis o$ mouse )a%a, 61A involvemen% migh% be e4#ec%e) (a-ima e% al., 1988=
ana!a e% al., 1988+. he #ossibili%y e4is%s ho,ever %ha% %he 61A sys%em migh% also %arge% #re-
malignan% cells an) %ha% #olygene%ic $ac%ors obscure %he %rue involvemen% o$ 61A varia%ion in human
haemo#oie%ic neo#lasia= Mac! e% al. (1995+ have )iscusse) %he #ossible relevance o$ 61A varia%ion %o
#re)is#osi%ion %o 6..
-!"!7! 4pi%enetic factors
here is very li%%le in$orma%ion on %he #ossible role o$ en)ogenous e#igene%ic $ac%ors %ha% migh%, $or
e4am#le, accoun% $or %he irregular inheri%ance o$ haemo#oie%ic neo#lasia in $amilies. Princi#al o$ %he
#o%en%ial e#igene%ic mechanisms in neo#lasia are #aren%-o$-origin (genomic im#rin%ing+ e$$ec%s on
mu%an% gene e4#ression ,hich al%hough s%ill largely obscure may #lay a role in %he inheri%ance o$
susce#%ibili%y %o cer%ain soli) %umours (3ec%ion 2+.
Ei%h %he #ossible e4ce#%ion o$ %he :91 gene (:einberg, 1992+ %here is no #ublishe) in$orma%ion on
im#rin%ing-li!e e$$ec%s in any o$ %he human )isor)ers or genes )irec%ly associa%e) ,i%h haemo#oie%ic
neo#lasia. In #ar%icular, %he ini%ial claim %ha% %he %(9=22+ %ransloca%ion in &M1 is sub-ec% %o #aren%-o$-
origin e$$ec%s (6aas e% al., 1992+ has recen%ly been re$u%e) by molecular analysis o$ %he associa%e) BCR
an) AB3 genes (iore%os e% al., 1998= Melo e% al., 1998+. /ever%heless !no,le)ge in %his ,hole area is
s#arse an) a role $or e#igene%ic $ac%ors in leu!aemia0lym#homa #re)is#osi%ion canno% be )iscoun%e)=
aylor an) Birch (199>+ an) Brec!on e% al. (1991+ have #rovi)e) s#ecula%ive commen% on %his issue.
-!"!2! &he %enetic component of lympho'haemopoietic neoplasia
"iven %he high bir%h inci)ence an) increase) ris! o$ lym#ho-haemo#oie%ic neo#lasia %here is a s%rong
e4#ec%a%ion %ha% .o,n syn)rome (.3+ ,ill ma!e %he grea%es% con%ribu%ion %o leu!aemia0lym#homa in
%he #o#ula%ion, #ar%icularly in res#ec% %o chil)hoo) neo#lasms. Assuming %ha% %he inci)ence o$
chil)hoo) leu!aemia0lym#homa is aroun) 1 in 2;;; (Par!in e% al., 1988+ %he values ci%e) in 3ec%ion
8.2.5 in res#ec% o$ inci)ence an) ris! im#ly %ha% .3 ,ill con%ribu%e u# %o aroun) 25 o$ %hese neo#lasms
in chil)hoo). A))i%ional )a%a ci%e) in 3ec%ion 8.2.5 #rovi)e, ho,ever, no reason %o believe %ha% o%her
curren%ly recognise) )evelo#men%al or chromosomal gene%ic abnormali%ies ma!e signi$ican%
con%ribu%ions %o leu!aemia0lym#homa in %he human #o#ula%ion.
I% may also be -u)ge) %ha%, overall, heri%able )e$ec%s o$ %umour-associa%e) germ line genes (#ro%o-
oncogenes an) %umour su##ressor genes+ are rare $ea%ures o$ lym#ho-haemo#oie%ic neo#lasia (3ec%ion
8.2.2+. ,o gene%ic en%i%ies associa%e) ,i%h such mu%a%ion, 1i7:raumeni syn)rome (1:3+ an)
neuro$ibroma%osis %y#e 1 (/:1+ )o ho,ever carry a signi$ican% )egree o$ ris! o$ %hese neo#lasms. In %he
case o$ 1:3, %he inci)ence in %he #o#ula%ion is very lo, (see 3ec%ion >+ an) %he con%ribu%ion %o
#o#ula%ion ris! ,ill be negligible. /:1 is ho,ever $ar more common ( 1 in 2;;;+, largely as a
conse9uence o$ a high )e novo germ line mu%a%ion ra%e (6uson e% al., 1989+. 6o,ever, al%hough /:1
#a%ien%s cons%i%u%e u# %o 1;5 o$ cases o$ myelo#roli$era%ive syn)rome (MP3+ an) associa%e) myeloi)
leu!aemias in chil)ren (3hannon e% al., 1992+, MP3 is uncommon an) /:1 seems li!ely %o un)er only a
small $rac%ion (?;.55+ o$ %o%al lym#ho-haemo#oie%ic neo#lasia in chil)hoo).
In %he case o$ %he gene%ic )isor)ers associa%e) ,i%h )e$ec%s o$ %he immune sys%em an)0or e4hibi%ing
chromosomal ins%abili%y, e.g. Eis!o%%7Al)ri)ge syn)rome, severe combine) immuno)e$iciency
)isease, a%a4ia-%elangiec%asia, :anconi anaemia an) Bloom syn)rome (see 3ec%ion 8.2.8 an) 8.2.>+
%here is o$%en a high ris! %o %he in)ivi)ual o$ )evelo#ing sub%y#e s#eci$ic neo#lasia. hese )iseases are
68
ho,ever rare in %he #o#ula%ion an) on %his basis i% may be -u)ge) %ha% collec%ively %hey seem li!ely %o
con%ribu%e subs%an%ially less %han 15 %o #o#ula%ion ris!.
3ince in %he ma-ori%y o$ %he )isor)ers )iscusse) in %his 3ec%ion o$ %he re#or% %here is an e4#ec%a%ion %ha%
neo#lasia ,ill be e4#resse) in chil)hoo), a summa%ion o$ %he es%ima%ions o$ gene%ic con%ribu%ions
#rovi)e) above lea)s us %o -u)ge %ha% aroun) 2785 o$ chil)hoo) leu!aemia0lym#homa is associa%e)
,i%h !no,n gene%ic abnormali%ies (see also /aro), 199;+.
3ome cre)ence %o %his in)irec% es%ima%e is #rovi)e) by an e#i)emiological s%u)y o$ chil)hoo) cancers
(/aro) e% al., 1991+. In %his survey o$ 1>,58> cases o$ neo#lasia, %here ,ere 7285
leu!aemias0lym#homas o$ ,hich 159 (2.25+ sho,e) evi)ence o$ an un)erlying gene%ic con)i%ion.
.o,n syn)rome con%ribu%e) %he grea%es% number o$ gene%ic cases (nM128 or 1.85 o$ %he %o%al+ ,hile
much smaller con%ribu%ions ,ere ma)e by /:1 (nM1; or ;.185 o$ %he %o%al+ an) immuno)e$iciency
)isor)ers (nM12 or ;.185 o$ %he %o%al+.
3ince, ho,ever, %here is no a #riori e4#ec%a%ion %ha% gene%ic #re)is#osi%ion %o lym#ho-haemo#oie%ic
neo#lasia in chil)ren ,ill al,ays be accom#anie) by o%her recognisable clinical $ea%ures, %he 2785
value $or %he gene%ic con%ribu%ion no%e) above may %en) %o be an un)eres%ima%e. /ever%heless, %he
$ailure o$ %,in s%u)ies %o reveal clear evi)ence o$ a gene%ic com#onen% $or any%hing o%her %han early
onse% 6., %he a##aren% rari%y o$ $amilial leu!aemia an) %he con$lic%ing )a%a $rom s%u)ies on
consanguini%y argue %ha% a value o$ 2785 shoul) no% signi$ican%ly un)eres%ima%e %he gene%ic
con%ribu%ion %o chil)hoo) haemo#oie%ic neo#lasia.
Al%hough a gene%ic con%ribu%ion %o leu!aemia0lym#homa in %he a)ul% #o#ula%ion is more )i$$icul% %o
es%ima%e, $amily an) consanguini%y s%u)ies sugges% %ha% i% is small an) almos% cer%ainly less %han %ha%
,hich a##lies %o chil)ren. hus, on %he basis o$ e4is%ing !no,le)ge i% is -u)ge) %ha% 55 is a reasonable
value $or %he gene%ic con%ribu%ion as a##lie) %o a #o#ula%ion o$ all ages. In ma!ing %his -u)gemen% i% is
ho,ever recognise) %ha% %he )a%a base available is sub-ec% %o consi)erable uncer%ain%y in res#ec% o$
leu!aemogenic mechanisms an) #o%en%ial varia%ion in %he in%erac%ion o$ gene%ic an) environmen%al
$ac%ors lea)ing %o e$$ec%s on #ene%rance0e4#ressivi%y o$ mu%a%ions= also %o clinical $ac%ors such as
unrecognise) )isease resul%ing in #re- or early #os%-na%al mor%ali%y.
-!,! (ummary and conclusions
1. 3#eci$ic chromosomal rearrangemen%s involving changes in %he ac%ivi%y o$ #ro%o-oncogenes are a
charac%eris%ic $ea%ure o$ %he )evelo#men% o$ lym#ho-haemo#oie%ic neo#lasia= %hese even%s involve
ei%her gene -u4%a#osi%ions or gene $usions. 1oss o$ chromosome segmen%s enco)ing #ossible %umour
su##ressor genes, gene mu%a%ions an) numerical chromosomal changes have also been charac%erise) in
some sub%y#es.
2. :amilial lym#ho-haemo#oie%ic neo#lasia is very rare al%hough some sub%y#es are $oun) in e4cess in
1i7:raumeni syn)rome an) neuro$ibroma%osis.
2. 3%u)ies o$ lym#ho-haemo#oie%ic neo#lasia in %,ins an) in chil)ren ,i%h congeni%al abnormali%ies
have no% reveale) a s%rong gene%ic com#onen%. ,in s%u)ies have ho,ever #rovi)e) evi)ence $or a
gene%ic com#onen% %o early-onse% 6o)g!in )isease.
69
8. *4cess lym#ho-haemo#oie%ic neo#lasia is seen mos% clearly in rare au%osomal recessive )isor)ers
associa%e) ,i%h chromosomal ins%abili%y an)0or immuno)e$iciency. 3ome o$ %hesePa%a4ia-
%elangiec%asia, :anconi anaemia, an) Bloom syn)romePare believe) %o be )e$icien% in ./A )amage
#rocessing.
5. I% is -u)ge) %ha% %he gene%ic com#onen% %o lym#ho-haemo#oie%ic neo#lasia is #oorly )e$ine) an)
#robably less %han %ha% $or soli) %umours. I% is a% i%s grea%es% in chil)ren ,here i% may accoun% $or 2785
o$ )isease ,i%h .o,n syn)rome as %he grea%es% single source.
.! 4vidence on associations bet3een tumori%enic radiosensitivity and heritable
predisposition to cancer
A cen%ral 9ues%ion %o be a))resse) in %his re#or% is %he e4%en% %o ,hich human heri%able #re)is#osi%ion %o
s#on%aneously arising cancer is re$lec%e) in an increase in e4cess ris! a$%er e4#osure %o ionising
ra)ia%ion. As ,ill be seen, %here is a #auci%y o$ )a%a on ,hich %o ma!e )irec% -u)gemen%s on %his
9ues%ion an), $or %his reason, a%%en%ion is $irs% given %o %he mechanis%ic as#ec%s o$ %he #roblem. :or %his,
%he $un)amen%al )a%a o$ 3ec%ion 2, 3ec%ion 2 an) 3ec%ion 8 assume #ar%icular im#or%ance bu% also
inclu)e) is )iscussion on %umorigenic ra)iosensi%ivi%y in animal mo)els o$ heri%able cancer.
he secon) a##roach a)o#%e) is %o see! semi-9uan%i%a%ive evi)ence o$ %umorigenic ra)iosensi%ivi%y in
#a%ien%s ,i%h !no,n or sus#ec%e) heri%able )isor)ers ,ho have receive) ra)io%hera#y in res#ec% o$ a
#rimary %umour. In such cases clinical evi)ence o$ e4cess neo#lasia arising ,i%hin %he irra)ia%e) $iel)
an) cumula%ive mor%ali%y )a%a #rovi)e some in)ica%ion o$ %he e4%en% %o ,hich %he un)erlying heri%able
)isor)er #re)is#oses %o secon), %hera#y-rela%e) neo#lasia.
:inally, evi)ence o$ increase) %umorigenic ra)iosensi%ivi%y associa%e) ,i%h heri%able cancer
#re)is#osi%ion ,ill be revie,e) ,i%h em#hasis on #reliminary re-evalua%ion o$ %he )a%a $rom %he
Da#anese A-bomb cohor% $or evi)ence o$ %he e4#ression o$ e4cess cancer ris! in %he #u%a%ive cancer-
#re)is#ose) subgrou#s %ha% are e4#ec%e) amongs% %he many %housan)s o$ in)ivi)uals e4#ose) %o
ionising ra)ia%ion in 6iroshima an) /agasa!i. A%%en%ion ,ill be given no% only %o curren% limi%a%ions o$
conven%ional e#i)emiological a##roaches %o %he #roblem in han) bu% also %o %he o##or%uni%ies #resen%e)
by ne, an) #o,er$ul s%ra%egies %ha% u%ilise closely cou#le) molecular gene%ic an) e#i)emiological
%echni9ues.
.!1! Mechanistic aspects of tumori%enic radiosensitivity
In 3ec%ion 2, 3ec%ion 2 an) 3ec%ion 8 o$ %his re#or% %he molecular gene%ics o$ %umour in)uc%ion an)
)evelo#men% ,ere )iscusse) in %he con%e4% o$ %he germ line mu%a%ions %ha% are curren%ly -u)ge) %o be
involve) in heri%able #re)is#osi%ion %o cancer. hree #rinci#al ca%egories o$ %umour #re)is#osing
mu%a%ions ,ere i)en%i$ie). "ene%ic )e$ec%s in ./A )amage #rocessing ,ere seen, $or e4am#le, %o a##ly
in %he case o$ a%a4ia-%elangiec%asia (A-+ an) heri%able non-#oly#osis colon cancer (6/P&&+ bu% may
also a##ly %o cer%ain )isor)ers associa%e) ,i%h breas% cancer susce#%ibili%y. .e$ec%s in %umour
su##ressor genes re#resen%e) %he mos% abun)an% ca%egory an) inclu)e) %he ma-ori%y o$ !no,n
gene%ically )ominan% )isor)ers, e.g re%inoblas%oma ('B+, $amilial a)enoma%ous #oly#osis (:AP+, an)
Von 6i##el 1in)au syn)rome (V61+. Pro%o-oncogene )e$ec%s ,ere -u)ge) %o be %he leas% common
$orm, re#resen%e) only by mul%i#le en)ocrine neo#lasia an) some cases o$ $amilial melanoma.
70
As no%e) #reviously, such ca%egorisa%ion, ,hils% convenien%, is some,ha% im#recise. his is bes%
illus%ra%e) by %he mu%a%ions o$ p53 in 1i7:raumeni syn)rome (1:3+ an) ./A misma%ch re#air genes in
6/P&& ,hich may be $unc%ionally inclu)e) in bo%h ./A re#air an) %umour su##ressor gene
ca%egories= also, by %he in)ica%ions %ha% %he BRCA breas% cancer susce#%ibili%y genes may #lay roles in
./A me%abolism. In s#i%e o$ %his im#recision o$ classi$ica%ion some general #ro-ec%ions on %he im#ac%
o$ ra)ia%ion )amage on %he e4#ression o$ cancer in %hese )i$$eren% geno%y#es are #ossible.
.!1!1! Genetic defects in #$A processin%
he )a%a an) )iscussion o$ 3ec%ion 2 argue s%rongly %ha% %he sensi%ivi%y o$ mammalian cells %o ionising
ra)ia%ion is )e%ermine) #rinci#ally by %he ca#aci%y %o correc%ly re#air )ouble s%ran) ./A lesions. A
mos% im#or%an% observa%ion is %ha% cellular ra)iosensi%ivi%y in human A- an) many ro)en% soma%ic cell
mu%an%s is no% accom#anie) by e9uivalen% hy#ersensi%ivi%y %o o%her ./A )amaging agen%s. In a similar
,ay cells $rom mos% bu% no% all gene%ic ca%egories o$ %he human sun sensi%ive )isor)er, 4ero)erma
#igmen%osum (OP+ are sensi%ive %o AV' an) some chemical agen%s bu% no% %o ionising ra)ia%ion (see
Arle%%, 1992= hac!er, 1992+. he broa) message $rom %hese observa%ions is %ha% ./A )amage re#air
#rocesses %en) %o o#era%e in a Hlesion s#eci$icI $ashion ,i%h #erha#s $e, con%rolling genes being share)
by )i$$eren% re#air #a%h,ays.
Accor)ingly, on %he basis o$ an assume) )irec% rela%ionshi# be%,een lesion-s#eci$ic ./A re#air
ca#aci%y an) cancer )evelo#men%, %here shoul) be no a #riori e4#ec%a%ion %ha% human cancer
#re)is#osi%ion associa%e) ,i%h )e$ec%s in all $orms o$ ./A )amage #rocessing ,ill sho, increase)
cancer ris! a$%er ionising ra)ia%ion. Al%hough %he s%reng%h o$ %he lin! be%,een cellular ra)iosensi%ivi%y
an) cancer #re)is#osi%ion may be 9ues%ione) (3ec%ion 2+ i% is ho,ever %o be e4#ec%e) %ha% %here ,ill be
some human gene%ic )isor)ers o$ ./A )amage recogni%ion an) re#air ,hich ,ill sho, eleva%e) cancer
ris! a$%er e4#osure %o a broa) range o$ ./A )amaging agen%s.
A% #resen% i% is #ossible %o %en%a%ively i)en%i$y 1:3 ,hich involves mu%a%ion o$ %he p53 gene as one
such case. As )escribe) in 3ec%ion 2, %he p53 #ro%ein is in%ima%ely involve) in ./A )amage
recogni%ion, cell cycle chec!#oin% con%rol an) a#o#%o%ic res#onse. 3ince %he ./A )amage recogni%ion
$unc%ions o$ %he p53 #ro%ein may no% )e#en) cri%ically u#on lesion %y#e, increase) sensi%ivi%y %o a broa)
range o$ carcinogens may be an%ici#a%e) in p53-)e$icien% )isor)ers. 3%u)ies ,i%h p53-)e$icien% mice
len) some su##or% %o %his conclusion (see 3ec%ion 5.2+.
In %he case o$ 6/P&& #a%ien%s ,ho are he%ero<ygous $or one o$ $our genes involve) in ./A misma%ch
re#air (see 3ec%ion 2+ %here are no )a%a on ,hich %o -u)ge #ossible abnormali%ies o$ cellular res#onse %o
ionising ra)ia%ion. he #ro#ose) involvemen% o$ such re#air )e$iciency in %he $orma%ion an) resolu%ion
o$ ./A he%ero)u#le4es (:ishel an) Folo)ner, 1995+ coul) ho,ever have im#lica%ions $or ra)ia%ion-
in)uce) mu%a%ions in cancer )evelo#men% o$ 6/P&& #a%ien%s.
In conclusion, ,hile i% may be -u)ge) %ha% %he ma-ori%y o$ !no,n human ./A re#air )e$icien%
)isor)ers are #robably no% associa%e) ,i%h increase) cancer ris! a$%er ionising ra)ia%ion, %here ,ill be
some %ha% are. A% #resen% i% is #ossible %o i)en%i$y only in)ivi)uals carrying %he A- an) /B3 mu%a%ions
in %heir homo<ygous s%a%e as being #o%en%ially a% increase) ris!. 3ince ho,ever mos% re#air-)e$iciency
)isor)ers are recessive in %heir #rinci#al clinical mani$es%a%ions %here is %he #ossibili%y o$ #ar%ial
#heno%y#ic e$$ec%s, inclu)ing cancer, in he%ero<ygo%es ,ho ,ill be more common in %he #o#ula%ion
(3ec%ion >+. his may be o$ #ar%icular im#or%ance in %he case o$ A- he%ero<ygo%e ,ho have been
#ro#ose) %o e4#ress increases in bo%h chromosomal ra)iosensi%ivi%y an) s#on%aneous breas% cancer ris!
71
(3ec%ion 2 an) 3ec%ion 2+. In %he same con%e4%, i% may be %ha% some $orms o$ human ./A7re#air
)e$iciency are embryo-le%hal in %he homo<ygous s%a%e bu% e4#ress as cancer susce#%ibili%y in viable
ra)iosensi%ive he%ero<ygo%es.
.!1!"! Genetic defects in tumour suppressor %enes
*arly s%u)ies in re%inoblas%oma le) %o %he $ormula%ion by Fnu)son an) co,or!ers o$ %he %,o-hi%
conce#% o$ carcinogenesis ,hich ,as la%er sho,n %o be %he resul% o$ %he inac%iva%ion o$ %umour
su##ressor genes (see Fnu)son, 1992a an) Fnu)son, 1992b+. Accor)ing %o %his mo)el inheri%e)
mu%a%ion o$ one o$ %,o germ line co#ies o$ a given su##ressor gene ,ill lea) %o he%ero<ygosi%y $or %ha%
gene in all soma%ic cells o$ %he carrier. 1oss or mu%a%ion o$ %he remaining ,il) %y#e gene in a given
%arge% soma%ic cell o$ %he carrier %hen crea%es %he #o%en%ial $or monoclonal cancer )evelo#men%. "iven
%he mul%i#lici%y o$ such %arge% cells %he #robabili%y o$ such loss0mu%a%ion is su$$icien%ly high %o #rovi)e
$or an inci)ence o$ cancer )evelo#men% in some carriers %ha% a##roaches 1;;5. In %his ,ay cancer
#re)is#osi%ion is inheri%e) as a )ominan% gene%ic %rai% ,i%h an inci)ence ,i%hin a given $amily ,hich
grea%ly e4cee)s %ha% in non-carriers ,here %,o in)e#en)en% soma%ic mu%a%ions, involving %ha% same
gene #air, is )eman)e) $or cancer ini%ia%ion. In essence, %he #resence o$ %he $irs% germ line mu%a%ion in
carriers re)uces %he number o$ single cell gene %arge%s $or cancer ini%ia%ion $rom %,o %o one.
I% $ollo,s $rom %his %ha% %he remaining ,il) %y#e gene co#y (allele+ in soma%ic cells o$ %umour
su##ressor )e$icien% in)ivi)uals is ,holly e4#ose) %o no% only %he mu%agenic ac%ion o$ en)ogenous
me%abolic #rocesses such as ./A %hermoins%abili%y, o4i)a%ive a%%ac!, an) misre#lica%ion (Ames, 1989+
bu% also %he mu%agenic ac%ion o$ a broa) range o$ e4ogenous carcinogens. "iven %hese circums%ances
%here is a $irm #re)ic%ion o$ eleva%e) %umorigenic ra)iosensi%ivi%y in in)ivi)uals carrying germ line
mu%a%ions o$ %umour su##ressor genes. o ,ha% e4%en% can %his #re)ic%ion be mo)elle) in cellular
mu%a%ional sys%emsY
As ye% %here are no 9uan%i%a%ive cellular sys%ems ,i%h ,hich %o assess s#eci$ic %umour su##ressor gene
mu%a%ion a$%er ra)ia%ion. 6o,ever, $rom %he s%an)#oin% o$ soma%ic cell gene%ics such au%osomal %umour
su##ressor gene mu%a%ions are ,holly analogous %o %he in)uce) loss o$ $unc%ion o$ %he remaining ,il)
%y#e aprt an) )& alleles in ro)en% an) human soma%ic cell lines %ha% res#ec%ively carry single co#y gene
mu%a%ions a% %hese loci= in bo%h %hese cellular sys%ems %here is 9uan%i%a%ive evi)ence on %he mu%agenic
ac%ion o$ ra)ia%ion %ha% allo,s commen% u#on %he li!ely ra)iosensi%ivi%y o$ )i$$eren% $orms o$ %umour
su##ressor-)e$icien% geno%y#es.
hese )a%a on ra)ia%ion mu%agenesis o$ au%osomal genes in %he hemi- or he%ero<ygous s%a%e are
)iscusse) by hac!er (1992+ an) in 3ec%ion 2 o$ %his re#or%. In essence %hey sho, %ha% in some bu% no%
all circums%ances ionising ra)ia%ion is a very e$$icien% mu%agen in res#ec% o$ %he remaining ,il) %y#e
allele. he mos% #ro$oun) mu%agenic e$$ec%s o$ ra)ia%ion in %hese in vi%ro au%osomal mu%a%ion sys%ems
are seen ,hen %he $irs% mu%an% allele carries an in%ragenic mu%a%ion an) %here are no gene%ic losses in
genomic regions $lan!ing %ha% gene, i.e. a he%ero<ygous s%a%e. he mu%agenic ac%ion o$ ra)ia%ion is,
ho,ever, $ar less #ronounce) in hemi<ygous cells ,here %he $irs% mu%a%ion involves no% only com#le%e
loss o$ one o$ %he %,o genes bu% also losses %o a)-acen% $lan!ing ./A se9uences. As no%e) in 3ec%ion 2
i% is believe) %ha% %hese )i$$erences in in)uce) mu%a%ion ra%es re$lec% %he inabili%y o$ cells %o sus%ain
viabili%y ,hen %here is homo<ygous loss o$ cri%ical se9uences. hus ,hen %he $irs% au%osomal mu%a%ion
(analogous %o %he germ line mu%a%ion o$ a %umour su##ressor gene in a given )isor)er+ is a large, ./A
)ele%ion %he secon), ra)ia%ion-in)uce) mu%a%ion may be res%ric%e) %o %he in%ragenic region o$ %he
remaining ,il) %y#e allele, i.e. a small %arge% resul%ing in a commensura%ely lo, mu%a%ion ra%e.
72
&onversely, ,hen %he $irs% mu%a%ion is in%ragenic %he e$$ec%ive %arge% $or %he secon) in)uce) mu%a%ion
can be much larger, e4%en)ing #erha#s %o )ele%ion o$ a large #ar% o$ %he ,hole chromosome. In)uce)
mu%a%ion ra%es ,i%h such a large %arge% are %here$ore very high.
*4%ra#ola%ing %hese in vi%ro $in)ings %o ra)ia%ion e$$ec%s in a range o$ human %umour su##ressor gene
)e$iciencies is no% s%raigh%$or,ar). he genomic #osi%ion o$ %he %arge% gene in res#ec% o$ essen%ial
$lan!ing se9uences an) )i$$eren%ial e$$ec%s o$ hemi- an) homo<ygous gene losses in )i$$eren% cell %y#es
,ill bo%h #lay roles in )e%ermining %umorigenic res#onses (3ec%ion 2+. /ever%heless, in con-unc%ion
,i%h o%her )a%a, %,o #rinci#al messages emerge.
:irs%, %ha% since ionising ra)ia%ion is !no,n %o #rinci#ally e4er% i%s mu%agenic ac%ion in mammalian cells
via a molecular mechanism %ha% s%rongly $avours ./A )ele%ion (hac!er, 1992+ i% may be e4#ec%e) %o
be an e$$icien% agen% $or in vivo inac%iva%ion o$ %he remaining ,il) %y#e allele in soma%ic cells o$ %umour
su##ressor gene-)e$icien% humans. 3econ), %he rela%ive e$$ec%iveness o$ such a )ele%ion mechanism is
#re)ic%e) %o be a% i%s grea%es% ,hen %he $irs%, germ line mu%a%ion is in%ragenic in na%ure. Im#or%an%ly,
surveys o$ %he $orm o$ heri%able %umour su##ressor gene mu%a%ion in a range o$ )isor)ers (e.g able 2.8+
#rovi)e clear evi)ence %ha% in%ragenic germ line gene mu%a%ions are mos% common an) %ha% gross
)ele%ions are rare. hus, in mos% cases, %here is %he e4#ec%a%ion %ha% %umorigenic ra)iosensi%ivi%y ,ill be
high. *4#erimen%al s%u)ies ,i%h ro)en%s (3ec%ion 5.2+ an) human ra)io%hera#eu%ic observa%ions
(3ec%ion 5.2+ len) subs%an%ial su##or% %o %his con%en%ion.
.!1!,! Genetic defects in proto'onco%enes
:rom %he s%an)#oin% o$ !no,n mechanisms i% is some,ha% unclear as %o ,he%her germ line mu%a%ion o$
#ro%o-oncogenes is li!ely %o s%rongly a$$ec% sensi%ivi%y %o ra)ia%ion-in)uce) cancer. 3ingle co#y an)
usually s#eci$ic mu%a%ion o$ such genes is generally %hough% %o be )ominan%ly e4#resse) an) %o have
subs%an%ial e$$ec%s on cellular #heno%y#es (3ec%ion 2+. 6o,ever, in ins%ances ,here secon) soma%ic
even%s lea)ing %o loss o$ %he ,il) %y#e allele an)0or )u#lica%ion o$ %he mu%an% allele may increase
#heno%y#ic e4#ression, some )egree o$ %umorigenic ra)iosensi%ivi%y may be e4#ec%e). *9ually
increase) e4#ression o$ cancer ,oul) be e4#ec%e) i$ soma%ic loss o$ an unlin!e) %umour gene ,ere %o
increase %he #robabili%y o$ %he clonal )evelo#men% o$ neo#lasia.
his la%%er scenario migh% a##ly in %he case o$ mul%i#le en)ocrine neo#lasia %y#e 2A (M*/2A+ an)
o%her closely rela%e) )isor)ers ,hich resul% $rom germ line mu%a%ion o$ R6) #ro%o-oncogene an)
$amilial melanoma associa%e) ,i%h )e$ec%s in %he #1>
I/F8
gene (3ec%ion 2+.
In %he absence o$ any relevan% observa%ions %his scenario remains ho,ever s#ecula%ive an), since cancer
#re)is#osi%ion associa%e) ,i%h #ro%o-oncogene mu%a%ion a##ears %o be very uncommon in humans, %he
#auci%y o$ gui)ance on %his issue is no% -u)ge) %o be cri%ical.
.!"! Rodent models of cancer predisposition
'o)en% mo)els re#resen%ing )isease-associa%e) human germ line mu%a%ions are #laying an increasingly
im#or%an% role in biome)ical research. 3uch mo)els may be #rovi)e) by animals carrying na%ural germ
line mu%a%ions or, ,i%h increasing $re9uency, by %ransgenic animals in ,hich s#eci$ic mu%a%ions have
been #ro)uce) in germ cells by recombinan% ./A %echni9ues ("or)on, 1992+. In %he con%e4% o$ cancer
#re)is#osi%ion %he grea%es% #rogress is curren%ly being ma)e in res#ec% o$ ro)en% mo)els o$ s#eci$ic
human ./A re#air an) %umour su##ressor gene )isor)ers (Eilliams an) Dac!s, 199>+.
73
.!"!1! #$A repair deficient rodents
Asing recombinan% ./A Hgene !noc!ou%I %echni9ues, mouse mo)els o$ human 4ero)erma
#igmen%osum (OP+ (3an)s e% al., 1995= /a!ane e% al., 1995= )e Vries e% al., 1995+ an) 6/P&& (Ba!er
e% al., 1995= )e Ein) e% al., 1995= 'ei%mair e% al., 1995+ have been cons%ruc%e). hese mu%an% mice
sho, some bu% no% all o$ %he $ea%ures o$ %heir human coun%er#ar%s bu% mouse homologues o$ OP are, as
e4#ec%e), highly sensi%ive %o AV'-in)uce) s!in cancer. As ye% %here are ho,ever no )a%a rela%ing %o %he
res#onse o$ OP an) 6/P&& mice %o ionising ra)ia%ion. *9ually %here are no )a%a on %he carcinogenic
res#onse %o ra)ia%ion in na%urally occurring sci mice %ha% have a gene%ic )e$ec% in %he re#air o$ ./A
)ouble s%ran) lesions (3ec%ion 2+.
:ollo,ing %he molecular cloning an) charac%erisa%ion o$ a number o$ im#or%an% ./A re#air an) re#air-
rela%e) genes i% is ho,ever an%ici#a%e) %ha% ra)ia%ion carcinogenesis )a%a $or a range o$ relevan% gene-
!noc!ou% mice ,ill become available )uring %he ne4% $e, years. C$ #ar%icular no%e is %he recen%
cons%ruc%ion o$ gene !noc!ou%s $or At-, Brca1, Brca2, an) Ra51 (see also 3ec%ion 2+. :irs%, in %he case
o$ At- i% has been sho,n %ha% %he null mice are ra)iosensi%ive, )e$ec%ive in cell cycle con%rol an) #rone
%o %he s#on%aneous )evelo#men% o$ lym#homa an) %he associa%e) chromosomal rearrangemen%s (e.g
Barlo, e% al., 199>= Ou an) Bal%imore, 199>+. 3econ), embryonic le%hali%y an) ra)ia%ion
hy#ersensi%ivi%y in Brca2 null mice has been )emons%ra%e) %o be me)ia%e) by 'a)51 #ro%ein in)ica%ing
%ha% Brca #ro%ein may be a cri%ical co-$ac%or in %he re#air o$ ./A )sb (3haran e% al., 1997+.
.!"!"! &umour suppressor %ene deficient rodents
'o)en% mo)els o$ $amilial a)enoma%ous #oly#osis (Moser e% al., 199;= :o))e e% al., 1998+,
neuro$ibroma%osis %y#e 1 (Dac!s e% al., 1998+, 1i7:raumeni syn)rome (e.g .oneho,er e% al., 1992+ an)
%uberous sclerosis %y#e 2 (Fobayashi e% al., 1995+ have been charac%erise) as sho,ing increase) cancer
inci)ence al%hough %here are usually )i$$erences %o %heir human coun%er#ar%s in res#ec% o$ %he %umour
s#ec%rum an) o%her #heno%y#ic mani$es%a%ions. 1imi%e) )a%a on %he %umorigenic res#onse %o ra)ia%ion
are available $or %hree o$ %hese ro)en% mo)els.
.!"!"!1! Mice deficient in p.,
Mice he%ero<ygously )e$icien% in germ line p53 are analogous %o %he human cancer #rone )isor)er 1i7
:raumeni syn)rome (1:3+. 3uch mice genera%e) by gene !noc!ou% %echni9ues have been sho,n %o
e4hibi% an eleva%e) s#on%aneous inci)ence o$ %umours, #rinci#ally lym#homas an) sarcomas,
reminiscen% o$ 1:3 (.oneho,er e% al., 1992= 6arvey e% al., 1992= Fem# e% al., 1998+. hese mice are
also a% increase) ris! o$ %umour )evelo#men% a$%er e4#osure %o a chemical carcinogen (6arvey e% al.,
1992+.
Mos% im#or%an%ly ho,ever p53 he%ero<ygo%es (
K0L
+ have been sho,n %o be highly sensi%ive %o ra)ia%ion
%umorigenesis (Fem# e% al., 1998+. hese )a%a on p53 he%ero<ygo%es, ,hich are base) on %umour
mor%ali%y u# %o 8; ,ee!s o$ age $ollo,ing 8 "y gamma ray e4#osure, are given in :ig. 5.1. he
inci)ence o$ s#on%aneously arising $a%al %umours in p53
K0L
mice ,as $oun) %o be high ,i%h a me)ian
value $or %umour la%ency o$ Z7; ,ee!s. 3#on%aneous %umour inci)ence in p53 null (
L0L
+ mice ,as higher
s%ill bu% %he mos% )rama%ic e$$ec% o$ %he null p53 geno%y#e ,as %he shor%ening, %o 21 ,ee!s, o$ %he
me)ian la%en% #erio) $or s#on%aneous %umours.
74
:ig. 5.1. A##earance ,i%h %ime o$ %umours in irra)ia%e) an) unirra)ia%e) p53-)e$icien% mice ($rom
Fem# e% al., 1998+.
Irra)ia%ion o$ p53
K0L
mice increase) %umour inci)ence ,i%h no signi$ican% change in %he %umour
s#ec%rum bu% %he mos% #ro$oun) e$$ec% o$ irra)ia%ion ,as a shor%ening o$ me)ian %umour la%ency $rom
Z7; ,ee!s %o 8; ,ee!s, i.e %o,ar)s %he value )e%ermine) $or unirra)ia%e) p53
L0L
mice. In%eres%ingly,
irra)ia%ion ha) only a minor e$$ec% on %umour inci)ence an) la%ency in p53
L0L
mice im#lying %ha% %he
#resence o$ a single ,il) %y#e co#y o$ p53 ,as ra%e limi%ing $or %umorigenesis an), by im#lica%ion, %ha%
in
K0L
mice %he ,il) %y#e p53 allele re#resen%e) %he #rinci#al %arge% $or ra)ia%ion.
his la%%er conclusion ,as su##or%e) by molecular analysis o$ %umours o$ p53
K0L
mice ,hich sho,e)
%ha% ,hereas 557755 o$ s#on%aneous %umours ha) los% %he remaining ,il) %y#e p53 allele, $or ra)ia%ion
in)uce) %umours %ha% $igure rose %o 9>5. More in%riguing ho,ever ,as %he $in)ing %ha% ,hile only 2;5
o$ s#on%aneous %umours ha) )u#lica%e) %he resi)ual mu%an% p53 allele, such )u#lica%ion charac%erise)
aroun) 8;5 o$ ra)ia%ion in)uce) %umours. hus, mu%an% p53 gene )u#lica%ion via mi%o%ic
recombina%ion or ,hole chromosome 11 non)is-unc%ion $ollo,e) by re)u#lica%ion a##eare) %o be
charac%eris%ic o$ ra)ia%ion %umorigenesis.
.uring %he 8;-,ee! %ime s#an o$ %hese s%u)ies nei%her con%rol nor irra)ia%e) ,il) %y#e (p53
K0K
+ mice
)evelo#e) %umours. An)er %hese circums%ances i% is no% #ossible %o a)e9ua%ely 9uan%i$y %he )egree o$
%umorigenic ra)iosensi%ivi%y associa%e) ,i%h p53 )e$iciency. /ever%heless, in %he absence o$ %umours in
con%rol an) irra)ia%e) ,il) %y#e animals, %he increase in %umorigenic ra)iosensi%ivi%y in p53
K0L
animals
mus% be subs%an%ial an) is also accom#anie) by a shor%ening in la%ency. hese $ea%ures a##ear %o be
associa%e) ,i%h a %umorigenic mechanism a$%er ra)ia%ion %ha% involves ,il) %y#e p53 gene loss an)
mu%an% gene )u#lica%ion. :ollo,-u# s%u)ies on %he cy%ogene%ic res#onse o$ p53 geno%y#es in %he mouse
(Bou$$ler e% al., 1995+ allo, $ur%her commen% on %hese issues.
In %hese s%u)ies moc! an) 2 "y in vivo irra)ia%ion o$ p53
K0K, K0L
an)
L0L
mice ,as $ollo,e) by analysis $or
#ersis%en% s%able s%ruc%ural an) numerical chromosomal changes in bone marro, cell #o#ula%ions= %he
shor%-%erm ra)iobiological en)#oin%s o$ chroma%i) )amage re#air, sis%er chroma%i) e4change (3&*+ an)
mi%o%ic )elay ,ere also inves%iga%e) in s#leen cells in vi%ro. he in vivo $re9uency o$ s#on%aneously
arising s%able s%ruc%ural an) numerical aberra%ions ,as eleva%e) 2; $ol) in p53
K0L
an)
L0L
com#are) %o
K0
K
. /o e4cessive in)uc%ion o$ s%able s%ruc%ural aberra%ions ,as observe) in vivo an) in vi%ro s%u)ies
reveale) no evi)ence o$ a signi$ican% e$$ec% o$ p53 )e$iciency in res#ec% o$ chroma%i) )amage re#air or
75
3&* in)uc%ion a$%er ra)ia%ion. In con%ras%, in vivo s%u)ies sho,e) p53-)e$icien% geno%y#es %o be 1;715-
$ol) more sensi%ive %o %he in)uc%ion o$ numerical chromosomal changes (chromosomal gains losses+
an) in vi%ro s%u)ies reveale) a #ro$oun) )e$ec% in %he o#era%ion o$ #os%-irra)ia%ion mi%o%ic )elay in %hese
p53-)e$icien% geno%y#es im#lying $ailure o$ a "20M cell cycle chec!#oin% $or re#air. I% ,as conclu)e)
%ha% %his chec!#oin% $ailure ,as %he basis o$ %he chromosomal non)is-unc%ion mechanism $or increase)
hy#er#loi)y ,hich subse9uen%ly #rovi)e) %he )rive $or %he increase) %umorigenic ra)iosensi%ivi%y o$
p53-)e$icien% mice.
Cn %he basis o$ %his conclusion %he 9uan%i%a%ive )a%a o$ Bou$$ler e% al. (1995+ rela%ing %o ra)ia%ion
in)uce) hy#er#loi)y may be use) as a surroga%e %o -u)ge %he %umorigenic ra)iosensi%ivi%y o$ p53-
)e$icien% mice. hese )a%a sho,n in able 5.1 sugges% a $ac%or o$ 12712-$ol) increase in p53
K0L
mice
com#are) %o ,il) %y#e. I$ ho,ever %he )egree o$ hy#er#loi)y, as illus%ra%e) by %he range o$
chromosome numbers in able 5.1 column >, ,ere %o be a #osi%ive $ac%or in subse9uen% %umorigenic
)evelo#men%, %hen %he above -u)ge) value may un)eres%ima%e %he increase in %umorigenic
ra)iosensi%ivi%y associa%e) ,i%h p53 )e$iciency.
.!"!"!"! Mice deficient in Apc
Mice %ha% are he%ero<ygously )e$icien% in %he Apc gene are analogous %o %he human colon cancer #rone
)isor)er, $amilial a)enoma%ous #oly#osis (:AP+. he $irs% e4am#le o$ %his mouse mu%an% ,as i)en%i$ie)
$ollo,ing %he observa%ion o$ mul%i#le in%es%inal neo#lasia, %he *in #heno%y#e, in %he #rogeny o$ an :1
animal $ollo,ing #a%ernal e4#osure %o a chemical mu%agen (Moser e% al., 199;+. I% ,as $ur%her sho,n
%ha% (a+ %he *in #heno%y#e ma##e) %o mouse chromosome 18 in a region %ha% ,as syn%enic %o %he
human 59 region enco)ing APC (1uongo e% al., 1992+ an) (b+ %ha% %he *in mouse carrie) a mu%an%
allele o$ Apc charac%erise) by a nonsense mu%a%ion a% co)on 85; (3u e% al., 1992+. In subse9uen% s%u)ies
%he *in mu%a%ion in cer%ain gene%ic bac!groun)s has been sho,n %o #re)is#ose %o s#on%aneous
mammary carcinoma as ,ell as in%es%inal neo#lasia (Moser e% al., 1995+ an) %ha% %he #ene%rance an)
e4#ressivi%y o$ %he un)erlying Apc mu%a%ion is s%rongly mo)i$ie) by a chromosome 8 enco)e) locus
%erme) *o-1 ,hich may re#resen% %he #hos#holi#ase gene, Pla2?5 (.ie%rich e% al., 1992, MacPhee e%
al., 1995+.
Molecular s%u)ies on %he s#on%aneously arising a)enomas o$ *in mice have sho,n %hem %o be
charac%erise) #rinci#ally by loss o$ %he ,hole o$ %he chromosome 18 %ha% enco)es %he ,il) %y#e Apc
allele ,hile %he mu%an% allele is re%aine) (1uongo e% al., 1998, 1evy e% al., 1998+. 3uch ,hole
chromosome 5 losses have no% been observe) in %he colonic %umours o$ human :AP #a%ien%s, a resul%
%ha% may re$lec% a signi$ican% )i$$erence in mechanisms o$ colon carcinogenesis be%,een mouse an)
man (Moser e% al., 1995+. Preliminary e4#erimen%s ,i%h *in mice have reveale) %ha% %he inci)ence o$
bo%h in%es%inal an) mammary %umours is increase) by e4#osure o$ animals %o %he chemical carcinogen
e%hyl ni%rosourea an) %ha% carcinogen sensi%ivi%y is cri%ically )e#en)en% u#on age a% e4#osure (Moser e%
al., 1995+. Cngoing ra)ia%ion %umorigenesis s%u)ies in hybri) *o-
D
*in mice sho, %ha% a ,hole bo)y
acu%e 4-ray )ose o$ 2 "y increases %he mean inci)ence o$ in%es%inal a)enomas $rom 11 %o 22 #er animal
(*llen)er e% al., 1997+. /o a)enomas ,ere score) in con%rol ,il) %y#e mice an) only rarely in irra)ia%e)
,il) %y#e mice %hus #rovi)ing evi)ence o$ %he large increase in absolu%e %umorigenic ris! associa%e)
,i%h Apc )e$iciency.
In a similar ,ay 1uongo an) .ove (199>+ assesse) %he %umorigenic e$$ec%s o$ gamma irra)ia%ion on
Min mice an) sho,e) s%a%is%ically signi$ican% increases in a)enoma inci)ence a$%er )oses o$ ;.55 an)
;.8 "y. he )i$$eren% gene%ic bac!groun)s o$ %he mice use) in %he s%u)ies o$ *llen)er e% al. (1997+ an)
76
1uongo an) .ove (199>+ #rovi)e evi)ence %ha% %he mo)i$ying locus *o-1 has e9uivalen% e$$ec%s on
s#on%aneous an) ra)ia%ion-in)uce) a)enoma inci)ence.
Im#or%an%ly, an) in accor) ,i%h mechanis%ic #re)ic%ions, s%u)ies in bo%h labora%ories give evi)ence o$
ra)ia%ion-associa%e) chr18 in%ers%i%ial )ele%ions in a)enomas %ha% encom#ass %he ,il) %y#e Apc gene
(1uongo an) .ove 199>= 3ilver e% al., 199>+.
Cverall, given %he high s#on%aneous inci)ence o$ in%es%inal neo#lasms in Apc-)e$icien% mice, %he
magni%u)e o$ %he increases in a)enoma inci)ence a$%er ra)ia%ion )oses u# %o 2 "y are mo)es% an) are
-u)ge) %o be broa)ly consis%en% ,i%h %he a##lica%ion o$ rela%ive ra)ia%ion ris! in %he case o$ %umour
su##ressor gene )e$iciency (see 3ec%ion 5.2.5+. his vie, is also su##or%e) by )a%a regar)ing gene%ic
mo)i$ica%ion o$ Apc #ene%rance.
.!"!"!,! Rats deficient in &sc"
.ominan%ly inheri%e) #re)is#osi%ion %o s#on%aneously arising renal carcinoma in %he ra% ,as originally
)escribe) by *!er an) Mossige (19>1+. *!er ra%s %y#ically )evelo# bila%eral mul%i#le renal carcinomas
,i%h %he res#onsible gene (RC+ being highly #ene%ran%. he RC gene has since been ma##e) %o %he
#ro4imal (9+ region o$ ra% chromosome 1; an), %hrough )irec% s%u)y an) lac! o$ syn%enic rela%ionshi#s,
#ossible associa%ions ,i%h ra% homologues o$ %he human !53, ;)1, an) *)+1 genes have been
e4clu)e) (Jeung e% al., 1992, 6ino e% al., 1992a+. 6o,ever a ne, conserve) lin!age grou# on ra%
chromosome 1; an) human 1>#12.2 has been es%ablishe) ,i%hin ,hich %he *!er RC gene an) %he ra%
homologue o$ human %uberous sclerosis %y#e 2 gene ()+C2+ ,ere sho,n %o be closely lin!e).
:ollo,ing %his, %he *!er mu%a%ion ,as charac%erise) as a germ line inser%ion o$ a 5!b ./A $ragmen%
in%o %he ra% )sc2 gene (Fobayashi e% al., 1995+. hus, %he *!er ra% #rovi)es a ro)en% homologue o$
human %uberous sclerosis %y#e 2 (see 3ec%ion 2+ an), li!e %he %umours o$ such #a%ien%s, %he renal
%umours o$ *!er ra%s sho, genomic losses in %he region o$ %he #re)is#osing gene (Fubo e% al., 1998+.
Al%hough %he overall #heno%y#ic mani$es%a%ions in human %uberous sclerosis #a%ien%s (3ec%ion 2+ an)
*!er ra%s )i$$er in many res#ec%s %hey share a s%rong #re)is#osi%ion %o renal %umours. his allo,s some
commen% u#on s%u)ies con)uc%e) on ra)ia%ion %umorigenesis in %his ro)en% mo)el (6ino e% al., 1992b+.
In %hese s%u)ies male an) $emale ra%s carrying %he *!er mu%a%ion ,ere e4#ose) in %he renal region %o
gamma ray )oses o$ ;, 2, > or 9 "y. Animals ,ere sacri$ice) a% 1;711 mon%hs, %he inci)ence o$ !i)ney
%umours ,as assesse) in serial %issue sec%ions an) a )ose res#onse $or %umour in)uc%ion ,as ob%aine).
hese )ose res#onse )a%a (able 5.2+ sho, %ha% renal %umour inci)ence increases linearly ,i%h )ose, %he
increase in yiel) a% 9 "y being 11712-$ol) grea%er %han con%rol values. A% %he %ime o$ %his s%u)y i% ,as
no% #ossible %o s#eci$ically i)en%i$y he%ero<ygous ()sc2
D7E
+ animals #rior %o e4#erimen%a%ion an)
%here$ore all o$$s#ring ,ere irra)ia%e). 3ince %he )sc2
E7E
geno%y#e is embryo le%hal %he irra)ia%e)
#o#ula%ion ,ill %here$ore com#rise e9ual numbers o$
K0L
an)
K0K
geno%y#es. /ever%heless, given %ha%
K0L

animals all )evelo# charac%eris%ic renal %umours %he )a%a o$ able 5.2 re$lec% only %he ra)ia%ion res#onse
o$ )sc2
D7E
male an) $emale animals. he au%hors no%e, ho,ever, %ha% $our o$ %he ra%s -u)ge) %o be )sc2
D7
D
geno%y#es ha) each )evelo#e) one or %,o renal %umours o$ a non-*!er %y#e a$%er )oses o$ > or 9 "y.
Cn %he basis o$ %he )a%a o$ able 5.2 i% may %here$ore be #ro-ec%e) %ha% no more %han eigh% %umours ha)
arisen amongs% 21 male #lus 22 $emale
K0K
animals receiving > or 9 "y, i.e ;.2 %umours #er animal. A
sum o$ %he mean %umour yiel)s #er
K0L
animal $ollo,ing %hese )oses #rovi)es a value o$ 28 ,hich
re)uces %o 28 a$%er sub%rac%ion o$ %he average s#on%aneous yiel). hus, accor)ing %o %he above
77
#ro-ec%ions, in %he )ose range >79 "y, %he increase in renal %umorigenic ra)iosensi%ivi%y in )sc2
D7E
ra%s
com#are) %o ,il) %y#e (
K0K
+ may, as a $irs% a##ro4ima%ion, be -u)ge) %o be 17;, i.e 28(
K0L
+0;.2(
K0K
+.
3ince, ho,ever, )sc2
D7E
ra%s ,oul) be e4#ec%e) %o )evelo# renal %umours a% an earlier age %han ,il)
%y#es an) %he s%u)y )eman)e) animal sacri$ice a% 1;711 mon%hs i% is almos% cer%ain %ha% %he ,il) %y#e
res#onse is un)eres%ima%e) an) conse9uen%ly %ha% %he above #ro-ec%ion signi$ican%ly overes%ima%es %he
)egree o$ %umorigenic ra)iosensi%ivi%y in %his animal mo)el o$ human %uberous sclerosis. I% is, ho,ever,
)i$$icul% %o esca#e %he conclusion %ha% )sc2-)e$icien% *!er ra%s e4hibi% renal-s#eci$ic %umorigenic
ra)iosensi%ivi%y %ha% is )rama%ically grea%er %han %ha% o$ %he ,il) %y#e.
.!"!,! Relative tumour ris) in different mouse strains
In %he same ,ay %ha% a na%urally arising )sc2 gene mu%a%ion )e%ermines %he renal carcinoma
susce#%ibili%y o$ *!er ra%s, )i$$erences in s#eci$ic %umour susce#%ibili%y be%,een )ivergen% inbre) mouse
s%rains #robably has gene%ic origins. Cn %his basis %he s%u)y o$ 3%orer e% al. (1988+ #rovi)es )a%a on
,hich %o commen% u#on gene%ic e$$ec%s in ra)ia%ion %umorigenesis. *s%ima%es o$ na%ural s#on%aneous
an) gamma ray in)uce) cancer ris!s ,ere ob%aine) $or nine neo#lasms arising in &26 an) &57Bl mice
an) com#are) ,i%h #revious )a%a on Balb& an) ':M mice. ,o #rinci#al messages emerge $rom %his
s%u)y. :irs%, %here ,as acce#%able concor)ance $or mos% neo#lasms $or rela%ive ra)iogenic ris! in mice
an) humans. 3econ), an) o$ )irec% relevance %o %his re#or%, in%ers%rain varia%ion in na%ural cancer ris!
,as broa)ly rela%e) %o %he varia%ion observe) in ra)iogenic cancer ris!. Assuming %ha% inheri%e) $ac%ors
are %he #rinci#al )e%erminan%s o$ na%ural cancer inci)ence in )i$$eren% %issues, i% $ollo,s %ha%
%umorigenic ra)iosensi%ivi%y is similarly a$$ec%e). As ye% i% is no% #ossible %o rela%e %hese $in)ings %o
s#eci$ic murine genes an) hence %o human geno%y#es bu% %he ma##ing s%ra%egies use) %o uncover %he
*!er mu%a%ion allo, $or %his in %he $u%ure. Cverall, a gene%ic e4#lana%ion $or %he )a%a an) conclusions o$
3%orer e% al., are consis%en% ,i%h subse9uen% $in)ings in )e$ine) cancer-#rone ro)en% geno%y#es ou%line)
earlier in %his 3ec%ion an) also ,i%h %he human ra)io%hera#y observa%ions %ha% $ollo,.
he ca#aci%y o$ na%ural inbre) mouse s%rains %o s%u)y %he in$luence o$ gene%ic $ac%ors on in)uce)
%umorigenesis has been ,ell )emons%ra%e) by %he s%u)ies o$ .eman% an) co-,or!ers (e.g :i-neman e%
al., 199>+. In such s%u)ies mul%i#le loci con%rolling chemical carcinogenesis in %he lung have been
reveale) an) evi)ence #rovi)e) on %he com#le4i%y o$ %he gene7gene in%erac%ions %ha% )e%ermine %he
inci)ence o$ in)uce) %umours.
.!,! Radiotherapeutic observation
.irec% observa%ion o$ increase) %umorigenic ra)iosensi%ivi%y in gene%ically cancer-#rone humans has
been ma)e in cases o$ re%inoblas%oma, nevoi) basal cell carcinoma syn)rome, neuro$ibroma%osis an)
1i7:raumeni syn)rome receiving ra)io%hera#y $or #rimary malignan% )isease. :or %hese )isor)ers an)
#ar%icularly $or re%inoblas%oma an) nevoi) basal cell carcinoma syn)rome %here is evi)ence o$
increase) ris! o$ secon), %hera#y-rela%e) cancer.
.!,!1! Retinoblastoma
A subs%an%ial $rac%ion o$ chil)ren ,i%h %he heri%able (bila%eral+ $orm o$ re%inoblas%oma ('B+ )ie as a
conse9uence o$ secon) #rimary neo#lasms %ha% )evelo# in la%er li$e (e.g Mulvihill an) McFeen, 1977=
Fings%on e% al., 1987= Mea)o,s, 1988= *ng e% al., 1992= Eong e% al., 1997+. 3ince unila%eral
re%inoblas%oma )evelo#s s#ora)ically as a non-heri%able neo#lasm in chil)ren i% has been #ossible %o
78
com#are %he cumula%ive mor%ali%y ra%es associa%e) ,i%h %he gene%ic an) non-gene%ic $orm o$ %his
malignancy.
:ig. 5.2 an) able 5.2 sho, a )a%a se% on 'B com#ile) by *ng e% al. (1992+. his re#resen%s a $ollo,-u#
o$ a cohor% o$ 1>;2 re%inoblas%oma #a%ien%s in %he A3A by la%erali%y an) rein$orces %he conclusion o$
3ec%ion 2 %ha% heri%able 'B #a%ien%s are #rone %o )evelo# a range o$ %umours, re%inoblas%oma usually
being %he $irs% o$ %hese. :ollo,ing )iagnosis o$ re%inoblas%oma, heri%able 'B #a%ien%s e4#erience a
ra#i)ly rising ris! o$ %umour mor%ali%y ,hich, a% 8; years a$%er )iagnosis rises %o aroun) 2>5 com#are)
%o only 1.55 in #a%ien%s ,i%h non-heri%able )isease (:ig. 5.2+. In %he heri%able 'B grou# %he #rinci#al
secon) cancers ,ere o$ bone an) connec%ive %issue al%hough e4cess melanoma, brain neo#lasms an)
%umours a% o%her si%es ,ere also observe) (able 5.2+. As no%e) by *ng e% al. (1992+ %hese )a%a broa)ly
accor) ,i%h #revious observa%ions al%hough %here are )i$$erences in %umour %y#es an) cumula%ive
mor%ali%y es%ima%es ,hich are #robably e4#laine) by )i$$erences in s%u)y )esign, #ar%icularly %he leng%h
o$ %he $ollo,-u# #erio).
:ig. 5.2. &umula%ive mor%ali%y $rom secon) #rimary neo#lasms )uring $ollo,-u# o$ %he en%ire cohor% o$
1>;2 re%inoblas%oma #a%ien%s by la%erali%y= bila%eral (heri%able+ an) unila%eral (non-heri%able+ ($rom *ng
e% al., 1992+.
:or %he #ur#oses o$ %his re#or% %he #rinci#al bene$i% o$ %he s%u)y o$ *ng e% al., is %he si<e o$ %he cohor%
an) %he long #erio) o$ $ollo,-u# ,hich allo, s#eci$ic commen% on %he in$luence o$ #rior ra)io%hera#y
$or re%inoblas%oma on %umour inci)ence an) mor%ali%y ra%es. hese )a%a ,hich are re#ro)uce) in able
5.2 an) :ig. 5.2 sho, %ha% %he ris! o$ secon) %umours in heri%able 'B is $ur%her increase) by #rior
ra)io%hera#y %o an e4%en% %ha% signi$ican%ly e4cee)s %ha% in non-heri%able 'B. In heri%able 'B e4cess
ris! o$ mor%ali%y #er 1;;; #erson years ,as es%ima%e) %o be 5.8 in %he irra)ia%e) cases com#are) %o 2.5
in %hose no% receiving ra)io%hera#y= :ig. 5.2 sho,s %he commensura%e )ivergence o$ %he cumula%ive
%umour mor%ali%y curves $or %hese %,o grou#s.
79
:ig. 5.2. &umula%ive mor%ali%y $rom secon) #rimary neo#lasms )uring $ollo,-u# o$ bila%eral (heri%able+
re%inoblas%oma #a%ien%s by %rea%men% ,i%h an) ,i%hou% irra)ia%ion ($rom *ng e% al., 1992+.
By con%ras%, in non-heri%able 'B %he e4cess ris! o$ mor%ali%y #er 1;;; #erson years ,as es%ima%e) %o be
;.8 an) ;.2 in %he irra)ia%e) an) non-irra)ia%e) grou#s res#ec%ively (able 5.2+. hus, as a $irs%
a##ro4ima%ion, %hese %umour mor%ali%y )a%a im#ly %ha% in heri%able 'B %umorigenic ra)iosensi%ivi%y as
measure) by cumula%ive mor%ali%y, is increase) by aroun) 57>-$ol) ,hen com#are) ,i%h non-heri%able
'B.
,o $ea%ures o$ %he )a%a sugges% ho,ever %ha% %his sim#ly -u)ge) $ac%or may un)eres%ima%e %he %rue
)i$$erence in %umorigenic ra)iosensi%ivi%y be%,een normal humans an) heri%able 'B. :irs%, as no%e) by
*ng e% al., %he ris! o$ secon) %umours in non-heri%able 'B a##eare) %o be grea%er %han e4#ec%e)
(rela%ive ris!M2.1= 955 &IM1.;77.2+. he reason $or %his remains %o be )e%ermine) $ully bu% may, in
#ar%, be associa%e) ,i%h %he #resence o$ occul% cases (#erha#s >7125+ o$ heri%able 'B in %he grou#
#resen%ing ,i%h unila%eral )isease. 3econ), since %he si%e o$ %he secon) %umour in rela%ion %o %he
irra)ia%e) $iel) coul) no% be s#eci$ie) %here is an inheren% %en)ency $or overall %umour mor%ali%y )a%a %o
un)eres%ima%e %he %rue number o$ ra)ia%ion-associa%e) malignancies. 3im#ly s%a%e), %he e4%en% %o ,hich
%he %umour inci)ence in heri%able 'B is increase) ,i%hin %he irra)ia%e) $iel) is e4#ec%e) %o be grea%er
%han %he increase in %heir rela%ive con%ribu%ion %o %umour mor%ali%y ,hich consi)ers all si%es. 'elevan% %o
%his issue are re#or%s o$ mul%i#le %umours ,i%hin %he locally irra)ia%e) %issues o$ heri%able 'B #a%ien%s
(see raboulsi e% al., 1988+.
he same A3A cohor% o$ re%inoblas%oma #a%ien%s have been %he sub-ec% o$ a $ollo,-u# nes%e) case-
con%rol s%u)y %ha% consi)ere) )oses an) %umour si%e (Eong e% al., 1997+. his s%u)y has #rovi)e)
evi)ence o$ a )ose res#onse rela%ionshi# $or %he a##earance o$ secon) bone an) so$% %issue sarcoma in
heri%able 'B #a%ien%s receiving ra)io%hera#y.
:or all sarcomas combine) %he ris! ,as evi)en% a% )oses Z5 "y an) rose %o aroun) 11-$ol) a% >; "y an)
above. :or so$% %issue sarcoma %he rela%ive ris!s sho,e) s%e#,ise increases in all )ose ca%egories ,hich
80
,ere s%a%is%ically signi$ican% a% 1;729.9 "y an) 2;759.9 "y. In %his ,ay %he $ur%her $ollo,-u# o$ %his
cohor% #rovi)es con$irma%ion o$ #revious s%u)ies sho,ing %ha% %he ris! o$ secon) cancers in heri%able
'B #a%ien%s is subs%an%ial an) is increase) $ur%her by high )ose ra)ia%ion e4#osure.
3ince %he number o$ secon), %hera#y-rela%e) %umours in %he 9uali$ying non-heri%able 'B cases ,as very
small %here is, ho,ever, almos% no in$orma%ion %o be gaine) on %he rela%ive %umorigenic ra)iosensi%ivi%y
o$ heri%able versus s#ora)ic 'B #a%ien%s. he )a%a are no% inconsis%en% ,i%h gene%ically )e%ermine)
increases in ra)iosensi%ivi%y bu% serve #rinci#ally %o highligh% %he uncer%ain%ies %ha% a%%ach %o any
9uan%i%a%ive -u)gemen%s %ha% may be ma)e.
In an a%%em#% %o con$irm %he increase) %umorigenic ra)iosensi%ivi%y o$ heri%able 'B #a%ien%s, analyses
are un)er,ay %o com#are ra)ia%ion ris!s o$ bone sarcoma in such #a%ien%s receiving %umour
ra)io%hera#y in in$ancy an) chil)hoo) ,i%h normal #ersons %rea%e) in chil)hoo), a)olescence an)
a)ul%hoo) $or non-malignan% )isease (1an), 1997+. hese analyses are base) u#on es%ima%e) )oses %o
%he local %issues in ,hich bone sarcomas ,ere observe).
he #reliminary resul%s, ,hile sub-ec% %o consi)erable numerical uncer%ain%y, #rovi)e $ur%her su##or% %o
%he hy#o%hesis %ha% bone %issue o$ heri%able 'B #a%ien%s has an eleva%e) sensi%ivi%y %o ra)ia%ion
sarcomagenesis. he magni%u)e o$ %his eleva%e) ris! remains mos% )i$$icul% %o es%ima%e bu% i% is
#robable %ha% heri%able 'B #a%ien%s are a% leas% 1;[ more sensi%ive %o ra)ia%ion sarcomagenesis %han
members o$ %he general #o#ula%ion (1an), 1997+.
.!,!"! $evoid basal cell carcinoma syndrome
*vi)ence %ha% nevoi) basal cell carcinoma syn)rome (/B&&3+ #a%ien%s are e49uisi%ively sensi%ive %o
%he carcinogenic e$$ec%s o$ ionising ra)ia%ion )a%es bac! %o 1989. 3charnagel an) Pac! (1989+ re#or%e)
on a 5-year-ol) male #a%ien% %y#ical o$ /B&&3 ,i%h a his%ory o$ ra)io%hera#y $or %hymic enlargemen%
,ho ha) )evelo#e) mul%i#le (Z1;;;+ #igmen%e) basal cell s!in lesions ,i%hin %he irra)ia%e) $iel) (:ig.
5.8+.
:ig. 5.8. Basal cell nevi a$%er %hymic irra)ia%ion in nevoi) basal cell carcinoma syn)rome. 'e#ro)uce)
$rom 3charnagel an) Pac! (1989+ ,i%h !in) #ermission. \ 1989, American Me)ical Associa%ion.
81
3ubse9uen%ly %here have been a number o$ re#or%s )e%ailing %he in)uc%ion o$ mul%i#le basal cell
carcinomas (B&&+ in /B&&3 #a%ien%s receiving cranios#inal ra)io%hera#y $or me)ulloblas%oma, a
%umour %o ,hich such #a%ien%s are #rone (see 3%rong, 1977= 6a,!ins e% al., 1979= &u%ler e% al., 19>8+.
3imilar $in)ings have been ma)e in /B&&3 #a%ien%s %rea%e) $or rhab)omyosarcoma (3ch,eisgu%h e%
al., 19>8+ an) o%her )isor)ers ('ayner e% al., 197>+. I% is, ho,ever, evi)en% $rom %he case re#or%s
summarise) by 3ou%h,ic! an) 3ch,ar%< (1979+ %ha% %umorigenic ra)iosensi%ivi%y in /B&&3 may no%
be uni$ormly high.
An e4am#le o$ %he res#onse o$ such /B&&3 me)ulloblas%oma #a%ien%s %o cranios#inal ra)io%hera#y is
sho,n in :ig. 5.5. Many hun)re)s o$ basal cell nevi arise ,i%hin %he irra)ia%e) $iel) )uring %he $irs% $ive
years #os%-irra)ia%ion ,i%h a %en)ency %o clus%er on %he #eri#hery o$ %he $iel) ,here %he %hera#y )ose
,as insu$$icien% %o s%erilise basal %arge% cells in %he s!in. In subse9uen% years a much smaller number o$
ne, nevi con%inue %o )evelo# ou%si)e %he irra)ia%e) $iel), #rinci#ally in sun e4#ose) areas (3%rong,
1977+ in)ica%ing %ha% %he )rama%ic ?5-year carcinogenic res#onse is ra)ia%ion )e#en)en%. In some
#a%ien%s, B&& )evelo#men% a$%er ra)ia%ion is seen as early as > mon%hs, a la%en% #erio) subs%an%ially
shor%er %han $or s#on%aneous B&& in /B&&3= in normal #a%ien%s %he la%en% #erio) $or ra)iogenic B&&
is re#or%e) %o be aroun) 2; years (see 3%rong, 1977+.
82
:ig. 5.5. Basal cell nevi an) carcinoma a$%er cranios#inal irra)ia%ion in nevoi) basal cell carcinoma
syn)rome (cour%esy o$ ". *vans+.
In a))i%ion %o B&&, $emale /B&&3 #a%ien%s are also #rone %o %he )evelo#men% o$ #os%-#uber%al ovarian
$ibromas bu% #re-#uber%al neo#lasms are rare. ,o young (?2.5 years+ $emale #a%ien%s surviving
%horacic an) lumbar s#ine irra)ia%ion $or me)ulloblas%oma ,ere ho,ever re#or%e) %o have )evelo#e)
mul%i#le #re-#uber%al ovarian $ibromas ?5 years #os%-irra)ia%ion (3%rong, 1977= 6eimler e% al., 1979+.
hus, unusually shor% la%ency $or ra)ia%ion-in)uce) malignancy seems %o be charac%eris%ic o$ /B&&3.
/one o$ %hese )a%a allo, $or s#eci$ic 9uan%i$ica%ion o$ %he %umorigenic ra)iosensi%ivi%y o$ /B&&3 an)
%here are insu$$icien% ra)io%hera#y observa%ions %o allo, $or %he %y#e o$ s%u)y con)uc%e) ,i%h here)i%ary
'B by *ng e% al. (1992+. In s#i%e o$ %his, %he in)uc%ion o$ such large numbers o$ B&& as illus%ra%e) in
:ig. 5.8 an) 5.5 an) %he inci)ence o$ o%her,ise rare mul%i#le ovarian neo#lasms in irra)ia%e) young
$emales #rovi)es s%rong evi)ence %ha% /B&&3 is a con)i%ion %ha% e4hibi%s a high level o$ gene%ically
)e%ermine) %umorigenic ra)iosensi%ivi%y. he %umours arising 5 years #os%-%hera#y in irra)ia%e)
/B&&3 are o$ %he same %y#e %ha% arise s#on%aneously in %he )isor)er, bu% %here are no re#or%s o$
83
e4%en)e) #os%-irra)ia%ion $ollo,-u# in or)er %o -u)ge ,he%her %his %umour s#ec%rum changes ,i%h age.
An im#or%an% $in)ing is %he unambiguously shor% la%ency $or ra)ia%ion-in)uce) %umours in /B&&3, a
$ea%ure %ha% is reminiscen% o$ %he res#onse o$ p53-)e$icien% mice.
.!,!,! 5i86raumeni syndrome and neurofibromatosis
A number o$ re#or%s highligh% %he #ossible role o$ gene%ic $ac%ors in %he )evelo#men% o$ secon) %umours
in chil)ren receiving chemo- an) ra)io%hera#y (e.g Mea)o,s e% al., 1977= Mea)o,s e% al., 198;=
uc!er e% al., 1988= 6a,!ins, 199;= 6eyn e% al., 1992= 'obison an) Mer%ens, 1992+. In a))i%ion %o %he
mos% obvious associa%ion ,i%h heri%able 'B, a crucial early $in)ing ,as ma)e in %he $amilies o$ $ive
chil)ren ,here %here ,as a high inci)ence o$ breas% cancer, acu%e leu!aemia, carcinoma o$ %he lung,
#ancreas an) s!in, brain neo#lasms, an) a)renocor%ical carcinoma (1i an) :raumeni 19>9+. :ur%her
s%u)y culmina%ing in a re#or% o$ 28 cancer $amilies (1i e% al., 1988+ le) %o such $amilial cancer
clus%ering being %erme) %he 1i7:raumeni syn)rome (1:3+. his )isor)er is no, !no,n %o be
associa%e), albei% no% e4clusively, ,i%h germ line mu%a%ion o$ %he p53 %umour su##ressor gene (3ec%ion
2+.
3imilar $ollo,-u# s%u)ies, )iscusse) by 3%rong an) Eilliams (1987+, o$ #a%ien%s )evelo#ing secon) so$%
%issue sarcoma sho,e) %ha% 901>1 eligible #a%ien%s $ollo,e) $or 272; years ha) )evelo#e) a secon)
neo#lasm com#are) ,i%h an e4#ec%e) ;.501>1. :amily s%u)ies ,ere consis%en% ,i%h a )iagnosis o$ 1:3
an) %he #resence o$ 509 o$ %hese secon)ary sarcomas ,i%hin %he irra)ia%e) $iel) is s%rongly sugges%ive o$
a rela%ively high )egree o$ %umorigenic ra)iosensi%ivi%y. More recen%ly, 6eyn e% al. (1992+ have a))e)
$ur%her su##or% %o %his conclusion by sho,ing 1:3-li!e $amilial #a%%erns o$ cancer in 12012 eligible
#a%ien%s $rom a %o%al o$ 22 ,ho )evelo#e) secon) cancers (#rinci#ally bone sarcoma an) acu%e
leu!aemia+ $ollo,ing ra)io%hera#y $or rhab)omyosarcoma.
he s#eci$ic involvemen% o$ germ line p53 )e$iciency in %he %umorigenic ra)ia%ion res#onse o$ 1:3 is
more )irec%ly evi)ence) by molecular s%u)ies o$ cancer #a%ien%s, some o$ ,hom ha) #resen%e) ,i%h
%hera#y-rela%e) bone an) so$% %issue sarcomas (oguchi)a e% al., 1992= Mal!in e% al., 1992+. hus,
al%hough %hese )a%a )o no% allo, $or 9uan%i$ica%ion o$ increase) %umorigenic ra)iosensi%ivi%y in humans
)e$icien% in p53, %he res#onses seen generally accor) ,i%h %hose o$ mice carrying a )e$iciency in %he
same gene (Fem# e% al., 1998+.
A number o$ s%u)ies re#or% %ha% neuro$ibroma%osis is a #osi%ive $ac%or $or %hera#y-rela%e) secon)
%umours in #a%ien%s (Fings%on e% al., 1987= 6eyn e% al., 1992= 'obison an) Mer%ens, 1992+. 3<na-)er e%
al. (199>+ $oun) >2 cases o$ single an) seven o$ mul%i#le neural %umours (sch,annomas, ves%ibular
sch,annomas, an) meningiomas+ %ha% )evelo#e) in a cohor% o$ 2;12 #eo#le given 4-ray beam %hera#y
(s!in )oses o$ 75; m"y #er course o$ %rea%men%+ be$ore age 1> $or benign hea) an) nec! con)i%ions,
i.e. a highly signi$ican% e4cess. 3i4%een o$ 25 %umours in %he seven mul%i#le %umour cases ,ere s#inal
roo% sch,annomas, com#are) %o 28 o$ %he >2 single %umours, a sugges%ive )i$$erence (PM;.;7+. here
,as no ra)ia%ion )ose )i$$erence ,i%h res#ec% %o %umour number (<ero, one, or mul%i#le+. Cnly one o$
%he mul%i#le %umour cases me% %he s%ric% )iagnos%ic cri%eria $or /:2 an) $ollo, u# molecular s%u)ies o$
can)i)a%e germ line mu%a%ions in mul%i#le %umour cases are necessary %o clari$y %he #ossible gene%ic
basis o$ %hese observa%ions.
.!,!-! ther %enetic conditions and familial associations
In a s%u)y o$ 28> sib-#airs ,ho receive) chil)hoo) ra)ia%ion %rea%men% $or benign con)i%ions, ,i%hin
$amily concor)ance ,as s%a%is%ically signi$ican% (PM;.;5+ $or benign an) malignan% %hyroi) neo#lasia
84
consi)ere) as a grou# ,i%h sugges%ive evi)ence (PM;.18+ o$ concor)ance $or ra)ia%ion-associa%e)
%hyroi) cancer (Per!el e% al., 1988+. hese resul%s im#ly %ha% $amilial $ac%ors ei%her gene%ic or
environmen%al #laye) a role in %he )e%ermina%ion o$ ris! in %he irra)ia%e) cohor% bu% )o no% #rovi)e
com#elling evi)ence o$ s#eci$ic gene%ic mo)i$ica%ion o$ ra)ia%ion res#onse.
3ince breas% cancer is believe) %o have a rela%ively large gene%ic com#onen%, gene%ic mo)i$ica%ion o$
ra)ia%ion res#onse migh% be evi)ence) by e4cess ris! o$ con%rala%eral )isease in cer%ain #a%ien%s
receiving sca%%ere) ra)ia%ion $rom %rea%men% o$ unila%eral breas% cancer. .a%a on %his an) o%her breas%
cancer cohor%s )iscusse) by Mar! e% al. (1998+ ho,ever #rovi)e no consis%en% evi)ence $or an e4cess
ris! o$ ra)ia%ion-associa%e) breas% or o%her cancers %ha% migh% have a gene%ic basis o%her %han 1:3 an)
1:3-li!e con)i%ions (3mi%h e% al., 1992+. Boice e% al. (1992+ $oun) %ha% >55 ,omen in ,hom a secon)
breas% cancer )evelo#e) $ive or more years a$%er %he ini%ial )iagnosis ,ere signi$ican%ly more li!ely %o
have receive) ra)io%hera#y %han 1189 ma%che) con%rols ,ho )i) no% have a secon) breas% cancer. he
e4cess ,as limi%e) %o ,omen %rea%e) be$ore 85 years o$ age, an) %he es%ima%e) ra)ia%ion-rela%e) ris!
,as similar %o %ha% $oun) in o%her s%u)ies o$ ,omen ,hose ra)ia%ion e4#osure ,as $or reasons o%her
%han breas% cancer %rea%men%. 3%orm e% al. (1992+ $oun) no e4cess o$ con%rala%eral breas% cancer ris! in
ano%her series o$ ,omen %rea%e) ,i%h a)-uvan% ra)io%hera#y. he absence o$ ris! ,as a%%ribu%e) %o %he
$ac% %ha% %he ages o$ %rea%men% $or mos% o$ %he cases ,ere ol)er %han %hose associa%e) in o%her s%u)ies
,i%h a##reciable ra)ia%ion-rela%e) ris!. o!unaga e% al. (1998+ $oun) 2; bila%eral cases, synchronous
an) asynchronous, among 8;9 $emale breas% cancer cases observe) in %he Da#anese A-bomb 133
sam#le )uring 195;71985, inclu)ing 15 o$ 592 cases among e4#ose) ,omen $or ,hom ra)ia%ion )ose
es%ima%es ,ere available. he #ro#or%ion o$ bila%eral cases )i) no% increase or )ecrease ,i%h ra)ia%ion
)ose, an) %here ,as %here$ore no sugges%ion %ha% %he bila%eral cases ,ere )ra,n $rom a sub#o#ula%ion
,i%h increase) ra)ia%ion sensi%ivi%y. here are also )a%a o$ #o%en%ial relevance %ha% concern secon)
cancers $ollo,ing %hera#y $or chil)hoo) 6o)g!ins )isease (6.+ (.onal)son an) 6ancoc!, 199>=
Bha%ia e% al., 199>+. In %he s%u)y o$ Bha%ia e% al. (199>+ %he ris! o$ %hera#y-rela%e) soli) %umours an)
es#ecially breas% cancer ,as sho,n %o be high (s%an)ar)ise) inci)ence ra%io $or breas% cancer o$ 75.2=
955 &IM88.97118.8+. C$ #ar%icular no%e ,as %he a%y#ical increase) ris! ,i%hin $ive years o$
ra)io%hera#y, an observa%ion %ha% $in)s echoes in %he gene%ically )e%ermine) early %umorigenic res#onse
o$ o%her #a%ien%s )iscusse) in %his 3ec%ion. he e4%en% %o ,hich %hese $in)ings re$lec% gene%ic
susce#%ibili%y in a subse% o$ 6. #a%ien%s remains mos% uncer%ain, bu% i% is no%able %ha% a #ro#or%ion o$
early onse% 6. in %he #o#ula%ion #robably has a gene%ic basis (see 3ec%ion 8+.
More in$orma%ion on $amilial #a%%erns o$ breas% cancer in ra)io%hera#y #a%ien%s is im#or%an% %o clari$y
%he #osi%ion. In %his con%e4%, an e4cess o$ breas% cancer has been re#or%e) in %he mo%hers o$ chil)ren
,ho )evelo#e) %hera#y-associa%e) secon) %umours (Birch e% al., 199;a an) Birch e% al., 199;b+. he
same nee) $or com#rehensive $amily s%u)ies also a##ly %o %he #ossibili%y o$ ascer%aining %he res#onse %o
ra)io%hera#y o$ #a%ien%s ,ho migh% #resen% ,i%h heri%able $orms o$ colon cancer ('us%gi, 1998+.
In a))i%ion, Fony e% al. (1997+ have recen%ly re#or%e) on a case con%rol s%u)y %o )e%ermine #ossible
in%erac%ions be%,een gene%ic $ac%ors an) ra)io%hera#y in chil)hoo) $or %he #ro)uc%ion o$ secon)
malignan% neo#lasms (3M/+. his s%u)y, ,hich involve) 25 chil)ren ,i%h 3M/ an) 9> chil)ren ,i%h
no 3M/, gave a rela%ively mo)es% o))s ra%io o$ 8.7 (955 &I 1.2717.1+ $or 3M/ in %hose %rea%e)
#a%ien%s ,i%h a $amily his%ory o$ early onse% cancer.
3econ)ary lym#ho-haemo#oie%ic neo#lasia can be a conse9uence o$ ra)io%hera#y in chil)hoo) (e.g
Fings%on e% al., 1987, Mea)o,s, 1988, 6a,!ins, 199;, 6eyn e% al., 1992+. "iven %he -u)gemen% %ha%
%he gene%ic com#onen% o$ %his ca%egory o$ %umours is rela%ively lo, (see 3ec%ion 8+ i% is no% sur#rising
85
%ha% no clear $amilial #a%%erns have ye% emerge) in #a%ien%s ,i%h %hera#y-associa%e) leu!aemia an)
lym#homas (Fings%on e% al., 1987= 6eyn e% al., 1992+. 3ince ho,ever p53 an) :91 germ line mu%a%ion
can #re)is#ose %o acu%e leu!aemia an) %here is a $amilial associa%ion $or early onse% 6o)g!inIs )isease
(see 3ec%ion 8+, a gene%ic basis may be e4#ec%e) in a $e, rare cases.
:inally, ,hile %here is unambiguous evi)ence on %he e4%reme sensi%ivi%y o$ a%a4ia-%elangiec%asia (A-+
homo<ygo%es %o %he )e%erminis%ic e$$ec%s o$ ra)io%hera#y (see Pri%char) e% al., 1982= :ig. 5.>+ %oo $e,
#a%ien%s have survive) %rea%men% %o allo, $or $ollo,-u# s%u)ies o$ %umorigenic ou%comes. 1evin an)
Perlov (1971+ no%e ho,ever %ha% chronic )erma%i%is an) basal carcinoma )evelo#e) in %he irra)ia%e)
$iel) o$ one A- #a%ien% ,ho ha) receive) irra)ia%ion o$ %he scal# $or %inea ca#i%is. he uncer%ain s%a%us
o$ e#i)emiological s%u)ies on %he %umorigenic res#onse o$ A- he%ero<ygo%es are )iscusse) la%er in %his
sec%ion.
:ig. 5.>. .e%erminis%ic %issue e$$ec%s a$%er irra)ia%ion in a%a4ia-%elangiec%asia. 'e#rin%e) by !in)
#ermission o$ Eiley-1iss Inc., a subsi)iary o$ Dohn Eiley ] 3ons, Inc., $rom Pri%char) e% al. (1982+. \
American &ancer 3ocie%y.
.!-! 4pidemiolo%ical aspects of tumori%enic radiosensitivity
he #ossibili%y %ha% gene%ic varia%ion may be re$lec%e) in )i$$eren%ial susce#%ibili%y among in)ivi)uals
%o ra)ia%ion carcinogenesis is highly #lausible by analogy %o o%her carcinogens an) o%her )isease
e4#erience. he observe) e4cesses o$ so$% %issue sarcoma, os%eosarcoma, an) basal cell carcinoma in
cer%ain cancer-#rone in)ivi)uals receiving ra)io%hera#y (3ec%ion 5.2+ #rovi)e #ersuasive evi)ence o$ a
gene%ically-rela%e) susce#%ibili%y %o ra)ia%ion carcinogenesis in #a%ien%s !no,n or s%rongly sus#ec%e) %o
be su$$ering $rom cancer-#re)is#osing gene%ic )isor)ers. C%her argumen%s have o$%en lac!e) cre)ibili%y
$or various reasons, ho,ever, es#ecially ,hen %he claime) associa%ion has been ,i%h lo,-)ose e4#osure
(Bross an) /a%ara-an, 1977= 1an), 1977= 3,i$% e% al., 1991= Boice an) Miller, 1992= 6all e% al., 1992=
1an) e% al., 1992+.
.!-!1! 7reast cancer ris) in ata0ia'telan%iectasia hetero9y%otes
86
In res#ec% o$ breas% cancer ris! an) #o%en%ial ra)iosensi%ivi%y much a%%en%ion has been given %o carriers
o$ %he A)* genePa%a4ia-%elangiec%asia he%ero<ygo%es. A #rinci#al reason $or %his a%%en%ion is %he
rela%ively high #revalence ( 1 in 2;;+ o$ A)* gene carriers in %he #o#ula%ion ,hich, )e#en)ing u#on
breas% cancer susce#%ibili%y an) ra)iosensi%ivi%y, may allo, $or a signi$ican% con%ribu%ion %o #o#ula%ion
ris!. As )e%aile) belo, i% is -u)ge) %ha% %he associa%ion be%,een A)* he%ero<ygosi%y an) breas% cancer
may no% be as secure as some commen%a%ors have sugges%e).
As no%e) in 3ec%ion > o$ %his re#or%, *as%on (1998+ has revie,e) earlier #ublishe) )a%a regar)ing %he
inci)ence o$ breas% cancer amongs% obliga%e an) #re)ic%e) a%a4ia-%elangiec%asia (A)*+ he%ero<ygo%es.
Al%hough %hese analyses broa)ly su##or%e) %he con%en%ion %ha% such he%ero<ygo%es )o sho, increase)
ris! o$ s#on%aneously arising breas% cancer, consi)erable uncer%ain%y ,as recognise). C$ #ar%icular
concern is %he unusually lo, inci)ence o$ breas% cancer in %he con%rols o$ %he %,o larges% s%u)ies (3,i$%
e% al., 1987= 3,i$% e% al., 1991+.
he cloning an) se9uencing o$ %he A)* gene has enable) )irec% e4amina%ion o$ %he hy#o%hesis %ha%
breas% cancer ris! is increase) among A)* he%ero<ygo%es. ,o a##roaches have been use). In %he $irs%,
./A $rom breas% cancer cases belonging %o cancer $amilies (Vorechovs!y e% al., 199>a+ or ,ho ,ere
bloo) rela%ives o$ A- homo<ygo%es (A%hma e% al., 199>+ have been assaye) $or germline A)*
mu%a%ions. In %he secon), %he assays have been a##lie) %o breas% cancer cases (Vorechovs!y e% al.,
199>b+ or early-onse% breas% cancer cases an) non-cases (:i%<geral) e% al., 1997+ $rom %he general
#o#ula%ion. he %,o a##roaches have yiel)e) some,ha% )i$$eren% resul%s lea)ing %o )i$$eren%
conclusions= ho,ever, %he $re9uency o$ A)* he%ero<ygo%es in %he general #o#ula%ion is no% !no,n ,i%h
su$$icien% accuracy $or %hese resul%s %o be -u)ge) s%a%is%ically inconsis%en% (Bisho# an) 6o##er, 1997+.
Vorechovs!y e% al. (199>a+ e4amine) 88 in)e4 cases ,i%h #rimary breas% cancer, each having a $amily
his%ory o$ breas% cancer an)0or a $amily his%ory o$ %umours #reviously associa%e) ,i%h A-
homo<ygosi%y or he%ero<ygosi%y. hree ins%ances o$ he%ero<ygo%ic germline A)* mu%a%ions ,ere
$oun), %,o in members o$ breas% cancer $amilies an) %he o%her in a $amily ,i%h mul%i#le cancers o%her
%han breas% cancer. he s%u)y )emons%ra%e) %he occurrence o$ germ line A)* mu%a%ions in cancer
$amilies bu% #rovi)e) li%%le insigh% in%o %he role o$ A)* as a breas% cancer ris! $ac%or. A more ambi%ious
a##roach ,as un)er%a!en by A%hma e% al. (199>+ ,ho )e%ermine) A- gene carrier s%a%us o$ 775 bloo)
rela%ives in 99 A- $amilies. C$ %hese, %here ,ere 22 $emale breas% cancer cases in 28 $amilies ,ho
coul) be #heno%y#e)= 25 ,ere A)* he%ero<ygo%es com#are) %o 18.9 e4#ec%e) on %he basis o$ %heir
!no,n $amilial rela%ionshi#s %o %he A- #roban)s. A s%a%is%ically signi$ican% o))s ra%io (C'+ o$ 2.8 ,as
ob%aine), ,i%h 955 con$i)ence limi%s 1.778.8, $or breas% cancer ris! among A)* he%ero<ygo%es as
o##ose) %o non-carriers. he o))s ra%io ,as non-signi$ican%ly higher $or cases ,i%h breas% cancer
)iagnosis a% age >; or ol)er %han $or younger cases, an) %he au%hors use) age-s#eci$ic o))s ra%ios %o
es%ima%e %ha%, i$ %he A3 #o#ula%ion $re9uency o$ A)* he%ero<ygo%es is 1.85, >.>5 o$ all breas% cancers
may occur in ,omen ,ho are A he%ero<ygo%es. his es%ima%e is several %imes higher %han %ha%
es%ima%e) $or BRCA1 carriers.
Vorechovs!y e% al. (199>b+ screene) 28 consecu%ive breas% cancer #a%ien%s using an e4on-scanning P&'
single-s%ran) con$orma%ion #olymor#hism assay $or mu%a%ion )e%ec%ion o$ A)* an) $oun) no evi)ence
o$ ei%her soma%ic A)* gene%ic changes in breas% %umour sam#les or mu%an% A)* carriers. Ei%h %his
small number o$ sub-ec%s, %he u##er 955 con$i)ence limi% $or %he $re9uency o$ A)* carriers among
breas% cancer #a%ien%s is 9.75. :i%<geral) e% al. (1997+ un)er%oo! a germ line mu%a%ional analysis in a
cohor% o$ 8;1 ,omen )iagnose) ,i%h breas% cancer a% age 8; or younger, an) 2;2 heal%hy ,omen ,i%h
no #rior his%ory o$ breas% cancer, using a c./A-base) #ro%ein %runca%ion assay. .e$ini%ive chain-
87
%ermina%ing mu%a%ions ,ere )e%ec%e) in 208;1 ,omen ,i%h breas% cancer (ra%e ;.55 ,i%h 955
con$i)ence boun)s ;.;>571.>5+ an) in 202;2 non-cases (ra%e 1.;5 ,i%h con$i)ence limi%s ;.1257
2.>5+. he ra%e ra%io is ;.5; (%he o))s ra%io is ;.5;1+ ,i%h con$i)ence boun)s ;.127>.95. hus, al%hough
;.5; is subs%an%ially less %han %he value 2.8 ob%aine) by A%hma e% al. (199>+, %he %,o es%ima%es are
s%a%is%ically consis%en%.
As #oin%e) ou% by Bisho# an) 6o##er (1997+ %he con$i)ence limi%s $or %he ra%e ra%io es%ima%e) by
:i%<geral) e% al., are ,i)e because %he es%ima%e) ra%e $or %he non-cancer ra%e )enomina%or is base) on
only %,o #osi%ive even%s. I$, ho,ever, ,e acce#% %he conclusion o$ A%hma e% al., %ha% %he #revalence o$
A)* is grea%er among breas% cancer cases %han in %he general #o#ula%ion, i% $ollo,s %ha% $our #osi%ive
$in)ings among 8;1 ,omen ,i%h an) 2;2 ,i%hou% breas% cancer mus% overes%ima%e %he #o#ula%ion
#revalence o$ germ line A)*, a% leas% a$%er a)-us%men% $or %he im#er$ec% ascer%ainmen% e$$iciency o$ %he
#ro%ein %runca%ion assay use) by :i%<geral) e% al., :or e4am#le, su##ose %he ascer%ainmen% e$$iciency %o
be 7;5, an) %he o))s ra%io es%ima%e o$ 2.8 ob%aine) by A%hma e% al., is !no,n ,i%hou% error an) a##lies
%o %he #o#ula%ion s%u)ie) by :i%<geral) e% al., Cn %his basis, %he #o#ula%ion #revalence o$ A)* in %he
:i%<geral) #o#ula%ion ,oul) be es%ima%e) as (80;.7;+0(2;2K2.8K8;1+M;.225, ,i%h 955 con$i)ence
limi%s ;.1;57;.795.
A more realis%ic assessmen% is ob%aine) by a))ing uncer%ain%y %erms $or %he A)* o))s ra%io among
breas% cancer cases an) $or %he ascer%ainmen% e$$iciency o$ %he #ro%ein %runca%ion me%ho), an) ob%aining
sub-ec%ive con$i)ence limi%s $or %he #o#ula%ion #revalence base) on a Mon%e &arlo simula%ion analysis.
he ra%ionale is as $ollo,s@ :or $i4e) ascer%ainmen% e$$iciency 6 an) $i4e) o))s ra%io R, %he number o$
#osi%ive $in)ings shoul) be )is%ribu%e) a##ro4ima%ely as a binomial ran)om variable ,i%h sam#le si<e
nF6K(2;2KRK8;1+ an) un!no,n binomial #robabili%y, p. hus, %he con)i%ional #robabili%y o$ ob%aining
$our #osi%ive $in)ings ,oul) be #re)ic%e) %o be
nP(XM8+M8p
8
(1Lp+
nL8
.
&onversely, %he con)i%ional li!elihoo) $unc%ion $or p, given XM8, 6, an) R, is also #ro#or%ional %o
p
8
(1Lp+
nL8
. hus, in a Bayesian sense, %he (con)i%ional+ sub-ec%ive uncer%ain%y $or p $ollo,s a be%a
)is%ribu%ion ,i%h 5 an) n72 )egrees o$ $ree)om. By con)uc%ing a large number o$ %rials, in ,hich
#seu)o-ran)om realisa%ions are genera%e) o$ 6, R, an) (con)i%ionally on %he realise) values o$ 6 an) R+
o$ p, i% is #ossible %o es%ima%e %he sub-ec%ive uncer%ain%y )is%ribu%ion o$ p con)i%ional only on XM8.
A lognormal uncer%ain%y )is%ribu%ion $or %he o))s ra%io R, ,i%h me)ian 2.8 an) geome%ric s%an)ar)
)evia%ion ("3.+ 1.5, agrees ,ell ,i%h %he 955 con$i)ence limi%s 1.778.8 ob%aine) by A%hma e% al., he
e$$iciency 6 o$ %he #ro%ein %runca%ion me%ho) migh% be assigne) a rec%angular uncer%ain%y )is%ribu%ion
,i%h minimum ;.55 an) ma4imum ;.85. A Mon%e &arlo simula%ion analysis base) on 1>;; in)e#en)en%
%rials #ro)uce) a cen%ral value o$ ;.295 $or %he #o#ula%ion #revalence o$ A)*, ,i%h 955 uncer%ain%y
limi%s ;.1;571.125 an) 9;5 limi%s ;.1257;.975. 3imilar resul%s (cen%ral value ;.295, 955 limi%s
;.11571.155, 9;5 limi%s ;.12571.;15+ ,ere ob%aine) assuming a lognormal uncer%ain%y )is%ribu%ion
$or 1L6 ,i%h me)ian ;.2 an) "3. 1.2, corres#on)ing %o sub-ec%ive 955 con$i)ence limi%s ;.577;.79
$or 6.
his analysis sugges%s %ha% %he $in)ings o$ A%hma e% al., an) :i%<geral) e% al., may be consis%en% only i$ a
#o#ula%ion #revalence less %han abou% 15 is assume) $or heri%able A)* mu%a%ions in %he #o#ula%ion
s%u)ie) by :i%<geral) e% al., Al%erna%ively, i% is conceivable %ha% %he %,o s%u)ies sim#ly may no% be
com#arable, as ,oul) be %he case i$ germ line A)* ,ere a s%rong ris! $ac%or only $or breas% cancer
)iagnose) a$%er 8; years o$ age.
88
In res#ec% o$ a #ossible associa%ion be%,een A)* an) ra)ia%ion-in)uce) breas% cancer %he curren%
#osi%ion is even more con%en%ious. 3,i$% e% al. (1991+ re#or%e) %ha% $emale he%ero<ygo%es have 5.1 %imes
%he breas% cancer ris! o$ %he general #o#ula%ion, %ha% 2;5 o$ he%ero<ygo%es have been e4#ose) %o
me)ical ra)ia%ion, an) %ha% %hose e4#ose) have 5.8 %imes %he breas% cancer ris! o$ %he non-e4#ose)
remain)er. Fuller an) Mo)an (1992+ an) Boice an) Miller (1992+ have sugges%e) al%erna%ive
in%er#re%a%ions o$ %he )a%a #resen%e) by 3,i$% e% al., lea)ing %o (s%a%is%ically non-signi$ican%+ rela%ive ris!
es%ima%es o$ 1.8 an) 1.>, res#ec%ively, $or me)ically e4#ose) c$. non-e4#ose) he%ero<ygo%es, an) have
#oin%e) ou% o%her as#ec%s o$ %he s%u)y %ha% re9uire clari$ica%ion or may viola%e #rinci#les o$
e#i)emiological in$erence. he es%ima%es #rovi)e) by 3,i$% e% al., im#ly rela%ive ris!s $or %he me)ically
une4#ose) an) e4#ose) he%ero<ygo%es o$ 2.> an) 15.1 %imes, res#ec%ively, %ha% o$ %he general
#o#ula%ion. he ra%io o$ e4cess rela%ive ris!s in %he %,o grou#s, 1.> %o 18.1, is 8.8. *4%reme sensi%ivi%y
%o %he carcinogenic e$$ec%s o$ ionising ra)ia%ion im#lies %ha% all he%ero<ygo%es mus% su$$er $rom %he
e$$ec%s o$ %he 1 m"y receive) by everyone, every year, $rom na%ural bac!groun) ra)ia%ion. I$ all o$ %he
e4cess breas% cancer ris! among he%ero<ygo%es is )ue %o ra)ia%ion e4#osure, %he ra%io o$ e4#osure
be%,een %he me)ically e4#ose) an) non-e4#ose) sub#o#ula%ions shoul) be abou% 8.8= o%her,ise, %he
ra%io mus% be even higher. hus, %he numerical es%ima%es #resen%e) by 3,i$% e% al., im#ly cumula%ive
levels o$ me)ical e4#osure $or 2;5 o$ %he he%ero<ygo%e #o#ula%ion %ha% are im#ossibly high (1an),
1992+. I% may be %ha% he%ero<ygo%es are in)ee) sensi%ive %o ra)ia%ion-rela%e) breas% cancer, bu% %he
curren% argumen% #resen%e) in su##or% o$ %ha% in$erence ,as $la,e). &oncerns on %he #o%en%ial
%umorigenic ra)iosensi%ivi%y o$ %hese he%ero<ygo%es shoul) also be %em#ere) by uncer%ain%ies no%e)
above on %he s%reng%h o$ %he associa%ion be%,een A)* an) s#on%aneous breas% cancer. In s#i%e o$ %hese
uncer%ain%ies, clear evi)ence has been #resen%e) %ha% heri%able mu%a%ions an) ionising ra)ia%ion
e4#osure are bo%h im#or%an% cancer ris! $ac%ors an), as )iscusse) earlier in %his 3ec%ion, in%erac%ion o$
%hese $ac%ors shoul) be e4#ec%e). As no%e) earlier in %his 3ec%ion o$ %he re#or%, %here is ho,ever no
e4#ec%a%ion %ha% all gene%ic )e%erminan%s o$ cancer ,ill sho, s%rong in%erac%ions ,i%h ra)ia%ion.
.!-!"! Contributions from family studies and modifiers of cancer ris)
I% has long been recognise) %ha% unusually high cancer ris! can be $amilial an) i% is becoming clear %ha%
such #a%%erns o$%en re$lec% inheri%e) susce#%ibili%y as )is%inguishe) $rom share) environmen%s an)
li$es%yles. 3%u)ies o$ here)i%ary )iseases #re)is#osing %o cancer have le) %o %he i)en%i$ica%ion o$ %umour
su##ressor genes, such as %he re%inoblas%oma susce#%ibili%y gene (RB1+, genes associa%e) ,i%h
neuro$ibroma%osis o$ %y#es 1 an) 2 (:91 an) :92+, an) %he (p53+ gene mu%a%ion in %he 1i7:raumeni
syn)rome (see 3ec%ion 2+. C%her s%u)ies, o$ !in)re)s ,i%h e4ce#%ionally high levels o$ cancer ris!, have
le) %o %he i)en%i$ica%ion o$ o%her %umour su##ressor genes, inheri%e) mu%a%ions o$ ,hich are associa%e)
,i%h increase) ris! o$ breas% an) ovarian cancer (BRCA1 an) BRCA2+ or heri%able non#oly#osis colon
cancer (*+52, *351, P*+1, an) P*+2+ (3!use an) 1u)lo,, 1995+.
here is subs%an%ial evi)ence %ha% %he e4cess cancer ris! associa%e) ,i%h e4#osure %o cer%ain
carcinogens, li!e ionising ra)ia%ion, may vary by se4 an) age a% e4#osure, an) %ha% i% may be mo)i$ie)
by li$e even%s (e.g. re#ro)uc%ive his%ory, %obacco use+ #rior %o or $ollo,ing e4#osure. Eomen ,i%h
heri%able mu%a%ions in BRCA1 or BRCA2 ,ere ini%ially es%ima%e) %o e4#erience be%,een 5 an) 1;5 o$
all breas% cancers occurring in %he A3 #o#ula%ion, an) %o have in)ivi)ual li$e%ime ris!s o$ 8;5 or more
(:or) e% al., 1998= Eoos%er e% al., 1998+. More recen% es%ima%es sugges% ho,ever %ha% less %han 25 o$ all
breas% cancers are )e%ermine) by genes o$ high #ene%rance al%hough %ha% $igure rises %o aroun) 1;5 in
cases )iagnose) be$ore age 8; (Pe%o e% al., 199>+. 6o,ever, al%hough %he )is%ribu%ion o$ %ha% ris! over
%heir li$e%imes is )is#ro#or%iona%ely heavier a% young ages %han in %he res% o$ %he #o#ula%ion, i% is no%
concen%ra%e) %here (:or) e% al., 1998+. hus, even $or a #o,er$ul ris! $ac%or #resen% $rom conce#%ion,
89
%he e4#ression o$ ris! a,ai%s $ur%her )evelo#men%al even%s. hus %he %iming, i$ no% %he li!elihoo), o$ %he
occurrence o$ $amilial breas% cancer a##ears %o be governe) %o a large e4%en% by even%s unrela%e) %o %he
#resence o$ germ line mu%a%ions. hese may be #resume) %o be %he same ca%egories o$ li$e%ime even%s
%ha% )e%ermine %he age-s#eci$ic )is%ribu%ion o$ s#ora)ic breas% cancer ris!. here is also %he #ossibili%y
o$ mo)i$ica%ion o$ e4#ression o$ such mu%a%ions in cer%ain gene%ic bac!groun)s (see 3ec%ion 5 an)
3ec%ion 7+. In con%ras%, a% leas% $or ris! a$%er age 25 or so, %he %iming o$ ra)ia%ion-rela%e) breas% cancer
ris! in #ar%icular, an) o$ mos% o%her ra)ia%ion-rela%e) soli) cancers in general, is similar %o %ha% o$ non-
ra)ia%ion-rela%e) cancer an) %here$ore ,oul) a##ear %o be almos% ,holly )e%ermine) by even%s
unrela%e) %o e4#osure (o!unaga e% al., 1998= A/3&*A', 1998+.
3i%e-s#eci$ic cancer ris!s vary by #o#ula%ion, an) %here is a small bu% gro,ing bo)y o$ in$orma%ion %ha%
allo,s us %o com#are )i$$eren% #o#ula%ions, ,i%h )i$$eren% si%e-s#eci$ic baseline cancer ra%es, ,i%h
res#ec% %o susce#%ibili%y %o ra)ia%ion carcinogenesis. :or breas% cancer, i% a##ears %ha% ra)ia%ion-rela%e)
ris!s, in absolut/ %erms, are similar in %he A3 an) Da#an, )es#i%e %he %,o %o seven-$ol) )i$$erence in
age-s#eci$ic baseline ra%es (Boice e% al., 1979= 1an) e% al., 198;= 1an), 1992= A/3&*A', 1998+,
,hereas $or s%omach cancer, ra)ia%ion-rela%e) r/lati0/ ris!s a##ear similar (/&'P, 1997+. More
generally, resul%s $rom migran% s%u)ies %en) %o in)ica%e %ha%, al%hough baseline, si%e-s#eci$ic cancer ra%es
may vary consi)erably by #o#ula%ion, such )i$$erences usually re$lec% common li$es%yle $ac%ors %ha%
%en) %o change slo,ly over %ime $ollo,ing arrival in %he hos% coun%ry, ra%her %han gene%ic %rai%s
charac%eris%ic o$ a #o#ula%ion as a ,hole (6aens<el an) Furihara, 19>8= Buell, 1972= Giegler e% al.,
1992+. hus, com#arisons o$ ra)ia%ion-rela%e) ris! in )i$$eren% #o#ula%ions seem unli!ely %o be use$ul
$or s%u)ying ?/n/tic varia%ion in ra)ia%ion susce#%ibili%y.
/ever%heless, i% is in%eres%ing %o s#ecula%e on %he role o$ heri%able mu%a%ions in rela%ion %o si%e-s#eci$ic
cancer ris! in coun%ries ,i%h ra)ically )i$$eren% baseline ra%es. :or e4am#le, Da#anese ,omen have
abou% one-$our%h %he li$e%ime breas% cancer ris! o$ A3 ,omen, ,hereas ra%es among %heir A3-born
)escen)an%s are %y#ical o$ A3 ra%es (Geigler e% al., 1992+= moreover, as #reviously men%ione), e4cess
ra%es associa%e) ,i%h s#eci$ie) ra)ia%ion e4#osures a##ear %o be abou% %he same in %he %,o coun%ries. I%
is %here$ore conceivable %ha% inheri%e) BRCA1 an) BRCA2 mu%a%ions migh% be res#onsible $or 1;72;5
o$ %he much lo,er level o$ Da#anese breas% cancer ris!= i% is in%eres%ing, $or e4am#le, %ha% ra%es o$ early-
onse% breas% cancer (i.e. be$ore age 25 or be$ore age 85+ in Da#an are abou% hal$ %hose among A3 Ehi%es
or among A3 resi)en%s o$ Da#anese )escen% in 1os Angeles or 6a,aii (Par!in e% al., 1992+, ,hereas
ra%es a% ol)er ages )i$$er by $ac%ors o$ 277. Al%erna%ively, Da#anese environmen%al an) li$es%yle $ac%ors
migh% re)uce %he in$luence o$ heri%able gene mu%a%ions in %he same ,ay %ha% %hese $ac%ors seem %o
minimise Da#anese baseline breas% cancer ris!.
An$or%una%ely, $e, s%u)ies have been #ublishe) on %he role #laye) by BRCA1 an) BRCA2 mu%a%ions in
Da#anese breas% cancer ris!. A recen% s%u)y by Inoue e% al. (1995+ analy<e) germline mu%a%ions o$ %he
BRCA1 gene in 18 Da#anese breas% cancer an) %,o breas%7ovarian cancer $amilies. he same nonsense
mu%a%ion, #reviously no% observe), ,as $oun) in %,o o$ %he breas% cancer $amilies, bu% no%hing in %he
o%hers. he s%u)y resul%s sugges% %ha% %he s#ec%rum o$ heri%able BRCA1 mu%a%ions may be subs%an%ially
)i$$eren% in e%hnically )is%inc% #o#ula%ions. Also, %he rela%ive rari%y o$ breas% cancer in Da#an may be a
ma-or obs%acle in $in)ing %rue breas% cancer $amilies, since %he numbers commonly use) in ,es%ern
s%u)ies %o )e$ine such a $amily in a high ris! #o#ula%ion may be sim#ly una%%ainable, an) environmen%al
an) li$es%yle $ac%ors may have more o$ a role in #ro)ucing cancer $re9uencies %ha% sa%is$y less s%ringen%
selec%ion re9uiremen%s.
.!-!,! (usceptibility to radiation carcino%enesis in :apanese A'bomb survivors
90
.ose-res#onse analyses o$ breas% cancer ris! among 6iroshima7/agasa!i A-bomb survivors e4#ose)
be$ore age 2; (1an) e% al., 1992= o!unaga e% al., 1998+ $oun) an e4cess rela%ive ris! o$ 12.5 a% one 3v
$or ra)ia%ion-rela%e) breas% cancer )iagnose) be$ore age 25, com#are) %o 2.2 among %hose )iagnose) a%
la%er ages, a s%a%is%ically signi$ican%, si4-$ol) )i$$erence (:ig. 5.7+. he $in)ing #er%ains %o ,omen
e4#ose) )uring ei%her chil)hoo) or a)olescence, bu% no% %o ,omen e4#ose) a$%er age 2;. Preliminary
analyses (1an), 1997+, base) on inci)ence )a%a %hrough 199;, )emons%ra%e %ha% %he mar!e) e4cess in
ra)ia%ion-rela%e) e4cess rela%ive ris! is seen among ,omen e4#ose) a% ;79 an) 1;719 years o$ age (:ig.
5.8, A an) B+.
:ig. 5.7. .ose-s#eci$ic ris! o$ ra)ia%ion-rela%e) breas% cancer among $emale A-bomb survivors e4#ose)
be$ore age 2; years o$ age@ overall (hori<on%al lines+ an) by age a% )iagnosis (#oin%s ,i%h error bars+.
91
92
:ig. 5.8. .ose-s#eci$ic e4cess rela%ive ris! o$ ra)ia%ion-rela%e) breas% cancer, by age a% e4#osure an)
age a% )iagnosis. A, e4#osure a% ages ;79 years= B, e4#osure a% ages 1;719 years= &, e4#osure a% ages
2;729 years= ., e4#osure a% ages Z8; years.
Moreover, %he mar!e)ly grea%er e4cess rela%ive ris! $or early-onse% breas% cancer as com#are) %o la%er-
onse% ris! )oes no% merely re$lec% a general %en)ency $or e4cess rela%ive ris! %o )ecline ,i%h increasing
age a% )iagnosis= %here is no evi)ence o$ a con%inuing )ecline ,i%h age $or cancers )iagnose) a$%er age
25, regar)less o$ age a% ra)ia%ion e4#osure (:ig. 5.8+. Ehile $ar $rom conclusive, %he $in)ing sugges%s
%he #ossibili%y o$ increase) susce#%ibili%y among a subgrou# gene%ically #re)is#ose) %o breas% cancer in
general an) %o early-onse% breas% cancer in #ar%icular, e.g. ,omen ,ho have inheri%e) mu%a%ions in
BRCA1, BRCA2, or o%her #re)is#osing genes o$ lo,er #ene%rance.
.!-!-! Genetic and molecular studies in irradiated populations
A search $or #ossible $amilial aggrega%ions o$ cancer in irra)ia%e) #o#ula%ions un)er s%u)y re#resen%s an
obvious gene%ic a##roach %o %he #roblem. Cne a%%em#%, %o e4#lore $amily his%ory o$ cancer as a #ossible
mo)i$ier o$ A-bomb ra)ia%ion as a cause o$ breas% cancer, $aile) because o$ a general lac! o$
93
in$orma%ion on %he #ar% o$ in%ervie,e) cancer cases an) con%rols abou% cancer )iagnoses ,i%hin %heir
$amilies, or even %hemselves (1an) e% al., 1998a an) 1an) e% al., 1998b+. ra)i%ionally, i% is no% usual
$or Da#anese #hysicians %o in$orm %heir #a%ien%s %ha% %hey have cancer. An al%erna%ive, no, being
e4#lore) a% %he 'a)ia%ion *$$ec%s 'esearch :oun)a%ion ('*':+ in 6iroshima an) /agasa!i, is %o use
e4is%ing recor)s %o i)en%i$y rela%ives o$ breas% cancer cases, $in) %heir a))resses an), $or sub-ec%s living
in 6iroshima or /agasa!i, ma%ch %heir names agains% %he local %umour regis%ries.
he recen% i)en%i$ica%ion o$ s#eci$ic genes associa%e) ,i%h $amilial susce#%ibili%y %o cancers o$ cer%ain
si%es, %he se9uencing o$ cer%ain o$ %hese, an) conse9uen% inves%iga%ions o$ %heir mu%a%ional s#ec%ra in
cancer cases #romise a more )irec% me%ho) o$ inves%iga%ing %he 9ues%ion o$ gene%ic susce#%ibili%y %o
ra)ia%ion carcinogenesis. he me%ho) #resu##oses %he availabili%y o$ %issue $rom cancer cases (an),
#ossibly, con%rols+ in an irra)ia%e) #o#ula%ion ,i%h a s%rong ra)ia%ion )ose res#onse, !no,n gene
se9uences $or %he can)i)a%e genes, an) (i)eally+ #reviously i)en%i$ie) $amilial mu%a%ions associa%e)
,i%h increase) ris!. Brie$ly, %he sugges%e) a##roach is %o com#are mu%a%ion $re9uencies an) s#ec%ra in
%erms o$ ra)ia%ion )ose an)0or es%ima%e) #robabili%y o$ ra)ia%ion causa%ion (e4cess ris! )ivi)e) by %o%al
ris!+, ,i%h a%%en%ion %o mo)i$ying $ac%ors such as age a% )iagnosis, age a% e4#osure, an) o%her $ac%ors
%hough% %o in$luence cancer ris! in general an) ra)ia%ion-rela%e) ris! in #ar%icular.
In %he con%e4% o$ %he #ossible involvemen% o$ BRCA1 an) BRCA2 germ line mu%a%ions in early-onse%
breas% cancers o$ %he A-bomb survivors i% ,oul) be o$ subs%an%ial value %o have in$orma%ion on %heir
con%ribu%ion %o breas% cancer in Da#an. here ,oul) be grea% a))i%ional bene$i% i$, as in %he case o$
De,ish #o#ula%ions o$ Ash!ena<i )escen%, %here ,ere %o be a )is#ro#or%iona%e con%ribu%ion %o heri%able
breas% cancer in Da#an $rom s#eci$ic gene mu%a%ions arising %hrough common )escen% (see &ollins, 199>
an) 3ec%ion >+. C%her molecular a##roaches %o es%ablishing a gene%ic basis $or ra)ia%ion-associa%e)
cancer ris! in %he Da#anese cohor% are available (see 3he$$iel) e% al., 1995+ bu% all o$ %hese may be
com#romise) by %he )i$$icul%ies alrea)y no%e) in con)uc%ing $amily s%u)ies on cancer inci)ence in
Da#an. Molecular s%u)ies on %umour ma%erial $rom cases can, as in %he case o$ p53-)e$icien% mice
(3ec%ion 5.2+, be in$orma%ive $or gene%ic in$luences on ra)ia%ion carcinogenesis bu%, usually, only ,hen
a large number o$ cases are available an) ,hen can)i)a%e germ line %arge% ./A se9uences are !no,n.
.!-!.! (tatistical considerations and modellin%
he 9ues%ion o$ a gene%ic basis $or sensi%ivi%y %o ra)ia%ion carcinogenesis is a secon)-or)er #roblem, as
con%ras%e) ,i%h %he $irs%-or)er #roblems o$ charac%erising gene%ic varia%ion an) ra)ia%ion )ose as
in)e#en)en% ris! $ac%ors. An int/raction mo)el )escribes ho, %he e$$ec% o$ one ris! $ac%or may vary
accor)ing %o %he level o$ ano%her. 6ere, ,e are concerne) ,i%h %he in%erac%ion o$ inheri%e) gene%ic
mu%a%ions an) ra)ia%ion )ose in %he causa%ion o$ cancer, -us% as ,e migh% consi)er %he in%erac%ion o$
)ose an) re#ro)uc%ive his%ory as ris! $ac%ors $or breas% cancer, or o$ )ose an) smo!ing his%ory $or lung
cancer. As ,i%h any in%erac%ion #roblem, %he li!elihoo) o$ ob%aining es%ima%es o$ use$ul #recision is
increase) i$ bo%h $ac%ors, ra)ia%ion )ose an) gene%ic #re)is#osi%ion %o cancer, are s%rongly associa%e)
,i%h ris!. hus, sui%able #o#ula%ions $or s%u)y are %hose !no,n %o have a s%rong ra)ia%ion )ose res#onse
$or %he cancer si%e un)er consi)era%ion, ,i%h many cases $or ,hich ra)ia%ion causa%ion is li!ely, an) a
s%rong li!elihoo) %ha% many o$ %he cases resul%e) $rom a gene%ic #re)is#osi%ion.
he #ossibili%y shoul) also be consi)ere) %ha% some germ line mu%a%ions migh% be associa%e) ,i%h
increase) ris! only a% high ra)ia%ion )oses. 3uch mu%a%ions ,oul) be unli!ely %o be i)en%i$ie) $rom
s%u)ies o$ non-irra)ia%e) #o#ula%ions. An i)eal si%ua%ion ,oul) be %o have normal %issue $rom bo%h cases
an) ma%che) con%rols, as ,ell as %umour %issue $rom cases, available $or analysis. I$ %he #o#ula%ion is
94
,ell s%u)ie) an) ,ell charac%erise) $or ra)ia%ion-rela%e) cancer ris!, cases an) con%rols can be ma%che)
on ra)ia%ion )ose as ,ell as on se4, year o$ bir%h, age a% e4#osure, an) o%her relevan% $ac%ors, an) %he
e4is%ing in$orma%ion on )ose res#onse can be incor#ora%e) in%o %he analysis ,i%h a resul%an% increase in
s%a%is%ical #o,er. 3u##ose, $or e4am#le, %ha% %he e4cess rela%ive ris! (*''+ #er 3v is es%ima%e) %o be
F1161 "9or si-plicit. oC notation2 G/ i?nor/ possibl/ 0ariation in os/ r/spons/ b. a?/2 s/x2 /tc1$ 3/t
# )eno%e ra)ia%ion )ose in 3v, le% X )eno%e #resence or absence o$ a #ar%icular mu%a%ion or class o$
mu%a%ions, an) le% A )eno%e %he un!no,n e4cess rela%ive ris! associa%e) ,i%h %he mu%a%ion (i.e. ,i%h
XM1+. I$ %he )ose res#onse )oes no% )e#en) u#on %he value o$ X, %he $ollo,ing (a))i%ive+ mo)el hol)s
$or rela%ive ris! RR@
RR(.,X+M1K^XK1.>..
he mul%i#lica%ive mo)el corres#on)s %o ano%her sim#le si%ua%ion, in ,hich %he ris! o$ ra)ia%ion-rela%e)
cancer is increase) by #resence o$ %he mu%a%ion in %he same ra%io as %he ris! o$ ra)ia%ion-in)e#en)en%
cancer@
RR(.,X+M(1K^X+(1K1.>.+.
I% is #ossible %o )iscrimina%e be%,een %he a))i%ive an) mul%i#lica%ive mo)els by embe))ing %hem in a
more general mo)el, li!e %he $ollo,ing@
,hich re)uces %o %he a))i%ive mo)el ,hen HM1 an) %o %he mul%i#lica%ive mo)el ,hen HM;. C%her
general mo)els can be )erive) ,i%h %he same #ro#er%ies, e.g.
RR(#,X+M1K^XK1.>#K_#X
,hich re)uces %o %he a))i%ive mo)el ,hen BM; an) %o %he mul%i#lica%ive mo)el ,hen BFA. Ei%h bo%h o$
%hese general mo)els, i% is #ossible %o %es% ,he%her %he )a%a are consis%en% ,i%h ei%her o$ %he %,o sim#le
mo)els. he %,o general mo)els )i$$er some,ha% in ho, %hey charac%erise )e#ar%ures $rom %he %,o
sim#le mo)els, bu% ,i%h each, i% is #ossible %o ma!e in$erences abou% such )e#ar%ures base) on %he
es%ima%e) value o$ %he a))i%ional #arame%er (H or B+.
Al%hough i% clearly ,oul) be )esirable %o ob%ain $resh bloo) an) %issue sam#les $rom cases an) ma%che)
con%rols, i% seems unli!ely %ha% su$$icien% numbers %o es%ablish a gene%ic role in ra)ia%ion carcinogenesis
coul) be ob%aine) ,i%hou% grea% )i$$icul%y an) e4#ense in many o$ %he irra)ia%e) #o#ula%ions no, un)er
s%u)y. Ei%h $ormalin-$i4e), #ara$$in-embe))e) bloc!s o$ %umour an) a)-acen% normal %issue, #lus
lym#h no)es, ob%aine) a% surgery $rom cancer cases only, i% is #ossible %o %es% $or )e#ar%ures $rom %he
mul%i#lica%ive in%erac%ion mo)el, accor)ing %o ,hich %he #ro#or%ion o$ cases ,i%h inheri%e) mu%a%ions
shoul) no% vary by ra)ia%ion )ose (all o%her %hings being e9ual+. hus, ,e can as! ,he%her %he increase)
sensi%ivi%y %o ra)ia%ion associa%e) ,i%h %he mu%a%ion is less %han, %he same as, or grea%er %han %ha% $or all
o%her causes o$ cancer consi)ere) as a grou#, bu% no% ,he%her %here is evi)ence o$ ra)ia%ion sensi%ivi%y
as in)ica%e) by s%a%is%ical inconsis%ency ,i%h %he a))i%ive mo)el.
he )i$$icul%y -us% men%ione) occurs because availabili%y o$ gene%ic in$orma%ion only $or cases
#reclu)es es%ima%ion o$ %he e$$ec% o$ a #ar%icular heri%able mu%a%ion, or grou# o$ mu%a%ions, on cancer
ris!. 1e% I be %he #robabili%y %ha% a #erson ran)omly selec%e) $rom %he s%u)y #o#ula%ion ,ill have a
heri%able mu%a%ion o$ %he gene in 9ues%ion. An)er %he a))i%ive mo)el, %he rela%ive ris! o$ a heri%able
mu%a%ion (XM1+ $or a case (CM1+ ,i%h )ose #, rela%ive %o a case ,i%h )ose <ero, is
95
RR(XM1`CM1,#+M(1K^Ka#+0(1K^+[(1K^b+0(1Ka#K^b+.
hus, ,i%h !no,n A, , I, i% ,oul) be #ossible %o %es% %he a))i%ive as ,ell as %he mul%i#lica%ive mo)el.
he 9ues%ion is ,he%her, in a #o#ula%ion %ha% has no% #reviously been s%u)ie) $or cancer ris! in rela%ion
%o mu%a%ions o$ %he gene o$ in%eres%, es%ima%es o$ A an) I $rom ano%her #o#ula%ion coul) be use) ,i%h
any con$i)ence.
.!-!1! Irradiated %roups for potential study
.!-!1!1! 7reast cancer amon% A'bomb survivors
he A-bomb survivor cohor% has a very high signal-%o-noise ra%io $or in$orma%ion on ra)ia%ion-in)uce)
breas% cancer, having, in absolu%e %erms, abou% %he same e4cess ris! #er uni% )ose as me)ically-
irra)ia%e) Ees%ern #o#ula%ions %ha% have been s%u)ie), bu% a much lo,er baseline ra%e. In)ivi)uals can
be i)en%i$ie) ,hose cancers #robably ,oul) no% have occurre) in %he absence o$ e4#osure, an) o%hers
(many more+ ,hose cancers very #robably ,ere no% ra)ia%ion-rela%e). :ormalin-$i4e), #ara$$in-
embe))e) %issue bloc!s are available $or mos% o$ %he 892 cases acce#%e) in%o %he series o$ 1;92 cases
on %he basis o$ #a%hology revie, by %he inves%iga%ors in a curren% s%u)y. 'a)ia%ion-rela%e) ris! )e#en)s
u#on age a% e4#osure in 1985= %hus abou% 8; o$ 287 cases (,i%h %issue+ ,ho ,ere un)er 2; years o$ age
a% e4#osure ,ere #robably cause) by ra)ia%ion, 8; o$ 278 ,ho ,ere be%,een 2; an) 8;, an) only $our
o$ 128 ,ho ,ere ol)er. :ormalin-$i4e), archival breas% %umour %issue is available $or abou% 15 early-
onse% cases in %he grou# un)er 2; a% e4#osure, o$ ,hom, i$ %he es%ima%e o$ 12.5 e4cess rela%ive ris! a% 1
3v can be believe), over hal$ are #robably ra)ia%ion rela%e).
he #o#ula%ion seems highly sui%able $or inves%iga%ions o$ BRCA1 an) BRCA2 mu%a%ions. A% lo,
)oses, ,e migh% e4#ec% %o $in), in cases, a )ecreasing %ren) in %he $re9uency o$ heri%able mu%a%ions ,i%h
increasing age a% )iagnosis. I$ an inheri%e) mu%a%ion )oes no% increase susce#%ibili%y %o ra)ia%ion
carcinogenesis or i$ susce#%ibili%y is increase) less %han $or o%her ris! $ac%ors, %hen (con%rolling $or age
a% )iagnosis+ mu%a%ion $re9uency shoul) )ecrease ,i%h increasing )ose. I$ %here is a mar!e) increase in
susce#%ibili%y, mu%a%ion $re9uency shoul) increase ,i%h )ose. I% is #ossible %ha% %he same mo)el may no%
hol) $or early-onse% an) la%e-onse% cases.
here is a clinical sub-sam#le o$ survivors ,ho are invi%e) %o come %o %he 'a)ia%ion *$$ec%s 'esearch
:oun)a%ion ('*':+ every %,o years. Bloo) sam#les are %a!en an) lines o$ immor%alise) lym#hocy%es
have been s%ore) $or 2;;; sub-sam#le members. I% is #ossible %ha% a case-con%rol s%u)y migh% be )one
res%ric%e) %o #ar%ici#an%s in a biennial e4amina%ion cycle, bu% a more #romising a##roach may be %o
ma%ch con%rols $rom %he clinical sam#le %o cases $or ,hich only %issue bloc!s are available, an) %o use
in$orma%ion $rom cases ,i%h bo%h bloo)s an) %issue bloc!s %o es%ima%e %he e$$ec% o$ using )i$$eren% !in)s
o$ biological ma%erials (an) #erha#s also %he )i$$erence be%,een %umour an) non-%umour %issue, a
#ossible con$oun)er+.
.!-!1!"! 7reast cancer in other irradiated populations
he #ossibili%y o$ ra)ia%ion-rela%e), early-onse% breas% cancer occurs in several me)ically irra)ia%e)
#o#ula%ions un)er s%u)y in %he Ani%e) 3%a%es an) 3,e)en. hese inclu)e ,omen %rea%e) )uring
chil)hoo) or a)olescence $or %uberculosis by $luorosco#ically moni%ore) #neumo%hora4 (6rubec e% al.,
1989+ or $or scoliosis moni%ore) by 4 ray (6o$$man e% al., 1989+, an) ,omen irra)ia%e) )uring in$ancy
$or enlarge) %hymus (6il)re%h e% al., 1989+ or $or hemangioma. 'a)ia%ion-rela%e) e4cess ris!s have
been observe) in all %hese #o#ula%ions= also, %he baseline levels o$ ris! are several %imes higher %han in
Da#an. issue $rom early-onse% cases $rom %he #neumo%hora4 an) scoliosis #a%ien% #o#ula%ions, #lus a
96
cohor% o$ O-ray %echnologis%s ,i%h long-%erm occu#a%ional e4#osure %o ra)ia%ion, are being assaye) $or
BRCA1 mu%a%ions in a #ilo% s%u)y (Boice, 1997+. I% ,oul) be very in%eres%ing %o see i$ BRCA1 an)
BRCA2 mu%a%ion $re9uencies are similar in A3 #o#ula%ions an) in %he '*': cohor%, $or com#arable
ages a% )iagnosis, ra)ia%ion )oses, an) es%ima%e) #robabili%ies o$ ra)ia%ion causa%ion. C$ #ar%icular
in%eres% is ,he%her %he #ro#or%ion o$ gene%ically-rela%e) breas% cancer, bo%h early an) la%e onse% bu%
es#ecially %he $ormer, is higher among %he rela%ively lo,-ris! Da#anese %han among Ees%erners.
Assuming no )i$$erence in %he level o$ gene%ic #re)is#osi%ion %o breas% cancer, %he ans,er %o %his
9ues%ion shoul) be in$orma%ive abou% %he e4%en% %o ,hich a gene%ically-)e%ermine) ris! can be mo)i$ie)
by environmen%al an) li$e s%yle $ac%ors.
.!-!1!,! Colon cancer amon% A'bomb survivors
&olon cancer is abou% >;5 as $re9uen% among Da#anese as among Ees%erners. he number o$ cases, in
bo%h se4es, in %he '*': s%u)y #o#ula%ion is abou% %he same as %he number o$ breas% cancers among
,omen, ,i%h abou% hal$ %he *'' a% 1 3v (;.72+. here is less evi)ence o$ a )ecrease in *'' ,i%h
increasing age a% e4#osure %han $or breas% cancer. he recen% i)en%i$ica%ion, an) se9uencing, o$ %he
*351 an) *+52 genes believe) %o be res#onsible $or a high #ro#or%ion o$ heri%able non-#oly#osis
colon cancer (6/P&&+, o$$ers an o##or%uni%y %o inves%iga%e %he in%erac%ion o$ %hese genes ,i%h ionising
ra)ia%ion. In Ees%erners, 6/P&& is re#or%e) %o occur #re)ominan%ly in %he u##er segmen% o$ %he colon,
an) cancers occurring %here may %here$ore be %he mos% valuable $or s%u)y. In %he A-bomb survivors,
ho,ever, *'' #er 3v )oes no% a##ear %o vary among %he u##er, mi))le, an) lo,er segmen%s
(/a!a%su!a e% al., 1992+, a $in)ing %ha% gives li%%le encouragemen% %o %he i)ea %ha% *351 an) *+52
mu%a%ions may be ra)iosensi%ising. A ne, inci)ence s%u)y is #lanne), ,hich ,ill among o%her %hings
i)en%i$y cases ,i%h available %issue $or molecular assay. A search $or unusual #a%%erns o$ 6/P&&-
rela%e) microsa%elli%e ins%abili%y amongs% such %umours (3ec%ion 2+ ,oul) be a rela%ively
s%raigh%$or,ar) an) #o%en%ially re,ar)ing e4ercise.
.!-!1!-! varian cancer amon% A'bomb survivors
&ancer o$ %he ovary, li!e cancers o$ %he $emale breas% an) %he colon, is rela%ively rare among Da#anese
com#are) %o *uro#eans an) /or%h Americans. Among A-bomb survivors, i% is abou% one-$our%h as
$re9uen% as breas% cancer, bu% %he es%ima%es o$ *'' a% 1 3v are com#arable $or all ages combine).
Pa%%erns o$ *'' #er 3v ,i%h res#ec% %o age a% e4#osure are less clear %han $or breas% cancer, ho,ever.
Because ovarian cancer ris! is also %ie) %o BRCA1 mu%a%ions an) may also occur in e4cess in some
6/P&& $amilies, i% ,oul) seem reasonable %o inclu)e %issue $rom ovarian cancer cases in
inves%iga%ions o$ breas% an)0or colon cancer.
.!.! verall ;ud%ements on %enetically determined tumori%enic radiosensitivity
I% has been argue) on mechanis%ic groun)s %ha% %here is goo) reason %o believe %ha%, in many cases,
gene%ically )e%ermine) ris! o$ s#on%aneously arising cancer ,ill be accom#anie) by an increase in
sensi%ivi%y %o %he %umorigenic e$$ec%s o$ ionising ra)ia%ion. Base) u#on soma%ic cell mu%a%ion )a%a i% ,as
conclu)e) %ha% %he mos% cer%ain mani$es%a%ion o$ increase) %umorigenic ra)iosensi%ivi%y ,oul) occur in
%he case o$ human cancer #re)is#osi%ion associa%e) ,i%h inheri%e) )e$iciency in %umour su##ressor
genes (3ec%ion 5.1.2+. 3ome bu% no% all inheri%e) )e$iciencies in ./A re#air ,oul) also be e4#ec%e) %o
increase ra)ia%ion cancer ris! (3ec%ion 5.1.1+ bu% no clear -u)gemen% coul) be ma)e in res#ec% o$ very
rare )e$iciencies in #ro%o-oncogenes (3ec%ion 5.1.2+.
97
he above #re)ic%ion regar)ing %umour su##ressor gene )e$iciency is me% in %he %hree in$orma%ive
animal )a%a se%s curren%ly available in ro)en% mo)els o$ 1i7:raumeni syn)rome (p53-)e$iciency+
$amilial a)enoma%ous #oly#osis (Apc-)e$iciency+ an) %uberous sclerosis ()sc2-)e$iciency+. Al%hough
$ar $rom being 9uan%i%a%ively )e$ini%ive i% is -u)ge) %ha% in p53-)e$icien% mice %here may be an increase
in %issue-s#eci$ic %umorigenic ra)iosensi%ivi%y o$ aroun) 12-$ol) ,hile in )sc2-)e$icien% ra%s %ha%
increase maybe 1;;-$ol) or more (3ec%ion 5.2.2+. &urren%ly %here are no animal )a%a on ,hich %o
commen% on %he in$luence o$ s#eci$ic ./A re#air )e$iciencies bu% %his #osi%ion may be e4#ec%e) %o
change in %he near $u%ure (3ec%ion 5.1.1+. Ehe%her %hese )a%a $rom animal gene%ic mo)els may be
e4%ra#ola%e) ,i%h con$i)ence %o humans is ho,ever o#en %o )oub% since )i$$erences in gene%ic
bac!groun) may have #ro$oun) e$$ec%s on %he e4#ression o$ some germ line )e%erminan%s o$ cancer an)
%here are s#eci$ic e4#erimen%al $ea%ures %ha% can lea) %o over- an) un)er-es%ima%ion o$ in)uce) %umour
ris!. In s#i%e o$ %hese #roblems, %he ro)en% )a%a broa)ly su##or% %he con%en%ion o$ gene%ically increase)
ra)ia%ion ris! in cer%ain human )isor)ers.
his conclusion is more )irec%ly su##or%e) by ra)io%hera#eu%ic observa%ions in %he cancer-#rone human
gene%ic con)i%ions re%inoblas%oma ('B+, nevoi) basal cell carcinoma syn)rome (/B&&3+, 1i7:raumeni
syn)rome (1:3+ an) neuro$ibroma%osis (/:+= all %hese )isor)ers are associa%e) ,i%h %umour su##ressor
gene )e$iciencies.
In %he case o$ heri%able 'B %he #os%-ra)io%hera#y ris! o$ %umour mor%ali%y is $ive- %o si4-$ol) grea%er
%han in non-heri%able 'B an) may be grea%er s%ill ,hen com#are) ,i%h %ha% o$ normal in)ivi)uals
(3ec%ion 5.2.1+. I% ,as argue), ho,ever, %ha% %his sim#ly -u)ge) increase in %umorigenic ra)iosensi%ivi%y
may un)eres%ima%e %he %rue e$$ec% o$ RB germ line mu%a%ion on ra)ia%ion ris! a% )oses lo,er %han %hose
use) in conven%ional ra)io%hera#y. A $ur%her $ollo,-u# o$ %hese 'B cases only serve) %o highligh% %he
uncer%ain%y surroun)ing %he #rovision o$ 9uan%i%a%ive -u)gemen%s on rela%ive %umorigenic
ra)iosensi%ivi%y.
he case re#or%s on ra)io%hera#eu%ic res#onse in /B&&3 are relevan% since %hey #rovi)e evi)ence o$ a
rela%ively high level o$ gene%ically )e%ermine) susce#%ibili%y %o ra)ia%ion-in)uce) basal cell carcinoma
in %he lo, )ose #eri#hery o$ %he irra)ia%e) $iel) (3ec%ion 5.2.2+. Pos%-ra)io%hera#y observa%ions in 1:3
an), %o a lesser e4%en%, /: #a%ien%s are also consis%en% ,i%h increase) ra)ia%ion cancer ris! associa%e)
,i%h %umour su##ressor gene )e$iciency bu% )o no% allo, $or any 9uan%i%a%ive -u)gemen%s on %hese
e$$ec%s (3ec%ion 5.2.8+. he ma-or s%reng%h o$ s%u)ies ,i%h 1:3 #a%ien%s is %ha% %hey inclu)e $amilial an)
molecular inves%iga%ions ,hich allo, )irec% #arallels %o be )ra,n be%,een human an) ro)en% s%u)ies on
p53 gene )e$iciency.
:inally, %he s%u)y o$ Fony e% al. (1997+ on %he in%erac%ion o$ gene%ic $ac%ors an) ra)io%hera#y in %he
#ro)uc%ion o$ secon) malignan% neo#lasms (3M/+ in chil)ren #oin% %o,ar)s a rela%ively mo)es%
increase in ris! o$ 3M/ as a resul% o$ gene%ic $ac%ors= %he o))s ra%io $or %hose #a%ien%s having a $amily
his%ory o$ cancer ,as aroun) 5.
In a))i%ion %o %he consis%en% $in)ing o$ increase) %umorigenic ra)iosensi%ivi%y associa%e) ,i%h %umour-
su##ressor gene )e$iciency in humans an) ro)en%s %here are s%rong in)ica%ions %ha% ra)ia%ion
%umorigenic res#onse is $re9uen%ly associa%e) ,i%h signi$ican% an) some%imes )rama%ic re)uc%ion in
%umour la%ency. Al%hough no meaning$ul 9uan%i%a%ion o$ %his e$$ec% can be ma)e %he re)uc%ion o$ %umour
la%ency ,ill %en) %o $ur%her increase %he ra)ia%ion )e%rimen% %o such cancer-#rone in)ivi)uals.
3an!aranarayanan an) &ha!rabor%y (1995+ have also argue) %ha% shor%ene) la%ency ,ill %en) %o
accom#any increase) %umorigenic ra)iosensi%ivi%y in mos% cases o$ heri%able cancer #re)is#osi%ion.
98
Ehe%her such e$$ec%s have a s#eci$ic biological basis, e.g accelera%e) )evelo#men% o$ e4is%ing #re-
neo#las%ic clones $ollo,ing ra)ia%ion (3%rong, 1977+ or sim#ly re$lec% an increase) #robabili%y o$ early
)evelo#men% amongs% an increase) number o$ cancer ini%ia%e) cells remains %o be )e%ermine).
*#i)emiological s%u)ies on Da#anese A-bomb survivors have ye% %o #rovi)e une9uivocal evi)ence
regar)ing gene%ic e$$ec%s on ra)ia%ion cancer ris!s. he $in)ing o$ a >-$ol) increase in e4cess rela%ive
ris! #er 3v in res#ec% o$ early onse% breas% cancer in ,omen irra)ia%e) a% ages Z2; years is broa)ly
consis%en% ,i%h %he #resence o$ a gene%ic subgrou# o$ ra)iosensi%ive cases (3ec%ion 5.8.2+= %he
shor%ening o$ %umour la%ency in res#onse %o ra)ia%ion may be charac%eris%ic o$ gene%ically )e%ermine)
cancer ris!. In %he absence o$ in$orma%ion on $amilial #a%%erns o$ cancer ris! in %hese cases an) on
molecular s%u)ies o$ germ line can)i)a%e breas% cancer genes, o%her non-gene%ic e4#lana%ions o$ %hese
$in)ings remain, ho,ever, #ossible. he ini%ia%ion o$ $ollo,-u# s%u)ies %o resolve %hese 9ues%ions
shoul) be regar)e) as a #riori%y.
I% may be conclu)e) %ha% al%hough %he )a%a )iscusse) in %his 3ec%ion #rovi)e consis%en% evi)ence $or
gene%ically )e%ermine) increase in ra)ia%ion cancer ris! in a limi%e) se% o$ gene%ic con)i%ions in humans
an) e4#erimen%al animals, con$i)en% -u)gemen% on %he e4%en% o$ increase) ra)iosensi%ivi%y remains
mos% elusive. he e4#erimen%al an) ra)io%hera#eu%ic observa%ions )iscusse) in res#ec% o$ %umour
su##ressor gene )e$iciencies im#ly, as a $irs% a##ro4ima%ion, %ha% increases in %issue-s#eci$ic cancer ris!
$ollo,ing e4#osure %o mo)era%e %o high )oses o$ acu%e ra)ia%ion are li!ely %o be Z5-$ol) bu% #robably
?1;;-$ol) grea%er %han normal. he )irec% human )a%a $rom high )ose ra)io%hera#y $ollo,-u# s%u)ies
im#ly %ha% a gene%ically im#ose) increase) ris! in %he lo,er en) o$ %his range, say aroun) 1;-$ol),
migh% be realis%ic. A $ur%her elemen% o$ ra)ia%ion )e%rimen% may also be in%ro)uce) %hrough %he
shor%ening o$ %umour la%ency.
I% is ho,ever im#or%an% %o em#hasise s%rongly %he #auci%y o$ %he )a%a curren%ly available $or any
-u)gemen%s $or ra)iological #ro%ec%ion #ur#oses. :irs%, even i$ %he above es%ima%es on %he range o$
gene%ically im#ose) increase) ris! ,ere %o be con$irme) by s%u)y o$ o%her geno%y#es an) cancer %y#es,
grea% uncer%ain%y ,oul) con%inue %o surroun) %umorigenic res#onses a% lo, )oses an) lo, )ose ra%es.
3econ), almos% all %he )a%a se%s )iscusse) rela%e %o %umour su##ressor %y#e gene%ic )isor)ers o$
rela%ively high #ene%rance, i.e %hose e4hibi%ing a high s#on%aneous inci)ence o$ cancer. Ehe%her
ra)iological #ro%ec%ion -u)gemen%s on %hese may also a##ly %o gene%ic con)i%ions o$ lo,er #ene%rance
remains a ma%%er o$ con-ec%ure. hir), as )iscusse) in 3ec%ion 7, ra)ia%ion cancer ris!s are li!ely %o be
sub-ec% %o gene%ic7gene%ic an) o%her environmen%al7gene%ic in%erac%ions. he choice o$ a single value o$
%umorigenic ra)iosensi%ivi%y %o re#resen% all relevan% gene%ic con)i%ions an) %umour %y#es in all a$$ec%e)
in)ivi)uals is a gross sim#li$ica%ion o$ a mos% com#le4 #roblem. Al%hough %hese grea% uncer%ain%ies are
$ully recognise) %he choice o$ a Hbes% es%ima%eI single value o$ 1;-$ol) %o re#resen% gene%ically im#ose)
%umorigenic ra)iosensi%ivi%y has been ma)e in or)er %o allo, %he #resen%a%ion o$ illus%ra%ive calcula%ions
o$ ra)iological im#ac% in 3ec%ion 7. :inally, since e#i)emiological an) e4#erimen%al s%u)ies have ye% %o
clari$y %he %umorigenic res#onse o$ a%a4ia-%elangiec%asia homo- an) he%ero<ygo%es %o ra)ia%ion, %he
,hole 9ues%ion o$ res#onses associa%e) ,i%h ./A re#air )e$iciency remains o#en. here is ho,ever
unambiguous evi)ence o$ increase) s!in cancer in sunligh% e4#ose) regions o$ AV'-re#air )e$icien%
human 4ero)erma #igmen%osum (OP+ #a%ien%s (Fraemer e% al., 1998+ an) in animal mo)els o$ OP
(3ec%ion 5.1.1+. hus, i% may be reasonably argue) %ha% inheri%e) human )e$ec%s in relevan% ./A re#air
genes ,ill also be accom#anie) by increase) cancer ris!s a$%er ionising ra)ia%ion.
.!1! (ummary and conclusions
99
1. Fno,le)ge o$ $un)amen%al mechanisms o$ ./A )amage re#air, mu%agenesis, an) carcinogenesis
im#ly %ha%, in mos% cases, human cancer #re)is#osi%ion associa%e) ,i%h ./A re#air or %umour
su##ressor gene )e$iciency ,ill be associa%e) ,i%h increase) cancer ris! a$%er ra)ia%ion.
2. *4#erimen%al s%u)ies ,i%h animal gene%ic mo)els o$ human cancer-#re)is#osing )isor)ers #rovi)e
evi)ence $or signi$ican%ly increase) cancer ris! a$%er ra)ia%ion.
2. Pos%-ra)io%hera#y observa%ions in human #a%ien%s ,i%h %he cancer-#re)is#osing )isor)ers,
re%inoblas%oma, nevoi) basal cell carcinoma syn)rome, an) 1i7:raumeni syn)rome su##or% %he no%ion
o$ increases in absolu%e cancer ris! a$%er ra)ia%ion.
8. 'ecen% e#i)emiological an) molecular s%u)ies ,ea!en, bu% )o no% nega%e, %he associa%ion be%,een
a%a4ia-%elangiec%asia he%ero<ygo%es an) e4cess breas% cancer.
5. &onven%ional e#i)emiological a##roaches %o cancer ris! in gene%ically #re)is#ose) sub-#o#ula%ions
are unli!ely %o succee) $ully unless %hey can be cou#le) ,i%h a##ro#ria%e molecular analyses.
>. he availabili%y o$ cancer case series o$ su$$icien% si<e an) a high #robabili%y o$ ra)ia%ion causa%ion
#romises %ha% molecular e#i)emiology ,ill resolve some as#ec%s o$ %he #roblem o$ gene%ic e$$ec%s on
ra)ia%ion ris!.
7. As an in%erim -u)gemen% base) on animal an) human )a%a i% is sugges%e) %ha% %he ris! o$ cancer a$%er
ra)ia%ion may, in #rinci#le, be eleva%e) by u# %o aroun) 1;;-$ol) in some heri%able cancer )isor)ers=
limi%e) human )a%a im#ly values %ha% are lo,er %han %hose seen in animal mo)els. "rea% uncer%ain%ies
are recognise) an) s%resse) bu% a single bes% es%ima%e value o$ 1;-$ol) increase) ris! is sugges%e) $or
%he #ur#oses o$ illus%ra%ive calcula%ion o$ ra)iological im#ac%.
1! Computational modellin% of the impact of %enetic factors in radiation
carcino%enesis
In #revious sec%ions o$ %he )ocumen% molecular, gene%ic, clinical, an) e#i)emiological )a%a relevan% %o
gene%ic #re)is#osi%ion %o cancer have been ou%line). :rom a mechanis%ic vie,#oin% i% has been argue)
%ha% cancer #re)is#osi%ion associa%e) ,i%h germ line %umour su##ressor, #ro%o-oncogene, an) many
./A-#rocessing gene )e$ec%s ,ill %en) %o be accom#anie) by increase) susce#%ibili%y %o ra)ia%ion-
in)uce) )isease. In revie,ing ,ha% is, un$or%una%ely, a limi%e) se% o$ in$orma%ive )a%a, some su##or% $or
%his con%en%ion ,as ob%aine) $rom clinical, e#i)emiological, an) e4#erimen%al s%u)ies.
In accor) ,i%h #revious )iscussions i% is evi)en% %ha% in or)er %o ma!e es%ima%es o$ %he e4cess cancer in
a given irra)ia%e) human #o#ula%ion %ha% migh% be a%%ribu%e) %o a gene%ically #re)is#ose) subgrou# i% is
necessary %o have !no,le)ge o$ %,o cri%ical #arame%ers. :irs% %he number o$ in)ivi)uals ,i%hin %ha%
#o#ula%ion %ha% carry mu%an% genes %ha% #re)is#ose %o cancer overall= secon) %he overall )egree o$
%umorigenic ra)iosensi%ivi%y con$erre) by %he mu%an% gene %o %hese carriers.
A% #resen%, in$orme) -u)gemen% on a value $or %he overall $re9uency o$ cancer #re)is#ose) in)ivi)uals
in %he human #o#ula%ion is no% $easible an), albei% ,i%h $ull a##recia%ion o$ curren% uncer%ain%ies, ,e
consi)er only %hose charac%erise) )isor)ers ,here es%ima%es o$ #revalence have alrea)y been ma)e
(able >.1+. *9ually #roblema%ical is %he #rovision o$ -u)gemen%s on %he s#eci$ic )egree o$ %umorigenic
ra)iosensi%ivi%y associa%e) ,i%h any o$ %he gene%ic )isor)ers %ha% ,e have consi)ere). :rom %he revie,
100
o$ %he limi%e) )a%a given in 3ec%ion 5 an in%erim -u)gemen% o$ an increase in %umorigenic
ra)iosensi%ivi%y $or cer%ain %issues o$ be%,een 5- an) 1;;-$ol) in a $e, gene%ic )isor)ers ,as ma)e. he
uncer%ain%ies %ha% a%%ach %o such -u)gemen%s are ho,ever su$$icien%ly grea% a% #resen% %ha% i% ,oul) be
mos% #rema%ure %o a##ly a s#eci$ic $ac%or o$ %umorigenic ra)iosensi%ivi%y %o a s#eci$ic se% o$ )isor)ers
even i$ %he #revalence in %he #o#ula%ion ,as ,ell es%ablishe).
101
able >.1. :amilial cancer genes in man
a
102
In %he ligh% o$ %hese )i$$icul%ies a%%en%ion in %his sec%ion o$ %he re#or% is $ocusse) #rinci#ally on %he
)evelo#men% o$ gene%ically base) com#u%a%ional mo)els in%o ,hich given es%ima%es o$ )isease
#revalence, s%reng%h o$ #re)is#osi%ion an) %umorigenic ra)iosensi%ivi%y may be in%ro)uce) as $ur%her
)a%a accumula%e. hese mo)els are use) %o e4#lore )i$$eren% scenarios in res#ec% o$ %he in#u%
#arame%ers an) also %o e4#lore %he #ossible im#ac% o$ gene%ic susce#%ibili%y %o breas% an) colon cancer.
1!1! 6amilial cancer %enes: estimates of mutant %ene fre<uencies
In general, $or a single gene %rai%, %he $re9uency o$ %he mu%an% allele in %he #o#ula%ion can be com#u%e)
$rom %ha% o$ %he )isease in %he #o#ula%ion an) a !no,le)ge o$ ,hich geno%y#es are a$$ec%e), assuming
6ar)y7Eeinberg e9uilibrium (see 3ec%ion >.2+. :or e4am#le, i$ %here are %,o alleles A an) a a% an
au%osomal locus an) i$ %he a allele #ro)uces %he )isease only in %he aa homo<ygo%es, %hen %he )isease is
recessive an) %he $re9uency p o$ %he a allele in %he #o#ula%ion is %he s9uare roo% o$ %he )isease
$re9uency. I$, ho,ever, %he )isease is )ominan% an) cause) by %he #resence o$ %he A allele ,i%h allele
$re9uency p, %hen %he )isease ,ill be mani$es% in homo<ygo%es (AA+ an) in he%ero<ygo%es (Aa+= %heir
$re9uency in %he #o#ula%ion is p
2
K2p(1Lp+. :or rare )ominan% )iseases, (1Lp+ is nearly e9ual %o 1 an)
%he p
2
%erm can be neglec%e). :or %hese, %here$ore, %he allele $re9uency is a##ro4ima%ely one-hal$ o$ %he
)isease $re9uency.
able >.1 u#)a%e) $rom %he #a#er o$ 3an!aranarayanan an) &ha!rabor%y (1995+ summarises
a##ro4ima%e es%ima%es o$ #revalences o$ some $amilial cancers. Because o$ %he a##ro4ima%e na%ure o$
%hese es%ima%es, an) %he $ac% %ha% ,i%h some common cancers (e.g. %hose o$ %he breas% an) colon+, %he
#ro#or%ion )ue %o #re)is#osing germinal mu%a%ions are no% reliably !no,n (an) %hese can also vary in
)i$$eren% #o#ula%ions+, %he es%ima%es o$ mu%an% gene $re9uencies are also a##ro4ima%e as illus%ra%e) on
#ages 1;7 an) 1;8.
Ataxia(t/lan?i/ctasia (A-+. he overall observe) inci)ence o$ A- in %he A3 is abou% 102;;,;;;, ,i%h
%he highes% o$ 109;,;;; in Michigan (3,i$% e% al., 198>+. :or %he AF, %he observe) inci)ence is
101;;,;;; (Pi##ar) e% al., 1988+. Base) on inci)ence )a%a, %he minimum $re9uency o$ %he A)* gene in
%he A3 ,hi%e #o#ula%ion ,as es%ima%e) %o be ;.;;17 (3,i$% e% al., 198>+. he es%ima%e base) on %he
#ro#or%ion o$ close rela%ives o$ homo<ygous #roban)s (i.e. #e)igree analysis+ an) on %he assum#%ion
%ha% A- is a single homogeneous gene%ic syn)rome is higher, being ;.;;7, corres#on)ing %o a
he%ero<ygo%e $re9uency o$ 1.85 in %he #o#ula%ion (3,i$% e% al., 198>+. 'ecen% molecular s%u)ies have
sho,n %ha% %ha% A- is in)ee) a homogeneous gene%ic en%i%y (3avi%s!y e% al., 1995+.
Cn %he basis o$ more recen% )a%a, ho,ever, *as%on (1998+ es%ima%e) %ha% A- he%ero<ygo%es have a
$re9uency o$ abou% ;.55 an) have a rela%ive breas% cancer ris! o$ 2.9 (&I 2.277.2+. hese )a%a im#ly
%ha% A- he%ero<ygo%es migh% accoun% $or be%,een 1 an) 125 o$ breas% cancer in ,es%ern #o#ula%ions
bu% %ha% %he A)* gene ,oul) ma!e only a minor con%ribu%ion %o $amilial breas% cancer. he la%%er
in$erence res%s on %he curren% vie, %ha% %he #ro#or%ion o$ $amilial breas% cancers among all breas%
cancers is alrea)y small as )iscusse) belo,. As )iscusse) in 3ec%ion 2 an) 3ec%ion 5 more recen% )a%a
raise $ur%her 9ues%ions on %he associa%ion be%,een A)* he%ero<ygosi%y an) e4cess breas% cancer.
1!1!1!1! BRCA1 and BRCA2 in familial breast cancers
I% is es%ima%e) %ha% over 1;5 o$ %he ,omen )iagnose) o$ breas% cancer each year have a $amily his%ory
o$ %he )isease (C%%man e% al., 198>+. BRCA1 is es%ima%e) %o accoun% $or abou% hal$ o$ %he inheri%e)
103
breas% cancer an) abou% %hree 9uar%ers o$ breas% #lus ovarian cancer. *arlier segrega%ion analysis
sugges%e) %ha% %he $amilial clus%ering o$ breas% cancer may be accoun%e) $or by highly #ene%ran%
au%osomal )ominan% mu%a%ions ,i%h a combine) #o#ula%ion gene $re9uency o$ ;.;;;> %o ;.;;22 (&laus
e% al., 1991= /e,man e% al., 1988+. hese $re9uencies corres#on) %o abou% 1 in 2;; %o 1 in 8;; ,omen
in %he A3 being carriers o$ such mu%a%ions.
:or non-De,ish &aucasian ,omen in %he AF, on %he basis o$ %,o #o#ula%ion-base) )a%a on cancer
mor%ali%y in %he $irs%-)egree rela%ives o$ breas% an) ovarian cancer #a%ien%s, :or) e% al. (1995+ an) Pe%o
e% al. (199>+ es%ima%e %ha% %he BRCA1 mu%an% gene $re9uency is ;.;;;> (955 &I, ;.;;;27;.;;1+. As
s%a%e) above, %he gene $re9uency o$ ;.;;;> im#lies %ha% abou% 1 in 8;; ,omen carry a mu%a%ion an),
even a% %he u##er con$i)ence limi% o$ ;.;;1, %he carrier $re9uency ,oul) only be 1 in 5;;. he
assum#%ion use) here is %ha% bo%h %he e4cess ris! o$ ovarian cancer in %he $irs%-)egree rela%ives o$ breas%
cancer #a%ien%s an) %he breas% cancer e4cess in rela%ives o$ ovarian cancer #a%ien%s are en%irely
accoun%e) $or by BRCA1.
he calcula%ions o$ :or) e% al. (1995+ sho, %ha% %he #ro#or%ion o$ all breas% cancer cases )iagnose) in
%he general #o#ula%ion ()ue %o BRCA1+ is 7.55 be%,een ages 2;729 years, $alling %o 5.15 be%,een
ages 2;729 years, 2.25 be%,een ages 8; an) >9 years an) 1.15 be%,een ages 5; an) 7; years=
consi)ere) overall, 1.75 o$ all breas% cancers )iagnose) be%,een ages 2; an) >9 years is )ue %o
BRCA1 mu%a%ions. :or) e% al. (1995+ also no%e %ha% an im#or%an% unresolve) issue here is %he gene%ic
basis o$ $amilial breas% cancers ,hich is no% e4#laine) by BRCA1 or BRCA2. hey es%ima%e %ha% %he
combine) gene $re9uency o$ o%her highly #ene%ran% genes (inclu)ing BRCA2+ may be o$ %he or)er o$
;.;;;2 i.e. 1 in 1>;;.
In Ash!ena<i De,ish ,omen, %he BRCA1 mu%an% gene $re9uency a##ears %o be subs%an%ially higher. he
curren% es%ima%e is ;.;;87 (corres#on)ing a##ro4ima%ely %o 15 o$ %hese ,omen being carriers+= %his
$re9uency is $or one s#eci$ic mu%a%ion, namely, %he )ele%ion o$ an a)enine an) guanine resi)ue in co)on
185 o$ e4on 2 o$ %he gene an) )eno%e) as 185)elA" (3%rue,ing e% al., 1995a an) 3%rue,ing e% al.,
1995b= a!ahashi e% al., 1995= onin e% al., 1995+. Cn %he basis o$ age-)e#en)en% #ene%rance curves $or
%he observe) ris! o$ breas% cancer in BRCA1 $amilies, &ollins (199>+ has es%ima%e) %ha% 285 o$
Ash!ena<i De,ish ,omen ,i%h breas% cancer un)er age 2; ,oul) be e4#ec%e) %o have a BRCA1 germ
line mu%a%ion, com#are) %o 7.55 $or non-De,ish ,omen men%ione) earlier (:or) e% al., 1995+.
'oa e% al. (199>+ have recen%ly #ublishe) %he resul%s o$ an e4#an)e) #o#ula%ion-base) s%u)y, on %,o
BRCA1 mu%a%ions (1'5/lA@ an) 53'2insC+ an) one BRCA2 mu%a%ion (617>/l)+ in over 2;;;
Ash!ena<i De,ish ,omen, unselec%e) $or a #ersonal or $amily his%ory o$ breas% or ovarian cancer. he
carrier $re9uencies o$ %he BRCA1 mu%a%ions ,ere $oun) %o be@ 1.;95 (28021;8= 1'5/lA@+ an) ;.125
(80211>= 53'2insC+ an) %ha% $or BRCA2, 1.525 (8702;85+. hey no%e %ha% %he BRCA2 mu%a%ion may be
one-$our%h as #ene%ran% as %he BRCA1 1'5/lA@ mu%a%ions. As ,ill be evi)en%, %he 1'5/lA@ mu%a%ion
in BRCA1 an) 617>/l) in BRCA2 have a combine) carrier $re9uency o$ 2.>5. In ano%her #o#ula%ion
s%u)y involving 1255 De,ish ,omen, C))ou4 e% al. (19>>+ recor)e) a carrier $re9uency o$ ;.95
(1201255+ $or %he BRCA2 617>/l) mu%a%ion an) es%ima%e) %ha% $or %his mu%a%ion, %he '' $or
)evelo#ing breas% cancer by age 82 ,as 9.2 as com#are) %o an '' o$ 21 $or %he BRCA1 /l1'5A@
mu%a%ion (i.e. more %han a %hree-$ol) )i$$erence+.
1!1!1!"! Mutations in #$A mismatch repair %enes and hereditary non'polyposis colon cancer */$PCC+
104
:or 6/P&&, %he es%ima%e) range o$ #revalence in Ees%ern #o#ula%ions ,as originally es%ima%e) %o be
be%,een 1 in 5;; %o 1 in 2;; (corres#on)ing %o mu%an% gene $re9uencies o$ ;.;;1 %o ;.;;25+. 6/P&&
,as believe) %o accoun% $or abou% 25 %o 155 o$ colon cancers (Mec!lin, 1987= Vasen e% al., 1991=
1ynch e% al., 1992= 'us%gi, 1998+. As )iscusse) in 3ec%ion 2, %hese $igures (es#ecially %he 155+ remain
con%roversial an) )e#en) cri%ically on %he cri%eria use) $or )iagnosis. :ur%her, al%hough as o$ no,, $our
./A misma%ch re#air genes have been clone), %he rela%ive con%ribu%ions o$ mu%a%ions in %hese genes %o
6/P&& have no% been es%ablishe). All %his means is %ha% %he mu%an% gene $re9uency may even be lo,er
%han ;.;;1. In 3ec%ion 2 a #revalence es%ima%e o$ 1 in 2;;; ,as given on %he basis o$ a li!ely
con%ribu%ion o$ 6/P&& %o colon cancer in %he A3A o$ aroun) 25.
1!"! Population %enetic models of cancer predisposition and radiosensitivity
An im#or%an% #ur#ose o$ %his re#or% ,as %o )evelo# a gene%ically realis%ic com#u%a%ional mo)el $or %he
#ur#oses o$ -u)ging %he #o#ula%ion im#ac% o$ gene%ic #re)is#osi%ion on ra)ia%ion cancer ris!. ,o such
mo)els ,ere $ormula%e) an) #ublishe) (&ha!rabor%y an) 3an!aranarayanan 1995= &ha!rabor%y e% al.,
1997+. 6ere, an ou%line o$ %he mos% a##ro#ria%e o$ %hese mo)els is #rovi)e) an) i%s $unc%ion is
illus%ra%e) in a sim#le bu% ar%i$icial numerical e4ercise. Mos% im#or%an%ly, bes% es%ima%es o$ #revalence
an) s%reng%hs o$ cancer #re)is#osi%ion an) ra)iosensi%ivi%y (3ec%ion 5+ are use) in or)er %o mo)el %he
im#ac% on #o#ula%ion ris! a$%er ra)ia%ion e4#osure o$ s#eci$ic geno%y#es associa%e) ,i%h #re)is#osi%ion
%o breas% an) colon cancer. Du)gemen%s )evelo#e) $rom %his ,or! are carrie) $or,ar) in or)er %o
#rovi)e commen% in 3ec%ion 7 on %he im#lica%ions $or ra)iological #ro%ec%ion.
1!"!1!1! /ardy =einber% e<uilibrium
A basic $ea%ure o$ allele $re9uency in large #o#ula%ions is i%s s%abili%y over %ime in %he absence o$
)i$$erences in viabili%y or $er%ili%y among %he geno%y#es a% %he locus un)er consi)era%ion. In %he $ur%her
absence o$ assor%a%ive ma%ing, i.e. %en)ency o$ li!e %o ma%e ,i%h li!e, migra%ion, mu%a%ion, an)
geogra#hical sub)ivision o$ %he #o#ula%ion, geno%y#ic $re9uencies also remain cons%an% $rom genera%ion
%o genera%ion. In %he case o$ gene%ic )iseases, %his resul%s in %heir s%able #revalences in %he #o#ula%ion.
hese #ro#er%ies are summarise) in %he conce#% o$ H6ar)y7Eeinberg e9uilibriumI an) are $un)amen%al
%o %heories o$ #o#ula%ion gene%ics.
1!"!"! A Mendelian sin%le locus> autosomal dominant model of cancer susceptibility and radiosensitivity: A
hypothetical numerical e0ercise
&onsi)er a single au%osomal locus a% ,hich %here are %,o alleles, a, %he normal or H,il)-%y#eI allele an)
A, %he )ominan% cancer-#re)is#osing mu%an% allele, in a #o#ula%ion un)er 6ar)y7Eeinberg e9uilibrium.
he in)ivi)uals in %he #o#ula%ion ,ill have one o$ %he $ollo,ing %hree geno%y#es@ AA, Aa, an) aa.
1e% p )eno%e %he $re9uency o$ %he A allele an) JM%ha% o$ a so %ha% pKJM1. he geno%y#ic )is%ribu%ion o$
%he in)ivi)uals ,ill be as $ollo,s@
p
2
(AA+=2pJ(Aa+=J
2
(aa+.
Assume %ha% pM;.;1 an) JM;.99. In a #o#ula%ion o$ 1;,;;; in)ivi)uals, %he )i$$eren% geno%y#es ,ill be
)is%ribu%e) as $ollo,s@
1(AA+@198(Aa+@98;1(aa+. o%alM1;,;;;.
105
Assume %ha% AA an) Aa in)ivi)uals are cancer-#re)is#ose) (Hsusce#%iblesI+ an) %o %he same e4%en% an)
%he aa in)ivi)uals are no% (Hnon-susce#%iblesI+. Assume $ur%her %ha% %he bac!groun) cancer ris! $or aa
in)ivi)uals is 101;;; an) %ha% $or %he AA an) Aa, 101; i.e. %he la%%er geno%y#es have a 1;;-$ol) higher
HnormalI cancer ris! rela%ive %o aa in)ivi)uals. he e4#ec%e) $re9uency o$ cancers ,ill be@
o$ ,hich abou% 2; are $rom %he Hsusce#%iblesI an) abou% 1; $rom %he Hnon-susce#%iblesI.
Assume %ha% %he #o#ula%ion is irra)ia%e) an) %ha% all %he geno%y#es have %he sa-/ sensi%ivi%y %o
ra)ia%ion-in)uce) cancers. Assume $ur%her %ha% %he )ose is such %ha% i% causes a 15 ris! o$ in)ucing
cancers. 3o, in 1;,;;; in)ivi)uals, %here ,ill be a %o%al o$ 1;; in)uce) cancers (1;,;;;[;.;1M1;;+ an)
,ill be )is%ribu%e) as $ollo,s@
/o%e %ha% nearly all %he cancers come $rom %he Hnon-susce#%iblesI because o$ %heir high $re9uency. he
%o%al number o$ cancers one ,ill observe ,ill be 1;;K2;M12;. he rela%ive ris! (''+ o$ ra)ia%ion
e4#osure is 12;02;M8.2 an) e4cess rela%ive ris! (*''+M''L1M2.2.
Assume no, %ha% %he Aa an) AA have a 5;-$ol) hi?h/r ra)iosensi%ivi%y, namely, ;.5, rela%ive %o aa
(,hich is ;.;1 as be$ore+. An)er %hese con)i%ions, %he cancers in %he irra)ia%e) #o#ula%ion ,ill be
)is%ribu%e) as $ollo,s@
/o%e no, %ha% %he $re9uency o$ ra)ia%ion-in)uce) cancers is 198 o$ ,hich one-hal$ comes $rom %he
susce#%ibles. he %o%al number o$ cancers in %he irra)ia%e) #o#ula%ion is 198K2;M228, %he '' is
22802;M7.> an) *''M7.> -1M>.>.
here is a $our-$ol) message in %he above numerical e4ercise@
1. In %he absence o$ ra)ia%ion, %he loa) o$ e4cess cancers ()ue %o #re)is#osi%ion+ is )e#en)en% on %he
$re9uency o$ %he susce#%ible mu%an% allele (an) %hus on %he $re9uency o$ %he geno%y#es AA an) Aa
carrying %he mu%an% allele+ an) %he rela%ive ris! associa%e) ,i%h %he mu%an% geno%y#es= in %he e4am#le,
%he gene $re9uency o$ ;.;1 an) %he rela%ive ris! o$ 1;; means %ha% mos% cancers (i.e. 2;02;+ occur in %he
Hsusce#%iblesI=
2. I$ %he #o#ula%ion has uni$orm ra)iosensi%ivi%y ,i%h res#ec% %o %he susce#%ibili%y gene (i.e. %he rela%ive
ris! $or a given )ose o$ ra)ia%ion is %he same $or %he susce#%ible an) non-susce#%ible geno%y#es )es#i%e
he%erogenei%y ,i%h res#ec% %o cancer #re)is#osi%ion alone+, %hen %he rela%ive )is%ribu%ion o$ ra)ia%ion-
in)uce) cancers in %he susce#%ible an) non-susce#%ible grou#s is )e#en)en% on %he rela%ive $re9uencies
o$ %hese grou#s. In %he #resen% e4am#le, mos% o$ %he in)uce) cancers (98 ou% o$ 1;;+ occur in %he Hnon-
susce#%iblesI because %hey ou%number %he Hsusce#%iblesI (98;1 versus 198+=
106
2. I$ ho,ever, %he susce#%ible geno%y#es are also more ra)iosensi%ive, a higher #ro#or%ion o$ in)uce)
cancers ,ill occur in %he Hsusce#%iblesI (1;; ou% o$ 198 in %he e4am#le+= an)
8. Ei%h a mu%an% gene $re9uency o$ ;.;1 (,hich corres#on)s %o abou% 25 o$ %he #o#ula%ion being
he%ero<ygo%es $or %he mu%an% gene+, a 1;;-$ol) )i$$erence in cancer susce#%ibili%y an) 5;-$ol) )i$$erence
in ra)iosensi%ivi%y assume) in %he above calcula%ions, %he conven%ional e#i)emiologic measures sho,
an increase in ris! by a $ac%or o$ only abou% 2 ('' o$ 7.> $rom 8.2 an) *'' o$ >.> $rom 2.2+.
In %he above e4am#le, $or %he sa!e o$ sim#lici%y, no accoun% has been %a!en o$ %he $ollo,ing
$ac%s0observa%ions@ (i+ $or mos% common cancers, %he #ro#or%ion a%%ribu%able %o allelic varia%ion a% a
single locus is small (e.g. breas% an) colorec%al cancers+= (ii+ no% all mu%a%ions ,hich con$er cancer
susce#%ibili%y are $ully #ene%ran% an) (iii+ %he increase in ra)ia%ion ris! in susce#%ibles com#are) %o non-
susce#%ibles may vary ,i%h %he )ose o$ irra)ia%ion an) may also be a$$ec%e) by o%her $ac%ors. :ur%her,
%he e4am#le )iscusse) above a##lies %o a )ominan% mu%an% gene a% one locus con$erring cancer
#re)is#osi%ion= as is ,ell !no,n, %here are au%osomal recessive )iseases (e.g. A-+ $or ,hich
homo<ygo%es, an) #ossibly, also he%ero<ygo%es, may be a% a higher ris! $or bo%h na%urally-arising an)
ra)ia%ion-in)uce) cancers.
Au%osomal )ominan% an) recessive mo)els %a!ing in%o accoun% some o$ %hese $ac%ors have no, been
)evelo#e) by &ha!rabor%y an) 3an!aranarayanan (1995+ an) &ha!rabor%y e% al. (1997+. he )i$$erence
be%,een %he au%osomal )ominan% mo)els )iscusse) in %hese %,o #a#ers is %ha% in %he &ha!rabor%y e% al.
(1997+ #a#er, %he mo)el incor#ora%es )i$$erences in #ene%rance an) )ose )e#en)ence o$ ra)iosensi%ivi%y
)i$$eren%ials ,hereas %hese ,ere no% e4#lici%ly inclu)e) in %he &ha!rabor%y an) 3an!aranarayanan
(1995+ #a#er. 3ince incor#ora%ion o$ %he above %,o $ac%ors in %he mo)el is #er%inen% in %he #resen%
con%e4%, i% is %he mo)el given in &ha!rabor%y e% al. (1997+ ,hich is )iscusse) belo,.
1!"!,! Autosomal dominant model of cancer susceptibility and radiosensitivity 3hich incorporates differences in
penetrance and dose'dependence of radiosensitivity differentials
Para-/t/rs an assu-ptions.
he mo)el assum#%ions are %he $ollo,ing@
(i+ &ancer susce#%ibili%y is )ue %o a single au%osomal locus ,i%h %,o alleles, one a )ominan%
#re)is#osing allele (A+ an) %he o%her, a normal allele (a+= bo%h %he he%ero<ygo%es (Aa+ an) homo<ygo%es
(AA+ $or %he mu%an% allele are more ra)iosensi%ive %han %he normal homo<ygo%e=
(ii+ 6ar)y7Eeinberg e4#ec%a%ions hol) $or geno%y#e $re9uencies a% %he cancer-susce#%ible locus in %he
general #o#ula%ion=
(iii+ Cnly a #ro#or%ion o$ cancers (K+ o$ a given %y#e in %he #o#ula%ion is )ue %o %he locus un)er s%u)y=
(iv+ he )ominan% allele (A+ in he%ero<ygous con)i%ion (i.e. in Aa geno%y#es+ has a #ene%rance H (;?H
1$L in ho-o,.?ot/s2 th/r/ is co-pl/t/ p/n/tranc/ oC th/ -utant all/l/L an
(v+ .i$$eren%ial ra)iosensi%ivi%y is me)ia%e) %hrough %he same gene%ic #re)is#osi%ion i.e. #re)is#ose)
in)ivi)uals are also more ra)iosensi%ive= %hose ,ho have cancers )ue %o causes o%her %han %he
susce#%ibili%y locus have %he same general cancer ris! )ue %o ra)ia%ion e4#osures.
107
:or easy re$erence, able >.2 #resen%s all #arame%ers )e$ini%ions o$ %he mo)el an) %he no%a%ions use).
:ig. >.1 sho,s schema%ically %he ,ay in ,hich cancer #re)is#osi%ion an) ra)iosensi%ivi%y are assume)
%o cause ris! enhancemen% un)er %he )ominan% mo)el. hroughou% %his cha#%er, %he %erms Hgene%ic
#re)is#osi%ionI an) Hsusce#%ibili%yI are use) in%erchangeably an), unless o%her,ise s%a%e), %he %erm
Hra)iosensi%iveI is use) %o in)ica%e %he enhance) sensi%ivi%y o$ %he susce#%ible geno%y#es %o %he in)uc%ion
o$ cancers by ra)ia%ion.
able >.2. /o%a%ions an) in%er#re%a%ion o$ #arame%ers
:ig. >.1. 3chema%ic )iagram o$ %he e$$ec%s o$ ra)iosensi%ivi%y )i$$eren%ials, s%reng%h o$ #re)is#osi%ion
an) incom#le%e #ene%rance on in)ivi)uals o$ )i$$eren% geno%y#es (see 3ec%ion >.2.1.1+.
1!"!,!1! #efinition of the model: incorporation of cancer susceptibility and incomplete penetrance
108
As in)ica%e) in :ig. >.1, le% PAA, PAa an) Paa be %he $re9uencies o$ %he %hree geno%y#es AA, Aa an) aa. In
%his $orm, %hey ,oul) a##ly %o any grou# o$ in)ivi)uals in %he #o#ula%ion, even i$ %he geno%y#e
$re9uencies )o no% con$orm %o 6ar)y7Eeinberg e4#ec%a%ions. 3ince o$ %he %o%al cancers, a $rac%ion (K+
is assume) %o be )ue %o %he susce#%ibili%y locus an) only a $rac%ion (H+ o$ %he Aa geno%y#es e4#ress
susce#%ibili%y )ue %o incom#le%e #ene%rance o$ %he )ominan% allele (A+, %here are %,o Hris! grou#sI o$
in)ivi)uals, one ,i%h ris! R;R# an) %he o%her ,i%h R;. he %o%al #ro#or%ion o$ in)ivi)uals in %he $irs%
grou# is (PAAKHPAa+, an) %ha% in %he secon) grou#, (1LH+PAaKPaa.
In a))i%ion, since (1LK+ $rac%ion o$ %he cancers occurs irres#ec%ive o$ geno%y#e in in)ivi)uals ,i%h ris!
R;, %he Hbac!groun)I cancer ris! in a #o#ula%ion ,hich con%ains a susce#%ibili%y sub-grou# is given by
%he ,eigh%e) average (i.e. ,eigh%e) by %he res#ec%ive geno%y#ic $re9uencies in %he #o#ula%ion+@
(1+
:or a #o#ula%ion un)er 6ar)y7Eeinberg e9uilibrium, PAAMp
2
, PAaM2pJ, an) PaaMJ
2
an), un)er com#le%e
#ene%rance o$ %he )ominan% allele, HM1 so %ha% %he above e9ua%ion becomes
(1a+
I% is ins%ruc%ive %o no%e %ha% %he #olymor#hism a% %he susce#%ibili%y locus increases %he cancer ris! %o an
e4%en% )e%ermine) by %he con%ribu%ion o$ %he susce#%ible geno%y#es ci.e. K(1-J
2
+d. 6ence, as K
a##roaches ; or J a##roaches 1, RB ,oul) a##roach R;, namely, %he ris! in a #o#ula%ion ,i%hou% %he
susce#%ibili%y allele, A.
In an unirra)ia%e) #o#ula%ion, %he e4cess rela%ive ris! )ue %o %he #resence o$ #olymor#hism a% %he
susce#%ibili%y locus becomes@
(2+
(RBLR;+0R;Me(PAAKfPAa+(R#L1+
an) %he $rac%ion o$ cancers )ue %o i%s #resence is given by
(2+
Bo%h %hese measures c*9. 2 an) *9. 2 aboved are )ic%a%e) by %he occurrence o$ cancers con%ribu%e) by
%he susce#%ibles cK(PAAKHPAa+d $or any $i4e) value o$ R#Z1.
1!"!,!"! Incorporation of dose dependence of radiosensitivity differential in the model
:or incor#ora%ing )ose )e#en)ence o$ ra)iosensi%ivi%y )i$$eren%ials in %he mo)el, i% is assume) %ha% in
%he non-#re)is#ose) in)ivi)uals, a )ose . o$ ra)ia%ion increases cancer ris! by a $ac%or (1K.+, in
com#arison %o %he bac!groun) ris! (R;+= in %he #re)is#ose) geno%y#es (AA homo<ygo%es, an) a
#ro#or%ion H o$ %he Aa he%ero<ygo%es+, %he same )ose o$ ra)ia%ion increases %he cancer ris! by a $ac%or
109
(1K.Ri+. In %his $ormula%ion, %he slo#e o$ %he ra)ia%ion )ose e$$ec% curve is (,hich can be in%er#re%e)
as %he e4cess rela%ive ris! coe$$icien%+ $or all non-susce#%ible in)ivi)uals, ,hich is also a##ro4ima%ely
%he rela%ive ris! coe$$icien% in %he general #o#ula%ion. In con%ras%, $or a $rac%ion K o$ in)ivi)uals in
,hom %he )ominan% allele (A+ is $ully #ene%ran%, ci.e. K(PAAKHPAa+d, %he slo#e is Ri. here$ore, %he %o%al
cancer ris! in %he irra)ia%e) #o#ula%ion is given by
(8+
By subs%i%u%ing PAAMp
2
an) PAaM2pJ in %his e9ua%ion, ,e ob%ain %he %o%al cancer ris! in %he irra)ia%e)
#o#ula%ion ,hen incom#le%e #ene%rance is incor#ora%e).
Cnce %he %o%al cancer ris! is )e%ermine), %he %hree e#i)emiologic measures o$ in%eres%, namely, %he
rela%ive ris! cRR(.+d, a%%ribu%able $rac%ion cA9(.+d, an) %he #ro#or%ion o$ A9(.+ %ha% is )ue %o enhance)
ra)iosensi%ivi%y alone cA(.+d can be )erive). hese are given by
(5+
(>+
an)
(7+
As can be seen $rom %he $ormulae, all %hree measures o$ ris! are )e#en)en% on ra)ia%ion )ose.
A))i%ionally, %he rela%ive ris! cRR(.+d an) a%%ribu%able $rac%ion cA9(.+d, are )e#en)en% on %he s%reng%h
o$ #re)is#osi%ion (R#+, ra)iosensi%ivi%y )i$$eren%ial (Ri+, an) %he #ro#or%ion o$ susce#%ibles (K+. In
con%ras%, cA(.+d is in)e#en)en% o$ %he #ro#or%ion o$ susce#%ibles an) %he #ene%rance o$ %he )ominan%
allele.
1!"!-! $umerical applications
1!"!-!1! Rationale for the parameter values chosen for applyin% the model for breast cancer and hereditary non'
polyposis colon cancer
110
In %he case o$ BRCA1-associa%e) breas% cancer, %he #arame%er values use) in ris! com#u%a%ions are
some selec%e) combina%ions o$@ p (;.;;;>, ;.;;87+, K (;.;17, ;.;75, ;.28+ an) H (;.5;, ;.75, 1.;+. he
slo#e o$ %he )ose-e$$ec% curve is $i4e) a% M2.;, an) %hree )ose levels (. o$ ;.5, 1.;, an) 2.; "y+ are
consi)ere). he choice o$ # an) K values ,as )ic%a%e) by more recen% )a%a )iscusse) earlier in 3ec%ion
>.1 (*as%on e% al., 1995= :or) e% al., 1995= 3%rue,ing e% al., 1995b= &ollins 199>= Pe%o e% al., 199>+.
*s%ima%es $or #ene%rance (H+ use) $or BRCA1 mu%a%ions encom#ass %he range o$ values given in *as%on
e% al. (1995+. he value o$ M2.; has been chosen %o a##ro4ima%e %he e4cess rela%ive ris! coe$$icien%
es%ima%e) $or breas% cancer )a%a on A-bomb survivors call ages@ 1.59 (955 &I 1.;972.19+= hom#son e%
al., 1998bd. he ranges o$ )ose levels (.+, ra)iosensi%ivi%y )i$$eren%ials (Ri+, an) #re)is#osi%ion s%reng%h
(R#+ are arbi%rary. 6o,ever, in vie, o$ %he com#u%a%ions o$ (R#+ $rom cancer ris!s in rela%ives (*as%on
an) Pe%o, 199;+, an) o$ rela%ive ris!s o$ breas% cancer in Da#anese ,omen e4#ose) %o A-bomb ra)ia%ion
(1an) e% al., 1992= o!unaga e% al., 1998+, %he broa) ranges o$ R# $rom 1; %o 1;;; an) Ri $rom 1; %o
1;; hy#o%he%ically )escribes %he con%ribu%ion o$ %he BRCA1 locus %o cancer susce#%ibili%y an)
ra)iosensi%ivi%y. I% is em#hasise) %ha% no evi)ence s#eci$ically su##or%s such values $or heri%able breas%
cancer, nor in)ee) $or heri%able colon cancer consi)ere) belo,.
:or 6/P&&, %he #arame%er values use) in com#u%a%ions are %he $ollo,ing@ #M;.;;1, KM;.;2 an)
M;.72. he value is %he same as %ha% es%ima%e) by hom#son e% al. (1998b+ $or colon cancers in A-
bomb survivors (all ages an) bo%h se4es= 955 &I ;.2971.28+. he '# an) 'i ranges chosen are again
arbi%rary.
1!"!-!"! Results: breast cancer
able >.2, able >.8 an) able >.5 illus%ra%e %he numerical resul%s ob%aine) $or )i$$eren% combina%ions o$
#arame%er values $or breas% cancer )iscusse) above. I% shoul) be recalle) %ha% RR 9uan%i$ies %he ris! o$
ra)ia%ion-in)uce) cancer in a #o#ula%ion in %he #resence o$ #re)is#osi%ion an) ra)iosensi%ivi%y
)i$$eren%ials rela%ive %o one in %he absence o$ bo%h %hese $ac%ors. he ris! measure A9 )eno%es %he
#ro#or%ion o$ ra)ia%ion-in)uce) cancers )ue %o %he above he%erogenei%y an) A 9uan%i$ies %he #ro#or%ion
o$ A9 %ha% is )ue %o enhance) ra)iosensi%ivi%y alone.
able >.2. *s%ima%es o$ #o#ula%ion breas% cancer ris! ob%aine) using %he )ominan% mo)el o$ cancer
susce#%ibii%y an) ra)iosensi%ivi%y $or a range o$ Ri an) R# values, as a $unc%ion o$ #ene%rance (H+ an)
ra)ia%ion )ose (.+ ,hen KM1.75, pM;.;;;>, an) M2.; #er "y
111
able >.8. *s%ima%es o$ #o#ula%ion breas% cancer ris! ob%aine) using %he )ominan% mo)el o$ cancer
susce#%ibii%y an) ra)iosensi%ivi%y $or a range o$ Ri an) R# values, as a $unc%ion o$ #ene%rance (H+ an)
ra)ia%ion )ose (.+ ,hen KM7.55, pM;.;;;>, an) M2.; #er "y
able >.5. *s%ima%es o$ #o#ula%ion breas% cancer ris! ob%aine) using %he )ominan% mo)el o$ cancer
susce#%ibii%y an) ra)iosensi%ivi%y $or a range o$ Ri an) R# values, as a $unc%ion o$ #ene%rance (H+ an)
ra)ia%ion )ose (.+ ,hen KM285, pM;.;;87, an) M2.; #er "y
112
he resul%s sho,n in able >.2 may be )eeme) a##licable %o ra)ia%ion-in)uce) breas% cancers in non-
De,ish &aucasian ,omen $or ,hom %he es%ima%e) mu%an% gene $re9uency (pM;.;;;>+ an) %he
#ro#or%ion (K+ o$ breas% cancers )ue %o %he BRCA1 mu%a%ions (1.75 o$ all ,omen ,i%h breas% cancers
un)er age 7;+ are bo%h small. I% is clear %ha%@ (i+ RR values higher %han 1 can arise only ,hen bo%h Ri
an) R# are very high, e.g. a% a )ose o$ 2 "y, ,i%h RiM1;;, R#M1;;;, an) HM1, RR is 2.>8= $or o%her
combina%ions o$ Ri an) R# sho,n in able >.2, ho,ever, %he RR values are only marginally higher %han
1 an) (ii+ li!e,ise, %he )e#en)ence o$ A9 values on Ri an) R# is clearly seen.
he resul%s #resen%e) in able >.8 may a##ly $or ra)ia%ion ris! o$ early onse% breas% cancers in non-
De,ish &aucasian ,omen $or ,hom %he p is %he same as above (;.;;;>+ bu% K is higher (i.e. 7.55+. As
,ill be clear, $or %he same Ri, R#, H, an) . values as %hose in able >.2, %he RR values are higher (e.g.
$or RiM1;; an) R#M1;;;, %he RR is 8.22 (com#are) %o 2.>8 ,hen KM1.75+. :ur%her, a com#arison o$ %he
A values in able >.2 an) able >.8 reveals %ha% A is in)e#en)en% o$ K.
C%her general observa%ions %ha% can be ma)e $rom able >.2 an) able >.8 are %he $ollo,ing@ (i+ an
increase in #ene%rance o$ %he susce#%ibili%y allele causes an increase in ris! (RR an) A9+= an) (ii+ a% any
given level o$ #ene%rance an) combina%ion o$ Ri an) R# values, %he ris!s (RR an) A9+ increase ,i%h
ra)ia%ion )ose, bu% %he )ose-)e#en)ence o$ RR, A9 an) A )iminishes a% higher )ose levels= (iii+ A is
9ui%e high even ,hen RR is close %o 1 an) A9 is very small, i.e. mos% o$ %hese e4cess cancers are
con%ribu%e) by %he ra)iosensi%ivi%y )i$$eren%ial alone an) (iv+ A is in)e#en)en% o$ H, i.e. a% any given
ra)ia%ion )ose an) combina%ion o$ Ri an) R#, A is %he same a% all levels o$ #ene%rance use).
he mo)el #re)ic%ions un)er con)i%ions ,hen bo%h %he mu%an% gene $re9uency an) %he #ro#or%ion o$
cancers ascribe) %o %he locus un)er s%u)y are higher (as seems %o be %he case ,i%h early-onse% breas%
cancers in Ash!ena<i De,ish ,omen+, are sho,n in able >.5. As e4#ec%e), even a% mo)era%e levels o$
Ri an) R#, %he ris!s are higher %han %hose #resen%e) in able >.2 an) able >.8. As no%e) earlier, in all
cases, ,i%h an increase in #ene%rance, %he ris!s are enhance), as e4#ec%e).
:ig. >.2, :ig. >.2, :ig. >.8 an) :ig. >.5 )e#ic%, $or %he breas% cancer e4am#le (early-onse% breas% cancers
in non-De,ish &aucasian ,omen+, %he #re)ic%ions o$ %he mo)el ,hen pM;.;;;>, KM;.;75 an) M2.;
over a ,i)er range o$ arbi%rary Ri an) R# values $or HM;.5 an) .M;.5 "y= HM;.5 an) .M2.; "y= HM1.;
an) .M;.5= an) HM1.; an) .M2.; "y. I% is ,or%h no%ing %ha% %he %o# #anels o$ :ig. >.2, :ig. >.2, :ig. >.8,
113
:ig. >.5 an) :ig. >.5 are i)en%ical (an) are su#erim#osable on each o%her+, bu% %he scales $or RR are
)i$$eren%.
:ig. >.2. 'ela%ionshi#s be%,een RR, A9, an) A ,hen HM;.5 an) .M;.5 "y. :or %his an) :ig. >.2, :ig.
>.8 an) :ig. >.5 %he o%her #arame%er values use) ,ere pM;.;;;>, KM7.55 an) M2.; (see able >.2+.
114
:ig. >.2. 'ela%ionshi#s be%,een RR, AR, an) A ,hen HM;.5 an) .M2.; "y. 3ee :ig. >.2 $or o%her
#arame%er values.
115
:ig. >.8. 'ela%ionshi#s be%,een RR, A9, an) A ,hen HM1.; an) .M;.5 "y. 3ee :ig. >.2 $or o%her
#arame%er values.
116
:ig. >.5. 'ela%ionshi#s be%,een RR, A9, an) A ,hen HM1.; an) .M2.; "y. 3ee :ig. >.2 $or o%her
#arame%er values.
A com#arison o$ %he %o# #anels o$ :ig. >.2 an) :ig. >.2 (or o$ %hose o$ :ig. >.8 an) :ig. >.5+ sho,s %ha%@
(i+ changes in RR occur as a resul% o$ changes in )ose= (ii+ a% any given level o$ #ene%rance, ,hen RiM1
(i.e. no )i$$eren%ial ra)iosensi%ivi%y+, %he RR es%ima%es s%ay %he same (i.e. in)e#en)en% o$ )ose+ an) are
)riven by #re)is#osi%ion s%reng%h= $or ins%ance, ,i%h RiM1 an) R#M1;;;, %he RR values a% ;.5 "y (:ig.
>.2+ an) 2 "y (:ig. >.2+ are %he same, namely ??5= (iii+ %he e$$ec% o$ a given combina%ion o$ Ri an) R#
values on RR is more #rominen% a% ;.5 "y %han a% 2.; "y= $or e4am#le, ,hen RiM1;; an) R#M1;;;, %he
117
RR is abou% 2 a% ;.5 "y an) abou% 5 a% 2.; "y (see also able >.8+, )es#i%e a $our-$ol) )i$$erence in )ose
an) (iv+ ,i%h %he p an) K values use), large increases in bo%h Ri an) R# values are re9uire) %o resul% in
RR values a##reciably higher %han 1.
A similar com#arison o$ %he mi))le #anels o$ :ig. >.2 an) :ig. >.2 (or o$ %hose o$ :ig. >.8 an) :ig. >.5+,
sho,s %ha% %hese are not i)en%ical in)ica%ing %ha% $or given combina%ions o$ Ri an) R# values, %he A9
es%ima%es are )ose-)e#en)en%, being higher a% 2.; "y %han a% ;.5 "y. :or e4am#le, ,hen RiM1; an)
R#M1;;;, A9 is abou% ;.2 a% ;.5 "y an) ;.2 a% 2.; "y.
:inally, a com#arison o$ %he bo%%om #anel o$ :ig. >.2 ,i%h %ha% o$ :ig. >.2 (or o$ %hose o$ :ig. >.8 an)
:ig. >.5+ sho,s, again, %ha% %hese are no% i)en%ical in)ica%ing %ha% A, in a))i%ion %o being )e#en)en% on Ri
an) R# also )e#en)s on )ose. 6o,ever, a% each o$ %he )oses, %he bo%%om #anels o$ :ig. >.2 an) :ig. >.5
(or o$ :ig. >.2 an) :ig. >.8+ are su#erim#osable on each o%her sho,ing %ha% A is in)e#en)en% o$ H
)es#i%e )i$$erences in #ene%rance.
he )e#en)ence o$ A on Ri an) R# illus%ra%e) in %hese $igures can be summarise) as $ollo,s@ (i+ ,hen no
cancer-#re)is#ose)0ra)iosensi%ive subgrou# is #resen% in %he #o#ula%ion (i.e. R#M1 an) RiM1+, all %he
in)uce) cancers are )ue %o ra)ia%ion= (ii+ ,hen R#M1 an) Ri increases, A ra#i)ly a##roaches 1 (no%e %ha%
%he M-a4is scale is logari%hmic+ an) (iii+ $or any $i4e) value o$ RiZ1, ,hen R# increases, A )ecreases. :or
e4am#le, a close scru%iny o$ :ig. >.5 ,ill sho, %ha% ,hen RiM5 (corres#on)ing %o %he $our%h line above
%he X-a4is+ an) R# increases in %he range $rom 1 %o 1;;; (no%ing %ha% %he R# scale is %o be rea) $rom righ%
%o le$%+, A #rogressively )ecreases %o reach a value o$ abou% ;.8.
1!"!-!,! /ereditary non'polyposis colon cancer
able >.> summarises %he resul%s o$ calcula%ions using pM;.;;1, KM;.;2, an) M;.72. As can be seen,
bo%h p an) K are small an) conse9uen%ly, even ,hen %he #ene%rance is 1;;5, ,i%h %he combina%ions o$
Ri an) R# values use), %he ris!s are only marginally increase) an) are much less ,hen #ene%rance is
lo,.
able >.>. *s%ima%es o$ #o#ula%ion 6/P&& ris! ob%aine) using %he )ominan% mo)el o$ cancer
susce#%ibili%y an) ra)iosensi%ivi%y $or a range o$ Ri an) R# values, as a $unc%ion o$ #ene%rance (H+ an)
ra)ia%ion )ose (.+ ,hen KM25, pM;.;;1, an) M;.72 #er "y
118
1!"!.! Cancer predisposition and radiosensitivity due to recessive mutations at an autosomal locus
As may be recalle), ,i%h %he )ominan% mo)el, al%hough %here are %hree geno%y#es a% %he cancer
susce#%ibili%y locus, mos% o$ %he in)uce) cancers are con%ribu%e) by %he he%ero<ygo%es. here$ore, ,hen
recessive mu%a%ions a% an au%osomal locus are involve) in cancer #re)is#osi%ion, even ,hen %he mu%an%
homo<ygo%es $or %he r/c/ssi0/ allele sho, subs%an%ially large R# values, %he im#ac% on ra)ia%ion cancer
ris!s %o %he #o#ula%ion ,ill be very small because o$ %he rari%y o$ %hese homo<ygo%es= %he ris!s ,ill be
enhance) only ,hen %he he%ero<ygo%es sho, a high )egree o$ cancer #re)is#osi%ion (in ,hich case %he
mo)el is no longer a recessive mo)el, bu% a )ominan% mo)el ,i%h incom#le%e #ene%rance o$ %he mu%an%
gene+. :or such a si%ua%ion, *9. 5, *9. > an) *9. 7 )iscusse) earlier $or %he )ominan% mo)el $or
#re)ic%ion o$ RR, A9, an) A, res#ec%ively, can be mo)i$ie) by incor#ora%ing a $e, no%a%ional changes.
3ince %he $re9uency o$ he%ero<ygo%es (Aa+ can be a##ro4ima%e) by 2J (J being %he $re9uency o$
recessive mu%an% alleles+ %he %erm cPAAKHPAad re#resen%ing geno%y#e $re9uencies in *9. 5, *9. > an) *9.
7 nee)s %o be subs%i%u%e) by 2J yiel)ing
(8+
(9+
an)
(1;+
119
he above $ormula%ions %hus e4%en) %he au%osomal )ominan% mo)el %o an au%osomal recessive one in
,hich he%ero<ygo%es $or %he recessive mu%an% gene sho,s #re)is#osi%ion %o cancer. /o%e %ha% %he
#ro#or%ion o$ A9 )ue %o ra)iosensi%ivi%y )i$$eren%ials cA(.+d*9. 1; )oes no% )e#en) on geno%y#e
$re9uencies as is %he case ,i%h %he )ominan% mo)el *9. 7. /o numerical illus%ra%ions are given because
o$ %he $ac% %ha%, a% #resen%, %here are no clear e4am#les o$ %his %y#e o$ cancer #re)is#osi%ion.
1!,! (ummary and conclusions
his cha#%er )iscusses an au%osomal )ominan% mo)el an) i%s use %o assess %he im#ac% o$ %he #resence o$
cancer-#re)is#ose) subgrou#s in a #o#ula%ion (,hich are also assume) %o be more sensi%ive %o
ra)ia%ion-in)uce) cancers+, on ra)ia%ion cancer ris!s com#are) %o one ,hich )oes no% have %hese
subgrou#s. he mo)el #re)ic%ions are illus%ra%e) using curren% es%ima%es o$ mu%an% gene $re9uencies $or,
an) #ro#or%ions o$, cancers associa%e) ,i%h %he loci, BRCA1 (breas% cancer+ an) 6/P&& (here)i%ary
non-#oly#osis colon cancers+, an) arbi%rarily chosen ranges o$ values $or s%reng%h o$ cancer
#re)is#osi%ion, ra)ia%ion )ose-res#onse an) ra)iosensi%ivi%y )i$$eren%ials. A))i%ionally, %he e4%ension %he
above mo)el %o a si%ua%ion in ,hich cancer #re)is#osi%ion an) ra)iosensi%ivi%y are )ue %o recessive
mu%a%ions a% an au%osomal locus is also )iscusse). he main conclusions are %he $ollo,ing@
1. Irra)ia%ion o$ a he%erogeneous #o#ula%ion o$ %he %y#e men%ione) above, resul%s in higher cancer ris!s
com#are) %o a #o#ula%ion ,hich is no% he%erogeneous in %his regar). 6o,ever, unless %he mu%an% gene
$re9uencies (p+, #ro#or%ion o$ cancers a%%ribu%able %o %he locus un)er s%u)y (K+, ra)iosensi%ivi%y
)i$$eren%ials (Ri+, an) #re)is#osi%ion s%reng%h (R#+ are all su$$icien%ly large, %he enhancemen% in ris!s is
small an) may no% be )e%ec%able.
2. All %hree measures o$ ris! (rela%ive ris! cRRd, a%%ribu%able $rac%ion cA9d, an) %he $rac%ion o$ A9 )ue %o
ra)iosensi%ivi%y )i$$eren%ials cAd are all )ose rela%e). A% any given level o$ #ene%rance an) combina%ion
o$ Ri an) R# values, RR an) A9 increase ,i%h )ose, bu% %he )ose )e#en)ence o$ RR, A9 an) A
)iminishes a% higher )ose levels.
2. Incom#le%e #ene%rance o$ %he mu%an% gene has %he e$$ec% o$ H)ilu%ingI %he e$$ec%s o$ #re)is#osi%ion
s%reng%h an) ra)iosensi%ivi%y )i$$eren%ials= %he increase in ris!s is no% linearly rela%e) %o an increase in
#ene%rance.
8. :or non-De,ish &aucasian ,omen $or ,hom a p o$ ;.;;;> (BRCA1 mu%an% gene $re9uency+ o$
;.;;;> an) a K o$ 1.75 (#ro#or%ion o$ breas% cancers un)er age 7; )ue %o BRCA1 mu%a%ions+ have been
assume), %he mo)el #re)ic%s %ha% rela%ive ris!s, RR, ,ill be )e%ec%ably )i$$eren% $rom 1 only ,hen bo%h
%he ra)iosensi%ivi%y )i$$eren%ial, Ri, an) s%reng%h o$ #re)is#osi%ion R# are very high (e.g. a% RiM1;; an)
R#M1;;;, $or 1;;5 #ene%rance, RR is 2.>8 a% 2 "y+. he #re)ic%ion $or %he ra)ia%ion ris! o$ 6/P&& in
&aucasian #o#ula%ions is similar. In essence, on curren% !no,le)ge %he mu%an% gene $re9uencies
rela%ing %o gene%ic susce#%ibili%y %o breas% an) colon cancer are %oo lo, %o ma!e a signi$ican% im#ac% on
ra)iological ris! in %y#ical human #o#ula%ions.
5. Ehen bo%h p an) K are higher (as seems %o be %he case $or breas% cancers in Ash!ena<i De,ish ,omen
(pM;.;;87 an) KM285 $or breas% cancers un)er age 2;+, %he #re)ic%e) RRs are Z 1 even a% mo)era%e
levels o$ Ri an) R#, i%s magni%u)e )e#en)ing on ra)ia%ion )ose an) #ene%rance o$ %he mu%an% gene. hus,
120
in cer%ain a%y#ical sub-#o#ula%ions ,here mu%an% gene $re9uencies $or cancer-#re)is#osing )isor)ers
are high )ue %o $oun)er e$$ec%s an) inbree)ing a gene%ic im#ac% on #o#ula%ion ris! a$%er ra)ia%ion can,
in #rinci#le, become im#or%an%.
>. An au%osomal recessive mo)el o$ cancer #re)is#osi%ion an) ra)iosensi%ivi%y ,ill be meaning$ul only
,hen he%ero<ygo%es sho, high R# values= $or such a si%ua%ion, %he au%osomal )ominan% mo)el can be
use) ,i%h a $e, no%a%ional changes.
7! Implications for radiolo%ical protection of data on cancer susceptibility
A% %he ou%se%, i% ,as recognise) %ha% %he s%a%e o$ !no,le)ge on %he #ossible in%erac%ions be%,een
ionising ra)ia%ion e4#osure an) relevan% human gene%ic $ac%ors ,as such %ha% i% ,oul) be #ossible only
%o #ain% a broa) #ic%ure o$ %heir im#ac% on ra)ia%ion-in)uce) carcinogenic ris! an) only #rovi)e some
in%erim -u)gemen%s in res#ec% o$ %he #ossible im#lica%ions $or ra)iological #ro%ec%ion.
he )a%a revie,s an) com#u%a%ional mo)elling so $ar #resen%e) #rovi)e, never%heless, su$$icien%
in$orma%ion $or #reliminary commen% u#on (a+ %he e4%en% %o ,hich curren% I&'P es%ima%es o$ cancer
ris! in %y#ical irra)ia%e) #o#ula%ions migh% be in$luence) by highly #ene%ran% gene%ic $ac%ors an) (b+ %he
ra)iological im#lica%ions $or in)ivi)uals ,i%h such $amilial )isor)ers.
A recurring %heme in %his )ocumen% has ho,ever been %he #roblem o$ ascer%ainmen% o$ cancer-
#re)is#osing human mu%a%ions o$ lo, #ene%rance. :or %hese, ,hile some s#ecula%ive commen% is
#ossible, %here is curren%ly no $irm scien%i$ic basis on ,hich %o ma!e meaning$ul -u)gemen%s. Ehile i%
is no% %he in%en%ion o$ %his re#or% %o #rovi)e )e%aile) commen%ary on $u%ure research nee)s,
consi)era%ion ,ill also be given %o %he broa) %o#ics %ha% ,ill nee) %o be a))resse) in or)er %o resolve %he
mos% im#or%an% uncer%ain%ies regar)ing %he rela%ionshi#s be%,een human cancer #re)is#osi%ion an)
ra)iological ris!.
he )a%a revie,s #resen%e) here have s%resse) %he in$orma%ion %ha% is arising $rom molecular
charac%erisa%ion o$ %he human germ line mu%a%ions %ha% un)erlie heri%able cancer susce#%ibili%y. hese
)a%a an) %he associa%e) %echnologies %ha% have been )evelo#e) have im#or%an% im#lica%ions $or
)iagnosis o$ %he relevan% )isor)ers. 3ince such )iagnos%ic %echni9ues are e4#ec%e) %o #lay an
increasingly im#or%an% role in me)ical gene%ics an) coul) conceivably im#inge on ra)iological
#ro%ec%ion, a%%en%ion is also given brie$ly %o $un)amen%al an) %echnical #roblems %ha% curren%ly surroun)
%heir a##lica%ion. :inally, in %he ligh% o$ %he consi)era%ions no%e) above a brie$ in%erim -u)gemen% is
#rovi)e) on %he im#lica%ions o$ gene%ic susce#%ibili%y %o cancer in %he con%e4% o$ ra)iological #ro%ec%ion
#rac%ices.
7!1! 6amilial cancer involvin% %enes of hi%h penetrance
he vas% ma-ori%y o$ %he in$orma%ion accruing on human cancer susce#%ibili%y in humans )erives $rom
s%u)ies o$ $amilies sho,ing segrega%ion o$ genes %ha% subs%an%ially increase %he li$e%ime ris! o$ a given
se% o$ neo#lasms= %his $ea%ure is o$%en accom#anie) by an early age-o$-onse% $or %he neo#lasms in
9ues%ion. ha% sai), environmen%al $ac%ors an) co-segrega%ing genes almos% cer%ainly #lay a role in %he
e4#ression o$ some o$ %hese high #ene%rance mu%a%ions= such mu%a%ions can be #resen% in some cases
,here %here is no obvious $amily his%ory o$ cancer an), e9ually, some !no,n carriers remain cancer
$ree (:rien), 199>+.
121
In s#i%e o$ %hese uncer%ain%ies, %he overall inci)ence o$ high #ene%rance cancer-#re)is#osing mu%a%ions
in %he #o#ula%ion can be es%ima%e) %oge%her ,i%h %heir li!ely con%ribu%ion %o %o%al cancer. In %he ligh% o$
%he )a%a revie,e) in #revious 3ec%ions an) %he vie,s e4#resse) by o%her commen%a%ors, i% is -u)ge) %ha%
%he overall inci)ence o$ %hese mu%a%ions in Ees%ern #o#ula%ions seems li!ely %o be less %han 15 an) %ha%
%hey #robably accoun% $or aroun) 55 o$ %o%al li$e%ime cancer. As no%e) earlier, %his con%ribu%ion %en)s
ho,ever %o be age )e#en)en% an) ,ill be grea%er in chil)ren an) young %o mi))le-age) a)ul%s
#resen%ing ,i%h cancer. Also evi)en% $rom %he )a%a revie, is %ha%, in %erms o$ $amilial cancer, soli)
%umours a##ear %o be sub-ec% %o grea%er gene%ic in$luences %han lym#ho-haemo#oie%ic neo#lasia. Among
,ell charac%erise) soli) %umour ca%egories available )a%a im#ly %ha% neo#lasia o$ %he breas%, colon an)
#ros%a%e have %he mos% signi$ican% gene%ic com#onen%s. 3ince %hese cancers are rela%ively common in
%he #o#ula%ion, %he genes res#onsible may be seen %o have %he grea%es% overall im#ac% on cancer
mor%ali%y.
he )a%a o$ 3ec%ion 5 #rovi)e) evi)ence %ha% in mos%, bu% no% all, cancer-#re)is#osing )isor)ers, %here
is %he e4#ec%a%ion %ha% gene%ic susce#%ibili%y %o s#on%aneously arising )isease ,ill be accom#anie) by
above-normal cancer ris! a$%er ionising ra)ia%ion e4#osure. I% is believe) %ha% %he %umour %y#es involve)
,ill generally be %he same $or s#on%aneous an) ra)ia%ion-in)uce) )isease.
Quan%i$ica%ion o$ %he )egree o$ increase) %umorigenic ra)iosensi%ivi%y associa%e) ,i%h $amilial cancer is
ho,ever highly #roblema%ical= %he grea% uncer%ain%ies %ha% a%%ach %o #rovi)ing -u)gemen%s on relevan%
issues are )iscusse) in 3ec%ion 5 an) 3ec%ion >. :or %he reasons given in 3ec%ion 5 no single $ac%or can
be e4#ec%e) %o )escribe %his e$$ec% in all such )isor)ers= as a $irs% a##ro4ima%ion i% is -u)ge) %ha% %he
absolu%e increase in ra)ia%ion ris! may $all be%,een 5- or less an) 1;;-$ol) as -u)ge) $rom all sources
o$ )a%a ,i%h %he limi%e) human )a%a being more consis%en% ,i%h increase) ris! ,i%hin %hese )isor)ers o$
less %han aroun) 1;-$ol). I% is s%resse) a% %his #oin% ho,ever %ha% %hese -u)gemen%s are no% ye% ,ell
$oun)e) since %hey )e#en) u#on incom#le%e e#i)emiological evalua%ions, ra)io%hera#eu%ic observa%ions
in o$%en isola%e) cases an) some,ha% uncer%ain )a%a ob%aine) in animal gene%ic mo)els o$ )isease. As a
conse9uence, a% %his s%age in !no,le)ge %he -u)gemen%s #rovi)e) here shoul) be use) ,i%h grea%
cau%ion. /ever%heless, %hey remain use$ul $or %he #ur#oses o$ ma!ing calcula%ions %ha% serve %o illus%ra%e
%he #ossible im#ac% o$ $amilial gene%ic susce#%ibili%y %o ra)iogenic cancer a% bo%h %he #o#ula%ion an)
in)ivi)ual levels.
7!1!1! 6amilial cancer and ris)s in a population
Assuming a value o$ ?15 $or $amilial cancer inci)ence an) o$ values o$ 571;;-$ol) %o )escribe %he
gene%ically )e%ermine) increase in ra)iogenic cancer ris!, %he com#u%a%ional mo)elling o$ 3ec%ion >
argue s%rongly agains% any ma-or im#ac% o$ $amilial cancer on overall ris!s in %he ,hole #o#ula%ion.
his mo)elling e4ercise sho,e) %ha% even $or breas% cancer ,here, on curren% !no,le)ge, %he gene%ic
con%ribu%ion %o ris! is rela%ively high, %he gene $re9uency is $ar %oo lo, %o #rovi)e $or a signi$ican%
)is%or%ion o$ ris! in %he ,hole #o#ula%ion. 3ince %he gene%ic con%ribu%ion %o %umours a% o%her common
si%es ,ill %en) %o be lo,er %here can be no reason %o s#ecula%e %ha% a$%er ra)ia%ion %he ris! o$ e4cess
cancer is concen%ra%e) in a gene%ically #re)is#ose) sub-$rac%ion o$ %he #o#ula%ion an) %ha% %he
remain)er are rela%ively ra)io-resis%an%.
he )a%a consi)ere) in 3ec%ion 5 an) 3ec%ion > #rovi)e no evi)ence o$ %he ,i)es#rea) an) very high
)egree o$ sensi%ivi%y %ha% ,oul) be nee)e) %o )rive ma-or ris!-)is%or%ing e$$ec%s= nor o$ )isor)ers ,here
%he e4#ression o$ gene%ically )e%ermine) cancer is largely )e#en)en% u#on ionising ra)ia%ion e4#osure.
he ra)io%hera#y $ollo,-u# )a%a ci%e) are o$ #ar%icular relevance %o %hese issues. &ancer #a%ien%s
122
receiving ra)io%hera#y are a selec%e) sub-#o#ula%ion ,i%hin ,hich %he gene%ic com#onen% is e4#ec%e) %o
be increase) %o #erha#s aroun) 2755 albei% in an age-)e#en)en% $ashion. hese )a%a #rovi)e ho,ever
no evi)ence o$ a ma-or $amilial com#onen% o$ ris!. :or breas% cancer, 3%orm e% al. (1992+ re#or% %ha%
$amily his%ory is a #osi%ive $ac%or $or ra)io%hera#y-rela%e) )isease (1;5 o$ cases in #a%ien%s versus >.85
in con%rols+ bu% %his )i) no% signi$ican%ly in$luence %he overall es%ima%e o$ ris!. hus al%hough ,omen
,i%h breas% cancer carry a 275-$ol) increase in ris! o$ a secon) breas% %umour %his ,as largely
in)e#en)en% o$ ra)ia%ion. hese )a%a %en) %o argue agains% a high level o$ increase) %umorigenic
ra)iosensi%ivi%y in here)i%ary breas% cancer an) su##or% in)irec%ly %he lo,er value o$ increase) ris! (no
more %han 1;-$ol)+ -u)ge) $rom o%her human )a%a. In s#i%e o$ %his $ailure %o i)en%i$y a ma-or $amilial
com#onen% o$ ris!, %he ra)io%hera#y )a%a are su$$icien% %o reveal evi)ence o$ increase) ris! o$ secon)
cancers in !no,n rare )isor)ersPre%inoblas%oma, 1i7:raumeni syn)rome, an) nevoi) basal call
carcinoma syn)rome (3ec%ion 5+.
Cverall, an) as a $ur%her sim#li$ica%ion o$ %he #roblem i% is sugges%e) %ha% %he available )a%a, al%hough
s#arse, ,oul) no% be inconsis%en% ,i%h a $amilial gene%ic con%ribu%ion %o cancer in an irra)ia%e)
#o#ula%ion %ha% re$lec%s %ha% ,hich a##lies %o s#on%aneously arising )isease, i.e no more %han 55. he
mechanis%ic argumen%s concerning %he #re)ominan% )isor)ers associa%e) ,i%h germ line %umour
su##ressor gene mu%a%ions %oge%her ,i%h %he animal )a%a o$ 3ec%ion 5 %en) %o su##or% %his con%en%ion.
hese mechanis%ic argumen%s an) one se% o$ animal )a%a also allo, brie$ commen% on ra)ia%ion ris!
rela%ive %o %ha% o$ o%her carcinogenic agen%s. Al%hough ionising ra)ia%ion ,as $rame) as a rela%ively
e$$icien% carcinogen in %umour-su##ressor gene )e$icien% ca%egories o$ #a%ien%s, $or %he reasons given in
3ec%ion 5 i% is believe) %ha% %hey ,oul) also be a% increase) ris! o$ cancer a$%er e4#osure %o a range o$
o%her environmen%al ./A )amaging agen%s.
7!1!"! 6amilial cancer and individual ris)
:rom %he )a%a revie, o$ 3ec%ion 5 i% is -u)ge) %ha% in many )isor)ers o$ $amilial cancer %he in)ivi)ual
carriers ,ill be sub-ec% %o an absolu%e increase in cancer ris!= %his $ac%or o$ increase ,as -u)ge) %o be in
%he range 571;;-$ol). .irec% human observa%ions $rom ra)io%hera#y $ollo,-u# s%u)ies sugges% %ha% %he
mos% a##ro#ria%e value $or %his $ac%or migh% be 1;-$ol). In consi)ering in)ivi)ual ris! in such cases i%
is ho,ever crucial %o rela%e %he e4%ra ris! im#ose) by a given ra)ia%ion e4#osure %o %ha% ,hich is
unavoi)ably carrie), i.e. %he eleva%e) ris! o$ s#on%aneous )isease.
In %he case o$ $amilial cancer )isor)ers ,hich are, by )e$ini%ion, o$ rela%ively high #ene%rance, i% is
sugges%e) %ha% %he s#on%aneous ris! o$ usually organ-s#eci$ic cancer is su$$icien%ly high %ha% even large
increases in %umorigenic ra)iosensi%ivi%y have only a marginal im#ac% on li$e%ime ris! a% lo, )oses o$
ra)ia%ion. In or)er %o illus%ra%e %his #oin% a %heore%ical )isor)er is consi)ere) in ,hich %here is a
s#on%aneous li$e%ime ris! o$ $a%al breas% cancer o$ 8;5 an) an increase in ra)ia%ion ris! o$ li$e%ime $a%al
breas% cancer o$ 1;-$ol) over normal i.e %he value -u)ge) %o be mos% consis%en% ,i%h human )a%a.
able B-17 o$ Publication 60 (I&'P, 1991+, re#ro)uce) here in a mo)i$ie) $orm as able 7.1,
recommen)s a lo, )ose ris! value o$ ;.25 3v
L1
$or li$e%ime $a%al breas% cancer in a #o#ula%ion o$ all
agesP$or %he #ur#oses o$ illus%ra%ive calcula%ion %his value is %a!en %o re#resen% %he ris! %o a normal
in)ivi)ual an) since i% a##lies %o bo%h se4es %he value $or $emales a##ro4ima%es %o ;.85 3v
L1
. hus, $or
a $emale in)ivi)ual ,i%h %he %heore%ical )isor)er, %he ra)ia%ion-rela%e) ris! o$ breas% cancer is 85 3v
L1

$or $a%al cancer #lus ano%her 85 $or non-$a%al cancer. In s#i%e o$ %he 1;-$ol) increase in absolu%e ris!,
$ollo,ing a #ro%rac%e) )ose o$ 1;; m3v, %a!en %o re#resen% an accumula%e) occu#a%ional e4#osure, %he
hy#o%he%ical ris! o$ $a%al breas% cancer in %ha% in)ivi)ual rises $rom 8;5 %o only 8;.85 or $rom 8;5 %o
123
8;.85 $or $a%al #lus non-$a%al breas% cancer. hus, unless %he in%erim -u)gemen%s ma)e have seriously
un)eres%ima%e) %he increase in absolu%e ris!, lo,-)ose e4#osure o$ occu#a%ional magni%u)e ,ill have
only a minor im#ac% on %o%al breas% cancer ris! associa%e) ,i%h $amilial )isor)ers. In)ee), even i$ a high
nominal value o$ 5;-$ol) $or increase) absolu%e ris! is %a!en %he #robabili%y o$ $a%al breas% cancer in %he
e4am#le given rises $rom 8;5 %o only 825 or $rom 8;5 %o 885 $or $a%al #lus non-$a%al breas% cancer.
able 7.1. Illus%ra%ive e4am#le o$ changes in absolu%e cancer ris! overall in a %heore%ical heri%able
)isor)er having a breas%-s#eci$ic increase in ris! o$ 1;-$ol) over normal
a
In consi)era%ion o$ a 1;-$ol) absolu%e increase in breas% cancer ris! %he same #ro%rac%e) ,hole bo)y
)ose o$ 1;; m3v %o %he gene%ically susce#%ible in)ivi)ual raises %he #robabili%y o$ $a%al breas% cancer
$rom %he normal value o$ ;.;85 %o ;.85. Assuming $or sim#lici%y %ha% ris! %o o%her organs o$ %he
a$$ec%e) in)ivi)ual remains normal, %he Publication 60 )a%a o$ able 7.1 may also be use) %o illus%ra%e
%he %rue im#ac% on absolu%e cancer ris! overall. Accor)ingly, al%hough %he eleva%e) breas% cancer ris! o$
;.85 means %ha% %he breas% becomes by $ar %he mos% ra)iosensi%ive organ o$ %he in)ivi)ual, ris! o$ $a%al
cancer overall rises by less %han %,o-$ol), i.e. $ollo,ing a #ro%rac%e) ,hole bo)y )ose o$ 1;; m3v,
$rom aroun) ;.55 %o aroun) ;.95. I% shoul) be recognise) ho,ever %ha% in gene%ic )isor)ers associa%e)
,i%h e4cess cancer a% mul%i#le si%es (see 3ec%ion 2+, %his increase in absolu%e ris! is e4#ec%e) %o be less
mo)es%. he same argumen%s may be a##lie) %o %he lo, )oses o$ ra)ia%ion (usually less %han a $e, %ens
o$ m3v+ associa%e) ,i%h me)ical )iagnos%ic #roce)uresP%he im#ac% on cancer ris! overall ,ill be
small.
6igh )oses o$ ra)ia%ion %o normal %issues e4#erience) in ra)io%hera#y or, much more rarely, as a
conse9uence o$ a ra)ia%ion acci)en%, #resen% ho,ever a #o%en%ially grea%er #roblem. his may be
illus%ra%e) by consi)ering %he same hy#o%he%ical e4am#le use) above (1;-$ol) absolu%e increase in
breas% cancer ris!+ bu%, in %his case, ,i%h %he in)ivi)ual #resen%ing $or breas% cancer ra)io%hera#y. In %he
course o$ such $rac%iona%e) high )ose ra)io%hera#y $or unila%eral breas% cancer i% is assume) %ha% %he
una$$ec%e) con%rala%eral breas% o$ %he #re)is#ose) #a%ien% ,ill receive a )ose o$ 2 3v %hrough sca%%ere)
or inci)en%al e4#osure. In %his hy#o%he%ical e4am#le a$%er correc%ing $or )ose0)ose ra%e e$$ec%s ([2+ an)
124
%he %issue mass a% ris! ([;.5 %o allo, $or irra)ia%ion o$ one breas% only+, I&'P-base) ris! in %he
#re)is#ose) #a%ien% remains a% 85 3v
L1
an) %here$ore %he 2 3v )ose %o con%rala%eral breas% ,ill be
con)i%ionally associa%e), given long-%erm survival $rom %he $irs% breas% cancer, ,i%h a ra)ia%ion-rela%e)
ris! o$ some%hing less %han 85 $or a $a%al secon) breas% cancer an) some%hing less %han 1>5 $or $a%al
#lus non-$a%al breas% cancer. he magni%u)e o$ %he ris! o$ a secon) breas% cancer ,ill also %en) %o
)e#en) u#on %he age a% ,hich %he ra)io%hera#y is )elivere), i.e. age o$ )iagnosis o$ %he $irs% neo#lasm.
I% is e4#ec%e) %ha% %here ,ill be a subs%an%ially smaller e4cess ris! $or e4#osure a$%er age 8; or 5;
com#are) ,i%h %rea%men% a% younger ages (A/3&*A', 1998+.
Al%hough %here is as ye% no evi)ence $or %he s%rong ac%ion o$ $amilial $ac%ors in con%rala%eral breas%
)isease a$%er ra)io%hera#y (3%orm e% al., 1992+, %he #rinci#al message o$ high )ose ris! %ha% may be
%a!en $rom %he above e4am#le broa)ly accor)s ,i%h ra)io%hera#eu%ic observa%ions o$ secon) cancers o$
o%her %y#es in %he cancer #re)is#osing )isor)ers re%inoblas%oma, 1i7:raumeni syn)rome, an) nevoi)
basal cell carcinoma syn)rome (3ec%ion 5+. I% is s%resse) ho,ever %ha% %he e4am#les given are
illus%ra%ive an) are no% in%en)e) %o #rovi)e s#eci$ic gui)ance on ris!.
Also no%e) in 3ec%ion 5 ,as %he seemingly charac%eris%ic shor%ening o$ la%ency o$ ra)ia%ion-associa%e)
%umours in human cancer #rone )isor)ers an) one animal gene%ic mo)el. he early age o$ onse% o$
s#on%aneously arising neo#lasms in %hese )isor)ers is $ully e4#ec%e) %o be re$lec%e) in %hose in)uce)
%hrough e4#osure %o e4ogenous carcinogens such as ra)ia%ion. his ,ill %en) %o a)) %o %he )e%rimen%
%ha% a%%aches %o %hese )isor)ers. here is as ye%, ho,ever, insu$$icien% in$orma%ion ,i%h ,hich %o #rovi)e
any 9uan%i%a%ive -u)gemen% on %his issue. Also, i$ as sugges%e) in 3ec%ion 5, %he la%ency e$$ec% in
9ues%ion )e#en)s u#on %he mul%i#lici%y o$ early carcinogenic cellular even%s %hen %here ,ill %en) %o be
s%rong )ose-)e#en)ence. Assuming %his %o be correc%, a $ur%her re)uc%ion o$ %umour la%ency in $amilial
cancer ,ill no% be a $ea%ure o$ lo, )ose ra)ia%ion e4#osure.
7!"! Cancer involvin% %enes of lo3 penetrance
Ehereas germ line cancer-#re)is#osing genes o$ high #ene%rance reveal %hemselves by Men)elian
segrega%ion o$ cancer in $amily #e)igrees, as #ene%rance )ecreases so %he normal #a%%erns o$ Men)elian
inheri%ance become obscure). Anless %he %umour in 9ues%ion is #ar%icularly rare, cancer inci)ence an)
)is%ribu%ion ,i%hin %he $amily a##roaches %ha% ,hich ,ill occur by chance. hus, as no%e) earlier,
$amily s%u)ies on cancer inci)ence are grea%ly limi%e) in %heir #o,er %o reveal gene%ic $ac%ors $or
common %umours %ha% have lo, or variable #ene%rance. Al%hough i% is #ossible %ha% such mu%a%ions are
no% uncommon in %he #o#ula%ion %here is no $irm scien%i$ic basis $or such a -u)gemen%.
In res#onse %o %his #roblem a%%em#%s have been ma)e %o use aggrega%e) $amily his%ories an)0or large
#o#ula%ions %o a%%em#% %o ans,er %he 9ues%ion as %o ,he%her %here is a ,i)es#rea) gene%ic com#onen% %o
human cancer (see 6ouls%on an) Pe%o, 199>+. Al%hough %here is some #osi%ive evi)ence o$ %his (e.g.
Birch e% al., 199;a an) Birch e% al., 199;b= hom#son e% al., 1988= :uchs e% al., 1998+, s%u)ies o$ %he
#aren%s o$ colorec%al cancer #a%ien%s (3on)er-gaar) e% al., 1991+, %,in s%u)ies (6rubec an) /eel, 1982+
an) some me)ical cen%re-base) inves%iga%ions on $irs% )egree rela%ives o$ chil)hoo) cancer #a%ien%s
(Pas%ore e% al., 1987= Bur!e e% al., 1991= Mon%ou e% al., 1998+ )o no% su##or% %he conce#% o$ general
inheri%ance o$ cancer susce#%ibili%y.
In %erms o$ sheer s%a%is%ical #o,er %he re#or% o$ Clsen e% al. (1995+ on 11,28; #aren%s o$ .anish chil)ren
,i%h cancer is #o%en%ially %he mos% im#or%an% s%u)y o$ %his %y#e. he s%u)y reveale) %ha% %he cancer ra%e
o$ %he #aren%s o$ chil)ren (?15 years+ ,i%h cancer ,as no% )i$$eren% $rom %ha% e4#ec%e) in %he general
125
#o#ula%ion. Al%hough %his s%u)y clearly in)ica%es %ha% cancer in chil)ren is no% a general gene%ic mar!er
$or cancer ris! in %he #aren%s i% )oes no% e4clu)e %he #resence o$ lo, #ene%rance mu%a%ions #ar%icularly
in res#ec% o$ a)ul% cancers.
3orensen (1995+ has #rovi)e) commen% on %his issue an) here i% is su$$icien% %o no%e %ha% uncer%ain%ies
remain in res#ec% o$ #ossible )i$$erences in cancer ra%es be%,een a)ul%s ,i%h an) ,i%hou% chil)ren, %he
relevance o$ chil)hoo) cancer #re)is#osing genes $or %he ,hole range o$ a)ul% cancers an), mos%
im#or%an%ly, %ha% %he s%u)y )esign in no% consi)ering ris! in siblings, age o$ onse% or his%o#a%hological
$ea%ures only allo,s e4clusion o$ ,i)es#rea) )ominan% cancer #re)is#osi%ion o$ mo)era%e %o high
#ene%rance. 6ence, %he lo, #ene%rance 9ues%ion remains unans,ere) an) in %he absence o$ heroic
e#i)emiological an) molecular inves%iga%ions is li!ely %o remain so $or some %ime %o come. he same
ra%her #essimis%ic vie, a%%aches %o )e%ermina%ion o$ %he %rue im#ac% o$ mo)i$ier genes, genomic
im#rin%ing an) mosaicism on cancer ris! in %he #o#ula%ion (see 3ec%ion 2 an) 3ec%ion 5+.
A% #resen% i% is only A)*
K0L
geno%y#es (a%a4ia-%elangiec%asia he%ero<ygo%es+ an) an allele o$ 5RA+ %ha%
migh% 9uali$y as lo, #ene%rance )e%erminan%s or mo)i$iers o$ cancer ris! having $re9uencies su$$icien%
%o #o%en%ially im#ac% on ris!s in %he #o#ula%ion (see 3ec%ion 2, 3ec%ion 5 an) 3ec%ion >+. I% shoul) be
em#hasise), ho,ever, %ha% $or bo%h 5RA+ an) A)*
K0L
human geno%y#es, %he #heno%y#ic mani$es%a%ion
o$ e4cess cancer is no% ,ell es%ablishe). :ur%her can)i)a%e lo, #ene%rance genes may come %o ligh% an)
inclu)e) here ,oul) be %he gene%ic $ac%ors %ha% may )e%ermine #roli$era%ive breas% )isease an)
chromosomal ra)iosensi%ivi%y in unselec%e) breas% cancer #a%ien%s (see 3ec%ion 2 an) 3ec%ion 8+.
In %he absence o$ gui)ance on %he overall con%ribu%ion o$ lo, #ene%rance genes %o s#on%aneous human
cancer no $irm -u)gemen%s are #ossible on %heir im#lica%ions $or ra)iological #ro%ec%ion. In %he ligh% o$
%he argumen%s #resen%e) in 3ec%ion 5 i% is ho,ever reasonable %o assume %ha% %he cancer ris! in carriers
o$ %hese genes ,oul) be increase) by ra)ia%ion e4#osure. Ei%h %his assum#%ion %heir #ossible im#ac% on
curren% es%ima%es o$ #o#ula%ion ris! may be $rame) as $ollo,s. I$ a large number (say 1;;; s+ o$ such
genes ,ere %o ma!e a##ro4ima%ely e9ual con%ribu%ion %o ra)iogenic cancer an) no s#eci$ic
combina%ions ,ere %o con$er high sensi%ivi%y %hen ris! ,oul) be broa)ly )is%ribu%e) in human
#o#ula%ions an) no signi$ican% )is%or%ion o$ #o#ula%ion ris! ,oul) be e4#ec%e). &onversely, i$ a smaller
number o$ genes (say 1;; s+ ,ere %o be involve) ra)ia%ion ris! migh% be e4#ec%e) %o be less uni$ormly
)is%ribu%e). his ris! )is%ribu%ion #roblem $or lo, #ene%rance mu%a%ions ,ill %en) %o be grea%es% i$
s#eci$ic gene combina%ions ,ere %o be #ar%icularly Hsensi%isingI-resolving such com#le4 mul%i$ac%orial
e$$ec%s is ,ell recognise) as a mos% )i$$icul% %as!. In general, ho,ever, a re)uc%ion in #ene%rance %en)s
%o )ilu%e %he #o#ula%ion im#ac% $rom cancer #re)is#osing genes (see 3ec%ion >+ ,hich means %ha% %he
#revalence o$ carriers ,oul) nee) %o be high in or)er %o signi$ican%ly a$$ec% curren% -u)gemen%s on
ra)iological ris!.
:inally, on %he 9ues%ion o$ in)ivi)ual ris! $or #ro#ose) lo, #ene%rance mu%a%ions, i% is sugges%e) %ha%
%he same argumen% use) $or $amilial cancer (see 3ec%ion 7.1.2+ ,ill %en) %o a##ly. Cn %he basis o$
in)ivi)ual ra)ia%ion ris! rela%ive %o baseline, lo, )ose e$$ec%s are e4#ec%e) %o be minor an) i% is only in
%he case o$ high )ose e4#osure %ha% %here ,oul) be cause $or concern. I% shoul) be recognise) ho,ever
%ha% !no,le)ge in %his area is $ar $rom com#le%e. he #ossibili%y remains %ha% %here are rare )isor)ers,
#robably o$ ./A )amage #rocessing, ,here %he ris! o$ s#on%aneous cancer is no% a% all remar!able bu%
,here e4#ression is subs%an%ially increase) by e4#osure %o ionising ra)ia%ion. 'elevan% %o %his is %ha%, in
%he absence o$ solar e4#osures, s!in cancer in AV'-re#air )e$icien% 4ero)erma #igmen%osum (OP+
#a%ien%s is uncommon (Fraemer e% al., 1998+, i.e in res#ec% o$ s!in cancer %he OP #heno%y#e is almos%
,holly )e#en)en% u#on %his s#eci$ic environmen%al insul%. I% remains %o be seen ,he%her %here are
126
#heno%y#ic varian%s o$ %he ra)iosensi%ive human a%a4ia-%elangiec%asia )isor)er %ha% sho, OP-li!e
)e#en)ence o$ cancer on ionising ra)ia%ion e4#osure. In such cases %he in)ivi)ual ris! o$ e4cess cancer
a$%er even lo, )oses o$ ionising ra)ia%ion may be high rela%ive %o baseline ris!.
7!,! Areas of future research in radiolo%ical protection
Much o$ %he !no,le)ge necessary %o im#rove -u)gemen%s on %he role an) im#ac% o$ gene%ic $ac%ors in
ra)ia%ion cancer ris! is e4#ec%e) %o )erive $rom research ou%si)e %he $iel) o$ ra)iological #ro%ec%ion.
he gene%ics o$ %he common cancers is )evelo#ing ra#i)ly, #ar%icularly in res#ec% o$ %he highly
#ene%ran% genes #re)is#osing %o breas% an) colon cancers. I% is im#or%an% ho,ever %ha% a be%%er vie, is
gaine), no% only o$ %he i)en%i%y an) role o$ cancer #re)is#osing genes o$ lo,er #ene%rance bu% also %heir
#revalence an) %he gene%ic7gene%ic an) gene%ic7environmen%al in%erac%ions %ha% gui)e #heno%y#ic
e4#ression. 'ecen% ra#i) a)vances in %he gene%ics o$ breas% cancer #rovi)e evi)ence %ha% such
in$orma%ion can, in #rinci#le, be gaine). As ,ell as being )irec%e) %o,ar)s s#eci$ic goals, ra)iological
#ro%ec%ion research may ,ell be able %o con%ribu%e %o,ar)s %he resolu%ion o$ some o$ %hese $un)amen%al
issues.
he )egree o$ %umorigenic ra)iosensi%ivi%y associa%e) ,i%h cancer-#re)is#osing )isor)ers ,as )iscusse)
in 3ec%ion 5. Al%hough $e, )irec%ly in$orma%ive e#i)emiological s%u)ies are curren%ly available, a
number o$ large #o%en%ially in$orma%ive human grou#s ,ere i)en%i$ie) $or $ur%her inves%iga%ions. Ei%h
%he #ossible e4ce#%ion o$ AV', %he e$$ec%s o$ ,hich are limi%e) %o %he s!in, $or no o%her environmen%al
carcinogen is i% #ossible %o achieve %his. hus, %he #o%en%ial s%u)ies no%e) may #rove %o be an im#or%an%
source o$ basic in$orma%ion on gene%ic7environmen%al in%erac%ions in human carcinogenesis.
In any $u%ure surveys o$ ra)ia%ion-rela%e) neo#lasms $or #ossible gene%ic $ac%ors i% ,oul) be o$ obvious
bene$i% %o gain in$orma%ion on age-o$-onse%, his%o#a%hology, an) ,here #ossible, %he $amily his%ory o$
cancer. "iven ongoing a)vances, #erha#s %he mos% im#or%an% issue is %he availabili%y o$ normal %issue
$rom ,hich %o ascer%ain ,he%her s#eci$ic germ line mu%a%ions charac%erise) any $rac%ion o$ %he cases.
A% #resen% %his s%ra%egy ,oul) be mos% #ro$i%ably a##lie) %o )e%ermine %he con%ribu%ion o$ BRCA an)
A)* genes %o ra)iogenic breas% cancer. Ei%h !no,le)ge o$ such con%ribu%ions in cases an) con%rols, %he
)oses receive) an) %he #revalence in %he normal #o#ula%ion o$ %he res#ec%ive gene )e$ec%s i% ,ill be
#ossible %o be%%er -u)ge %he )egree %o ,hich ra)iogenic ris! is increase) in gene carriers (see 3ec%ion 5+.
Al%hough %his s%ra%egy shoul), in #rinci#le, #rovi)e a more clear #ic%ure o$ %he #roblem, %he ,or! loa)
im#ose) by %he molecular analyses shoul) no% be un)eres%ima%e)Psome hun)re)s o$ unrela%e) breas%
cancer cases an) con%rols ,oul) nee) %o be analyse) a% %he ./A se9uence level (see 3ec%ion 5, also
3ec%ion 7.8+.
Animal )a%a have con%ribu%e) signi$ican%ly %o,ar)s %he -u)gemen%s ma)e in 3ec%ion 5 o$ %his re#or% on
gene%ically )e%ermine) ra)iogenic ris!. here are no, consi)erable o##or%uni%ies %o e4%en) %he
e4#erimen%al a##roaches %o mice )e$icien% in, $or e4am#le, BRCA, A)*, an) ./A misma%ch re#air
genes. "ene%ic an) molecular analysis o$ %he na%ural in%ers%rain )i$$erences in murine %umorigenic
ra)iosensi%ivi%y shoul) also be encourage).
&ellular an) molecular s%u)ies have #laye) cri%ical roles in un)ers%an)ing %he com#le4 rela%ionshi#s
be%,een ./A )amage re#air a$%er ra)ia%ion, cell cycle con%rol, genomic ins%abili%y, an) %he $unc%ions o$
#ro%o-oncogenes an) %umour su##ressor genes. 6ere i% is su$$icien% %o highligh% a $e, $ocal issues $or
$u%ure consi)era%ion.
127
3%u)ies on %he cellular an) chromosomal ra)iosensi%ivi%y o$ human an) ro)en% cell s%rains have #rove)
invaluable in %he i)en%i$ica%ion an) charac%erisa%ion o$ #heno%y#es relevan% %o ra)ia%ion %umorigenesis.
here is grea% sco#e $or $ur%her ,or! in %his area, #ar%icularly in res#ec% o$ novel mammalian genes
con%rolling ra)ia%ion res#onse an) %heir s%ruc%ural0$unc%ional rela%ionshi#s ,i%h %hose alrea)y
charac%erise) in lo,er organisms. More em#hasis coul) #erha#s be #lace) on #heno%y#es s#eci$ically
associa%e) ,i%h increase) sensi%ivi%y %o %he in)uc%ion o$ gene an) chromosomal mu%a%ions ra%her %han
sim#ly cell inac%iva%ion. In %his con%e4% %he )evelo#men% o$ more ra#i) an) reliable mu%a%ion sys%ems
,oul) be invaluable. Associa%e) ,i%h %he $ur%her )evelo#men% o$ %his ,hole area o$ research is %he nee)
$or im#rove) access %o relevan% cellular ma%erial. here is a s%reng%hening case $or %he es%ablishmen% o$
s#eci$ic ban!s o$ cells having !no,n or sus#ec%e) associa%ions ,i%h al%ere) ra)ia%ion res#onse.
7!-! &he application of dia%nostic technolo%ies
Al%hough %he clinical evalua%ion o$ $amilial cancer aggrega%ion remains a cri%ical %ool in %he
)e%ermina%ion o$ heri%able cancer, ra#i) s%ri)es have been ma)e in %he )evelo#men% o$ me%ho)s o$
molecular )iagnosis. :ollo,ing %he molecular cloning an) ./A se9uencing o$ a given $amilial cancer
gene, i% becomes #ossible %o )e%ermine %he na%ure an) )is%ribu%ion o$ %he mu%a%ions %ha% un)erlie %he
)isor)er. he %,o e4am#les s#eci$ically ci%e) in %his re#or% rela%e %o p53 mu%a%ion in 1i7:raumeni
syn)rome an) heri%able breas% cancer associa%e) ,i%h BRCA1 mu%a%ion= %he issues no%e) brie$ly belo,
a##ly, ho,ever, more generally.
Al%hough %here may be mu%a%ional se9uence Hho% s#o%sI in such germ line genes, %he mu%a%ions %en) %o
be )is%ribu%e) %hroughou% %he )i$$eren% e4ons. Par%icularly in %he case o$ large genes such as BRCA1
%here is, %here$ore, %he #o%en%ial $or a vas% array o$ )i$$eren% ./A se9uence mu%a%ions un)erlying %he
same or closely rela%e) clinical #heno%y#es.
In %he case o$ a $amily #e)igree segrega%ing a single gene-s#eci$ic mu%a%ion %he charac%erisa%ion o$ %ha%
mu%a%ion in one $amily member allo,s $or ascer%ainmen% o$ inheri%ance amongs% e4is%ing $amily
members. 'a#i) #olymerase chain reac%ion me%ho)ologies a##lie) %o ./A usually e4%rac%e) $rom
bloo) sam#les is generally $avoure)Pin some ins%ances ./A lin!age by microsa%elli%e analysis is
use), in o%hers )irec% mu%a%ional analysis is #ossible (Ja%es, 199>+. In %his ,ay carriers o$ %he mu%an%
gene are i)en%i$ie) %hus allo,ing $or gene%ic counselling, cer%ain -u)gemen%s on clinical #rognosis an),
in a $e, ins%ances, clinical in%erven%ion. hus, albei% ,i%h )ue a%%en%ion %o %he e%hical im#lica%ions
,hich are no% uni$orm ('eilly e% al., 1997+, %he molecular screening by consen% $or s#eci$ic gene
mu%a%ions segrega%ing ,i%hin $amily #e)igrees is becoming rela%ively common#lace.
Much more #roblema%ical is %he $easibili%y o$ a##lying e4is%ing molecular %echnologies %o %he screening
o$ relevan% gene mu%a%ions in unrela%e) in)ivi)uals. In %he con%e4% o$ heri%able cancer an) ra)iological
#ro%ec%ion such screening, i$ an) ,hen -u)ge) %o be e%hically an) #rac%ically a##ro#ria%e, migh% be
relevan% in %he case o$ #lanne) me)ical irra)ia%ions or o$ #ossible occu#a%ional e4#osures (see 3ec%ion
7.5+.
he #rinci#al #rac%ical )i$$icul%ies in such screening are %ha% since %he in)ivi)uals %o be %es%e) are
largely unrela%e), $irs%, %ha% lin!age s%u)ies are by )e$ini%ion rule) ou% an) secon), %ha% %he si%e o$ %he
mu%a%ion in carriers ,ill, in %he main, be )i$$eren%. In essence, ./A con$orma%ional analysis or #ro%ein
charac%erisa%ion $ollo,e) by ./A se9uencing ,oul) be necessary $or unambiguous )iagnosis an)
given %he mul%i#lici%y o$ )i$$eren% cancer #re)is#osing )isor)ers an) %heir rari%y %he screening %as!
becomes enormous. *ven in an unrela%e) subgrou# subs%an%ially enriche) $or a !no,n se% o$ genes, e.g.
128
BRCA genes in early onse% breas% cancer cases, %he %echnologies no%e) above sim#ly )o no% have %he
s#ee) or )egree o$ au%oma%ion %o ma!e #ossible %he rou%ine mass screening o$ say %housan)s o$ cases.
he single #ossible e4ce#%ion %o %his is %he gene mu%a%ions main%aine) in ,hole #o#ula%ions %hrough so
calle) $oun)er e$$ec%s, i.e ances%ral germ line even%s esca#ing #o,er$ul coun%er-selec%ion ,i%hin
#o#ula%ions %ha% sho, a )egree o$ inbree)ing. 3uch single mu%a%ions can be share) by a signi$ican%
$rac%ion o$ carriers o$ a single clinical )isor)er. :or e4am#le a single BRCA1 gene mu%a%ion is
es%ima%e) %o be share) by aroun) 15 o$ %he Ash!ena<i De,ish #o#ula%ion (3ec%ion 8 an) 3ec%ion >+, an
inci)ence %ha% ,oul) allo, $or mass screening using curren% %echnology= $oun)er e$$ec%s $or BRCA2 are
also #ronounce) in %his #o#ula%ion (see :rien), 199>+. he occurrence o$ $oun)er e$$ec%s o$ signi$ican%
magni%u)e, al%hough no% common, has also been no%e) $or BRCA2 in Icelan) (horlacius e% al., 199>+
an) $or h*351 mu%a%ions un)erlying here)i%ary non-#oly#osis colon cancer in :inlan) (Pa#a)o#oulos
e% al., 1998+.
In )ue course, ,i%h increasing %echnical innova%ion, %he )evelo#men% o$ me%ho)s $or mass gene%ic
screening shoul) ho,ever be an%ici#a%e). :orres% e% al. (1995+ an) Mashal an) 3!lar (199>+ #rovi)e
commen%aries on %hese )evelo#ing me%ho)ologies ,hich inclu)e novel ./A misma%ch hybri)isa%ion
me%ho)s, con$orma%ional analysis an) #ro%ein %runca%ion %es%ing. Au%oma%ion o$ %es%ing ,ill, ho,ever,
be %he !ey %o %he #roblem. In %his area %he )evelo#men% o$ so-calle) H./A chi#sI %o )e%ec%, by
$luorescence analysis, ./A misma%ches in mul%i#le micro-arrays o$ %arge% oligonucleo%i)e se9uences
cons%i%u%ing a ,hole gene is a %echnology %ha% is e4#ec%e) %o be $ully o#era%ional ,i%hin %he ne4% $e,
years (1i#shu%< e% al., 1995= Freiner, 199>+. 1abora%ory-scale s%u)ies u%ilising oligonucleo%i)e array
%echni9ues $or BRCA1 mu%a%ion analysis have alrea)y been re#or%e) (6acia e% al., 199>+ an) $ur%her
ra#i) )evelo#men% seems li!ely.
Irres#ec%ive o$ %hese )evelo#men%s i% is im#or%an% %o recognise, ho,ever, %ha% un%il %he $ull e4%en% o$
cancer-#re)is#osing gene%ic )e%erminan%s is !no,n %oge%her ,i%h %heir #ossible in%erac%ions an) clinical
im#lica%ions, %he %rue #re)ic%ive value o$ such %es%ing canno% be assure). As )iscusse) by :rien) (199>+,
%he highly variable #ene%rance in res#ec% o$ s#on%aneous cancer in carriers o$ %he sa-/ cancer
#re)is#osing mu%a%ion im#lies a ma-or #o%en%ial mo)i$ica%ion o$ ris! by gene%ic7gene%ic an)0or gene%ic7
environmen%al in%erac%ions. here is no reason %o believe %ha% ra)ia%ion ris!s in such !in)re) ,oul) no%
be similarly variable in ,hich case #rognos%ic -u)gemen%s on a given in)ivi)ual base) u#on gene%ic
%es%ing mus% be o#en %o )oub%.
7!.! (ummary and conclusions for radiolo%ical protection
As a resul% o$ %he ,or! com#ile) above, %he Main &ommission o$ I&'P has revie,e) %he ra#i)ly
)evelo#ing $iel) o$ human cancer gene%ics ,i%h a vie, %o #rovi)ing an in%erim -u)gemen% on %he
#rac%ical im#lica%ions $or ra)iological #ro%ec%ion. Al%hough cri%ical )a%a on ris! o$ ra)ia%ion
%umorigenesis are limi%e), i% is -u)ge) on %he basis o$ curren% !no,le)ge by %he &ommission %ha%@
1. In mos%, i$ no% all, ins%ances o$ $amilial cancer #re)is#osi%ion associa%e) ,i%h %he )ominan%
inheri%ance o$ s%rongly e4#ressing %umour su##ressor gene mu%a%ions %here ,ill be an absolu%e increase
in %he #robabili%y o$ ra)ia%ion-in)uce) cancer. he range o$ %his #robabili%y may vary be%,een $amilial
)isor)ers ,i%hin ,hich )i$$eren% %umour %y#es ,ill %en) %o #re)omina%e. Cverall, a range o$ increases in
absolu%e cancer #robabili%y o$ 5 or less %o 1;;-$ol) $or some si%es is im#lie) by available human an)
animal )a%a. I% is -u)ge) ho,ever %ha% a 1;-$ol) absolu%e increase in cancer #robabili%y $or some si%es
a$%er ra)ia%ion encom#asses %he human )a%a curren%ly available $or cer%ain %umours in a $e, gene%ic
129
)isor)ers. he )e%rimen% associa%e) ,i%h %his ris! increase is a% #resen% )i$$icul% %o 9uan%i$y. Cn %he one
han) because o$ %he high #robabili%y o$ s#on%aneously arising cancer, rela%ive ris! is small a% lo, )oses.
Cn %he o%her han), a shor%ening o$ %umour la%ency ,ill increase %he )e%rimen%.
2. In %he case o$ cancer #re)is#osi%ion associa%e) ,i%h )e$iciencies in ./A re#air i% is sugges%e) %ha%
some bu% no% all )isor)ers o$ %his %y#e ,ill sho, eleva%e) cancer ris! a$%er ra)ia%ion. /o -u)gemen%s can
be ma)e a% #resen% on %he )egree o$ such ris! bu% %he )a%a regar)ing increase) ra)ia%ion cancer ris!s in
a%a4ia-%elangiec%asia he%ero<ygo%es, ,ho are rela%ively common in %he #o#ula%ion, ,ere -u)ge) %o be
,ea!. .a%a on s#on%aneous cancer ris! in a%a4ia-%elangiec%asia he%ero<ygo%es in)ica%e, ho,ever, %ha%
increase) ra)ia%ion ris! canno% be )iscoun%e).
2. &om#u%a%ional mo)elling o$ %he con%ribu%ion o$ gene%ically im#ose) ris! o$ e4cess cancer in a %y#ical
irra)ia%e) human #o#ula%ion sho,e) %ha%, because o$ %heir lo, #revalence, $amilial cancer )isor)ers
can have a minor im#ac% only. Illus%ra%ive calcula%ions ,ere also ma)e ,i%h res#ec% %o e4cess cancer in
in)ivi)uals ,i%h $amilial )isor)ers $ollo,ing lo, an) high )ose e4#osures.
Cn %he basis o$ %hese )a%a an) -u)gemen%s %he #rac%ical im#lica%ions $or ra)iological #ro%ec%ion
#rac%ices may be $rame) as $ollo,s.
7!.!1! 4stimation of ris)s in 3hole populations
3ince e4is%ing e#i)emiological measures o$ ris!s %en) %o cen%re on rela%ively large an) he%erogenous
#o#ula%ions (I&'P, 1991, A/3&*A', 1998+ a gene%ic con%ribu%ion o$ un)e%ermine) magni%u)e is
alrea)y inclu)e) in curren% recommen)a%ions o$ ris! $rom %he &ommission ,hich has $or some %ime
recognise) %ha% ris! ,ill no% be uni$ormly )is%ribu%e). he use by %he &ommission o$ baseline cancer
)a%a in %he e4%ra#ola%ion o$ ris!s across #o#ula%ions %a!es accoun% o$ #ossible )i$$erences in gene%ic
con%ribu%ions be%,een #o#ula%ions. he issue is, %here$ore, no% %he vali)i%y o$ %he overall es%ima%e o$
ris! bu% ho, %ha% ris! is )is%ribu%e) an) ,he%her !no,n gene%ic $ac%ors im#ose an unacce#%able )egree
o$ )is%or%ion. 3ince, ho,ever, only 15 or less o$ %he #o#ula%ion $all in%o %he $amilial cancer ca%egory
,here signi$ican%ly increase) ra)ia%ion ris! migh% be an%ici#a%e), con$i)ence is gaine) %ha% e4is%ing
recommen)a%ions $rom %he &ommission on cancer ris! in irra)ia%e) #o#ula%ions are no% sub-ec% %o
unacce#%able gene%ic uncer%ain%y.
7!.!"! Ris)s in individuals 3ith familial cancer
In)ivi)uals having mos%, i$ no% all, cancer-#re)is#osing $amilial )isor)ers are e4#ec%e) %o be a%
increase) absolu%e ris! o$ cancer a$%er ra)ia%ion e4#osure. Bu%, as in)ica%e), a% lo, )oses %ha%
incremen%al ris! is small. A))i%ionally, %he in%er-in)ivi)ual varia%ion in cancer inci)ence %ha%
increasingly a##ears %o be a $ea%ure o$ many such )isor)ers sugges%s %ha% %here is li%%le value in
recommen)ing s#eci$ic res%ric%ions on lo, )ose e4#osure.
he %rue e4%en% o$ %he #roblem o$ high )ose ra)io%hera#y %o cancer #a%ien%s having $amilial cancer
)isor)ers is $ar more )i$$icul% %o -u)ge since i% )e#en)s cri%ically u#on %he es%ima%e o$ enhance) cancer
ris! (see 3ec%ion 7.1.2+. he )a%a revie,e) in %his re#or% are insu$$icien% %o allo, %his es%ima%e %o be
given ,i%h real con$i)enceP%ha% %here is a #o%en%ial #roblem shoul) no%, ho,ever, be )oub%e).
An%il such %ime %ha% %he %hera#y rela%e) cancer issue is more clearly )e$ine) %he &ommission consi)ers
%ha% i% is a##ro#ria%e %o sugges% only %ha% clinicians $ace) ,i%h %he #ros#ec% o$ %rea%ing
ra)io%hera#eu%ically #a%ien%s having $amilial cancer )isor)ers see! %o balance %he clinical bene$i%s %o %he
130
#a%ien% agains% a #ossible 1;-$ol) or more increase) chance o$ a secon) cancer arising in irra)ia%e)
normal %issue. In %he con%e4% o$ %his #roblem a number o$ issues may be i)en%i$ie). :irs%, %he
minimisa%ion o$ )ose %o normal %issues in Hgene%icI #a%ien%s is -u)ge) %o be more im#or%an% %han in
#a%ien%s ,i%h s#ora)ic (non-gene%ic+ neo#lasms. 3econ), ,here #ossible, consi)era%ion migh% be given
%o al%erna%ive cancer %rea%men%s bu% bearing in min) %ha% in many ins%ances %here ,ill also be enhance)
ris! $ollo,ing geno%o4ic chemo%hera#eu%ic agen%s. hir), al%hough no% $ormally es%ablishe), %here is
some reason %o believe %ha% chil)ren an) young #eo#le having gene%ic )isor)ers o$ cancer
#re)is#osi%ion ,oul) be a% #ar%icular ris!.
In general a $amily, or in)ee) an in)ivi)ual, his%ory o$ cancer shoul) aler% ra)io%hera#is%s %o %he
#ossibili%y o$ a gene%ic com#onen% %o %he )isease. In some ins%ances )iagnos%ic %es%s $or cer%ain o$ %hese
)isor)ers ,ill, in con-unc%ion ,i%h a me)ical gene%ics in#u%, be a##ro#ria%e (see 3ec%ion 7.5.2+.
7!.!,! Genetic testin% for cancer susceptibility in the conte0t of radiolo%ical protection
he &ommission is a,are o$ %he $un)amen%al an) %echnical #roblems %ha% curren%ly limi% %he screening
o$ unrela%e) in)ivi)uals $or cancer-#re)is#osing )isor)ers (3ec%ion 7.8+. Irres#ec%ive o$ %he gains in
!no,le)ge %ha% ,ill $ollo,, %he &ommission believes %ha% %here are cri%ically im#or%an% e%hical, social,
an) economic consi)era%ions %ha% nee) %o be )iscusse) an) resolve) #rior %o %he em#loymen% o$ such
gene%ic %es%s in almos% all con%e4%sP%he #ossible im#lica%ions $or ra)iological #ro%ec%ion #rac%ice is one
small #ar% o$ a much grea%er )eba%e.
:ac%ors im#inging on %he use o$ gene%ic %es%ing inclu)e@ %he im#lica%ions o$ a #osi%ive %es% e4%en) no%
only %o %he %es%e) in)ivi)ual bu% also %o a #ro#or%ion o$ his0her $amily= %he )esire o$ %he in)ivi)ual %o
have !no,le)ge o$ %he #robabili%y o$ $u%ure )isease (inclu)ing %he $amilial elemen%+ canno% be assume)
#ar%icularly i$ no reme)ial clinical in%erven%ion is available= a #osi%ive %es% has #o%en%ially $ar-reaching
economic conse9uences in res#ec% o$ li$e insurance, borro,ing ca#abili%ies, an) em#loymen% #ros#ec%s
Phence, %he con$i)en%iali%y o$ %es% resul%s is o$ cri%ical im#or%ance. hese an) o%her as#ec%s o$ %he
#roblem are being )eba%e) ,i)ely (*eles e% al., 199>= Masoo), 199>= 'eilly e% al., 1997+ an) ,ill no% be
consi)ere) $ur%her here.
"ene%ic %es%ing $or cancer #re)is#osi%ion an) o%her )isor)ers has or ,ill become a ma%%er $or legisla%ion
in all )evelo#e) coun%ries. As a conse9uence, %he &ommission )oes no% believe %ha% i% is a##ro#ria%e a%
%his s%age %o ma!e s#eci$ic recommen)a%ions on %he em#loymen% o$ gene%ic %es%ing in %he con%e4% o$
ra)iological #ro%ec%ion. 3ome general observa%ions on %he #o%en%ial a##lica%ions may, never%heless, be
use$ul even a% %his early #oin%.
he )a%a available sugges% %o %he &ommission %ha% %he mos% obvious 9ues%ion #ose) by cancer-
susce#%ibili%y %o ra)iological #ro%ec%ion arises ,hen high )ose ra)io%hera#y is in)ica%e). 3ince %he
gene%ic eleva%ion o$ ris! o$ a secon) cancer may be subs%an%ial %here is clear #o%en%ial bene$i% %o %he
#a%ien% in unambiguous gene%ic )iagnosis in or)er $or clinicians %o balance %he ris! o$ a secon) cancer
agains% %he li!ely %hera#eu%ic gain. As gene%ic %es%s become more #re)ic%ive, au%oma%e), an) e%hically
resolve), %he &ommission )oes no% $in) i% )i$$icul% %o envisage) %ha%, in a small #ro#or%ion o$ cancer
cases, %hey migh% #lay an im#or%an% $u%ure role in %he $ormula%ion o$ %he mos% a##ro#ria%e %hera#eu%ic
s%ra%egies.
*ven in %he mos% $avourable circums%ances i% is, ho,ever, $ar more )i$$icul% $or %he &ommission %o
#ro-ec% %he use o$ gene%ic %es%ing in cases o$ #o%en%ial lo,-)ose e4#osure in ei%her me)ical )iagnos%ic or
131
occu#a%ional se%%ings. I% is an%ici#a%e) %ha%, in %he main, such %es%ing ,oul) be #er$orme) on in)ivi)uals
,i%hou% cancer ,i%h a vie, %o -u)ging %he #o%en%ial $or ris! an) ,he%her avoi)ance o$ e4#osure ,as
a##ro#ria%e. In many coun%ries %he #ro-ec%e) number o$ gene%ic %es%s o$ %his %y#e an) hence %he cos%s
,oul) be very grea% in)ee) ye% a curren% -u)gemen% ,oul) be %ha% #o%en%ial bene$i% ,oul) accrue %o
aroun) only 15 or less o$ %hose %es%e). I% ,oul) also a##ear %ha% %he eleva%e) lo,-)ose ris! $or ,hich
avoi)ance migh% be sough% is small. hus, %he #o%en%ial bene$i%s o$ %es%ing are -u)ge) by %he
&ommission %o be very small ,hen ,eighe) agains% %he grea% cos%s involve). Cn %his basis %here seems
li%%le reason %o believe %ha% gene%ic %es%ing has a signi$ican% role in %he con%e4% o$ occu#a%ional e4#osure
%o ra)ia%ion. In some $u%ure circums%ances i% migh% be a##ro#ria%e %o consi)er gene%ic %es%ing in selec%e)
#a%ien%s #rior %o cer%ain me)ical )iagnos%ic e4#osures ,here rela%ively high )oses are involve) bu% a
,i)es#rea) a##lica%ion )oes no% a##ear li!ely.
7!.!-! Concludin% remar)s
he #rinci#al conclusion by %he &ommission is %ha%, on curren% !no,le)ge, %he #resence o$ $amilial
cancer )isor)ers )oes no% im#ose unacce#%able )is%or%ions in %he )is%ribu%ion o$ ra)ia%ion cancer ris! in
%y#ical human #o#ula%ions. :or in)ivi)uals ,i%h $amilial cancer )isor)ers, ra)ia%ion cancer ris!s
rela%ive %o baseline are -u)ge) by %he &ommission %o be small a% lo, )oses an) insu$$icien% %o $orm %he
basis o$ s#ecial #recau%ions. I% seems li!ely ho,ever %ha% ris!s %o %hose ,i%h $amilial cancer )isor)ers
,ill become im#or%an% a% %he high )oses receive) )uring ra)io%hera#y. A% #resen%, an) even #erha#s in
$u%ure, gene%ic %es%ing $or $amilial cancer )isor)ers )oes no% a##ear %o have a ma-or role in ra)iological
#ro%ec%ion #rac%iceP%he #rinci#al e4ce#%ion may be selec%e) cancer #a%ien%s $or ,hom ra)io%hera#y is
in)ica%e).
I% is s%resse) again %ha% %he )a%a curren%ly available $or %he )evelo#men% o$ %hese vie,s are limi%e) an)
%he -u)gemen%s given shoul) be regar)e) as being #reliminary. Many o$ %he uncer%ain%ies a%%aching %o
%hese -u)gemen%s have been consi)ere) by %he as! "rou# an) &ommission %oge%her ,i%h #ossible
research s%ra%egies %ha% may be use) %o im#rove !no,le)ge. C$ #ar%icular im#or%ance is %he nee) $or
!no,le)ge on %he i)en%i%y, #revalence, an) im#ac% o$ ,ea!ly e4#ressing mu%a%ions ,hich )o no%
mani$es% as $amilial cancer.
"iven %hese uncer%ain%ies %he &ommission ,ill main%ain close surveillance on %he ra#i)ly )evelo#ing
$iel)s o$ cancer gene%ics an) gene%ic e#i)emiology an), ,hen a##ro#ria%e, ,ill e4#an) an)0or revise %he
in%erim vie,s e4#resse) in %his re#or%.I&'P (199;+= 3aba%ini e% al. (1998+= 3errano e% al. (1992+= aylor
e% al. (1992+= aylor e% al. (1998a+=3hibu%ani e% al. (1991+
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A-1 %1 */1 @/n/t1 -, ##. 2>57281 6ull &e0t via &ross'e$ ` Vie, 'ecor) in 3co#us ` &i%e) By in
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&arlson, F.M., .ou, 3., &hi, /. /t al1, 1998. 3ingle missense mu%a%ion in %he %yrosine !inase ca%aly%ic
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&asares, 3., Ionov, J., 3%anbri)ge, *.D. /t al1, 1995. he microsa%elli%e mu%a%or #heno%y#e o$ colon
cancer cells is o$%en recessive. 8nco?/n/ 11, ##. 22;27221; Vie, 'ecor) in 3co#us ` &i%e) By in
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&assoni, A.M., 1998. Cncogenes an) ra)iosensi%ivi%y. 6ur1 %1 Canc/r ,?A, ##. 2797281 Abs%rac% ` Vie,
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ra)iosensi%ivi%y $or #re)ic%ing cancer ris!s in #o#ula%ions. Raiation R/s1 1-,, ##. 29272;1 6ull &e0t
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%umour #a%ien%s. :atur/ @/n/t1 ,, ##. 1277121 6ull &e0t via &ross'e$ ` Vie, 'ecor) in 3co#us ` &i%e)
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136
&ho, J., "orina, 3., De$$rey, P... /t al1, 1998. &rys%al s%ruc%ure o$ a #52 %umor su##ressor7./A
com#le4@ un)ers%an)ing %umorigenic mu%a%ions. +ci/nc/ "1., ##. 28>7255 Vie, 'ecor) in 3co#us `
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&lar!, .., Mei-ne, *., Bou$$ler, 3. /t al1, 199>. Polymor#hic microsa%elli%e analysis o$ recurren%
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Chro-1 Canc/r 11, ##. 228728> 6ull &e0t via &ross'e$ ` Vie, 'ecor) in 3co#us ` &i%e) By in 3co#us
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&lar!son, B... an) Boyse, *.A., 1971. Possible e4#lana%ion o$ %he high concor)ance $or acu%e
leu!aemia in mono<ygo%ic %,ins. 3anc/t i, ##. >9977;1 Article ` Vie, 'ecor) in 3co#us ` &i%e) By in
3co#us (28+
&laus, *.B., 'isch, /.D. an) hom#son, E..., 1991. "ene%ic analysis o$ breas% cancer in %he &ancer
an) 3%eroi) 6ormone 3%u)y. A-1 %1 5u-1 @/n/t1 -2, ##. 2227282 Vie, 'ecor) in 3co#us ` &i%e) By in
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&ohen, D.D., 1991. Programme) cell )ea%h in %he immune sys%em. A01 =--unol1 .?, ##. 55785 Abs%rac%
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189
&ohn, ..6., 3%arman, B.D., Blumberg, B. /t al1, 199;. 'ecurrence o$ le%hal os%eogenesis im#er$ec%a )ue
%o #aren%al mosaicism $or a )ominan% mu%a%ion in a human %y#e I collagen gene (&C11A1+. A-1 %1
5u-1 @/n/t1 -1, ##. 5917>;1 Vie, 'ecor) in 3co#us ` &i%e) By in 3co#us (59+
&ole, D., Arle%%, &.:. an) "reen, M.6.1., 1988. &om#ara%ive human cellular ra)iosensi%ivi%y@ II. he
survival $ollo,ing gamma-irra)ia%ion o$ -lym#hocy%es, -lym#hocy%e lines, lym#hoblas%oi) cell lines
an) $ibroblas%s $rom normal, a%a4ia-%elangiec%asia #a%ien%s an) he%ero<ygo%es. =nt1 %1 Raiat1 Biol1 .-,
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&ollins, A.'., 1992. Mu%an% ro)en% cell lines sensi%ive %o ul%raviole% ligh%, ionising ra)ia%ion an) cross-
lin!ing agen%s@ a com#rehensive survey o$ gene%ic an) biochemical charac%eris%ics. *utation R/s1 "9,,
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&ollins, :.3., 199>. B'&A1Plo%s o$ mu%a%ions, lo%s o$ )ilemmas. :1 6n?1 %1 */1 ,,-, ##. 18>7188
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&W%X, ".B. an) "y$%o)imou, D., 1991. ,inning an) mi%o%ic crossing-over@ some #ossibili%ies an) %heir
im#lica%ions. A-1 %1 5u-1 @/n/t1 -9, ##. 12;712; Vie, 'ecor) in 3co#us ` &i%e) By in 3co#us (18+
&oun%ryman, P.I., 6e))le, D.A. an) &ra,$or), *., 1977. he re#air o$ O-ray in)uce) chromosomal
)amage in %risomy 21- an) normal )i#loi) lym#hocy%es. Canc/r R/s1 ,7, ##. 52758 Vie, 'ecor) in
3co#us ` &i%e) By in 3co#us (8+
&o4, '., .ebenham, P.*., Masson, E.F. an) Eebb, M., 198>. A%a4ia %elangiec%asia@ a human mu%a%ion
giving high $re9uency misre#air o$ ./A )ouble s%ran) scissions. *ol1 Biol1 */1 ,, ##. 2197228
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&u%ler, .P., 6ol)en, &.A. an) Mac.onal), ..M., 19>8. Mul%i#le naevoi) basal cell carcinoma
syn)rome ("orlins syn)rome+. Clin1 6xp1 #/r-atol1 -, ##. 2727279 6ull &e0t via &ross'e$ ` Vie,
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)ys%ro#hy (.M.+0Bec!er muscular )ys%ro#hy (BM.+ $amilies s%u)ie) ,i%h %he )ysmor#hin c./A@
1oca%ion o$ brea!#oin%s on 6in)III an) BglII e4on-con%aining $ragmen% ma#s, meio%ic an) mi%o%ic
origin o$ %he mu%a%ions. A-1 %1 5u-1 @/n/t1 -,, ##. >2;7>29 Vie, 'ecor) in 3co#us ` &i%e) By in
3co#us (82+
137
)e Vries, *. an) van .riel, E., 1989. 6e1a nuclear #ro%ein recogni<ing ./A %ermini an) %ransloca%ing
on ./A $orming a regular ./A-mul%imeric #ro%ein com#le4. %1 *ol1 Biol1 "?2, ##. >5772
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)ys!era%osis congeni%a $ibroblas%s. A-1 %1 5u-1 @/n/t1 -1, ##. 25;7257 Vie, 'ecor) in 3co#us ` &i%e)
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.er!in)eren, ..D., Fo%en, D.E., /agel!er!e, /.D... /t al1, 1988. /on-ocular cancer in #a%ien%s ,i%h
here)i%ary re%inoblas%oma an) %heir rela%ives. =nt1 %1 Canc/r -1, ##. 89975;8 6ull &e0t via &ross'e$ `
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misma%ch re#air )e$iciency, me%hyla%ion %olerance, hy#er-recombina%ion an) #re)is#osi%ion %o cancer.
C/ll 2", ##. 221722; Article ` Vie, 'ecor) in 3co#us ` &i%e) By in 3co#us (528+
.ie%rich, E.:., 1an)er, *.3., 3mi%h, 1992. "ene%ic i)en%i$ica%ion o$ Mom-1, a ma-or mo)i$ier locus
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3co#us ` &i%e) By in 3co#us (822+
.ohner, 6., Pohl, 3., .ulgay-Mosschel, M. /t al1, 1992. risomy 12 in chronic lym#hoi) leu!aemiasP
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6n?1 %1 */1 ,,-, ##. 7927798 6ull &e0t via &ross'e$ ` Vie, 'ecor) in 3co#us ` &i%e) By in 3co#us
(22+
.oneho,er, 1.A., 6arvey, M., 3lagle, B.1. /t al1, 1992. Mice )e$icien% $or #52 are )evelo#men%ally
normal bu% susce#%ible %o s#on%aneous %umours. :atur/ ,.1, ##. 2157221 6ull &e0t via &ross'e$ `
Vie, 'ecor) in 3co#us ` &i%e) By in 3co#us (2288+
.ry-a, .P., Mu!ai, 3., Pe%ersen, '. /t al1, 1989. Paren%al origin o$ mu%a%ions in %he re%inoblas%oma gene.
:atur/ ,,9, ##. 55>7558 6ull &e0t via &ross'e$ ` Vie, 'ecor) in 3co#us ` &i%e) By in 3co#us (>1+
.uan, ..'., Pause, A., Burgess, E.6. /t al1, 1995. Inhibi%ion o$ %ranscri#%ion elonga%ion by %he V61
%umour su##ressor #ro%ein. +ci/nc/ "19, ##. 18;2718;> Vie, 'ecor) in 3co#us ` &i%e) By in 3co#us
(288+
.unning, A.M., &hiano, M., 3mi%h, /.'. /t al1, 1997. &ommon B'&A1 varian%s an) susce#%ibili%y %o
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&ross'e$ ` Vie, 'ecor) in 3co#us ` &i%e) By in 3co#us (71+
.uc!,or%h-'ysiec!i, ". an) aylor, A.M., 1985. *$$ec%s o$ ionising ra)ia%ion on cells $rom :anconiIs
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*as%on, ..:., :or), .., Bisho#, ... an) Breas% 8 1in!age &onsor%ium, 1995. Breas% an) ovarian cancer
inci)ence in B'&A1 mu%a%ion carriers. A-1 %1 5u-1 @/n/t1 .1, ##. 2>57271 Vie, 'ecor) in 3co#us `
&i%e) By in 3co#us (92>+
*as%on, ..:. an) Pe%o, D., 199;. he con%ribu%ion o$ inheri%e) #re)is#osi%ion %o cancer inci)ence.
Canc/r +ur0/.s 9, ##. 295781> Vie, 'ecor) in 3co#us ` &i%e) By in 3co#us (>8+
*as%on, ..:., Bisho#, ..., :or), .. /t al1, 1992. "ene%ic lin!age analysis in $amilial breas% an) ovarian
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138
*),ar)s, M.D., Eens%ru#, '.D., Byers, P.6. /t al1, 1992. 'ecurrence o$ le%hal os%eogenesis im#er$ec%a
)ue %o #aren%al mosaicism $or a mu%a%ion in %he &C11A2 gene o$ %y#e I collagen. he mosaic #aren%
e4hibi%s #heno%y#ic $ea%ure o$ mil) $orm o$ %he )isease. 5u-1 *utation 1, ##. 87758 6ull &e0t via
&ross'e$ ` Vie, 'ecor) in 3co#us ` &i%e) By in 3co#us (25+
*),ar)s, D.6., 19>9. :amilial #re)is#osi%ion in man. Br1 */1 Bull1 "., ##. 587>8 Vie, 'ecor) in
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*eles ', Pon)er B, *as%on ., 6or,ich A (*)s+ 199>. "ene%ic Pre)is#osi%ion %o &ancer. &ha#man an)
6all, 1on)on
*!er, '. an) Mossige, D.A., 19>1. A )ominan% gene $or renal a)enomas in %he ra%s. :atur/ 129, ##.
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*ng, &. an) Pon)er, B.A.D., 1992. he role o$ gene mu%a%ions in %he genesis o$ $amilial cancers. 9A+6B
%1 7, ##. 91;7919 Vie, 'ecor) in 3co#us ` &i%e) By in 3co#us (2;+
*ng, &., 1i, :.P., Abramson, ..6. /t al1, 1992. Mor%ali%y $rom secon) %umors among long-%erm
survivors o$ re%inoblas%oma. %1 :atl1 Canc/r =nst1 2., ##. 112171128 6ull &e0t via &ross'e$ ` Vie,
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*#s%ein, &.D., 198>. he &onse9uences o$ &hromosome Imbalance. Princi#les, Mechanisms an)
Mo)els. &ambri)ge Aniversi%y Press, &ambri)ge
*#s%ein, *.6., 199>. he gene%ics o$ human s!in )isease. Curr1 8p1 @/n/t1 #/0/l1 1, ##. 29572;;
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:earon, *.'. an) Vogels%ein, B., 199;. A gene%ic mo)el $or colorec%al %umorigenesis. C/ll 11, ##. 7597
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#a%ien%s ,i%h basal cell naevus syn)rome. A-1 %1 5u-1 @/n/t1 ,., ##. 587>> Vie, 'ecor) in 3co#us `
&i%e) By in 3co#us (17+
:einberg, A.P., 1992. "enomic im#rin%ing an) gene ac%iva%ion in cancer. :atur/ @/n/t1 -, ##. 11;7112
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:el)man, D."., 1ee, 3.1. an) 3eligman, B., 197>. Cccurrence o$ acu%e leu!aemia in $emales in a
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3co#us ` &i%e) By in 3co#us (2+
:i-neman, '.D.A., )eVries, 3.3., Dansen, '.&. /t al1, 199>. &om#le4 in%erac%ions o$ ne, 9uan%i%a%ive
%rai% loci 3luc1, 3luc2, 3luc2 an) 3luc8 %ha% in$luence %he susce#%ibili%y %o lung cancer in %he mouse.
:atur/ @/n/t1 1-, ##. 8>578>7 6ull &e0t via &ross'e$ ` Vie, 'ecor) in 3co#us ` &i%e) By in 3co#us
(17;+
:ili#ovich, A.6., Ma%hur, A., Fama%, .. e% al., 1998. 1ym#ho#roli$era%ive )isor)ers an) o%her %umour
com#lica%ing immuno)e$iciencies. Immuno)e$iciency 'evie,s, in #ress
:ili#ovich, A.6., Ma%hur, A., Fama%, .. an) 3ha#iro, '.3., 1992. Primary immuno)e$iciencies@ gene%ic
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139
:ishel, '., 1escoe, M.F., 'ao, M.'.3. /t al1, 1992. he human mu%a%or gene homolog M362 an) i%s
associa%ion ,i%h here)i%ary non#oly#osis colon cancer. C/ll 7., ##. 1;2771;28 Article ` Vie, 'ecor)
in 3co#us ` &i%e) By in 3co#us (159>+
:ishel, '. an) Folo)ner, '..., 1995. he i)en%i$ica%ion o$ misma%ch re#air genes an) %heir role in %he
)evelo#men% o$ cancer. Curr1 8p1 @/n/t1 #/0/l1 ., ##. 2827295 Abs%rac% ` Vie, 'ecor) in 3co#us `
&i%e) By in 3co#us (2;9+
:i%<geral), M."., Bean, D.M., 6e)ge, 3.'. /t al1, 1997. 6e%ero<ygous AM mu%a%ions )o no% con%ribu%e
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