Lp|genencs |n cancer

Def: WaddlngLon refers as Lhe causa| genotyp|c mechan|sms LhaL produce phenoLyplc eecLs ln Lhe nexL generauon aer mlLosls or
melosls (Palg, 2004). CurrenLly, eplgeneucs ls vlewed as all Lhe mechanlsms LhaL herlLably lnuence gene expresslon wlLhouL any
alLerauon ln Lhe unA sequence,Lhey can be modled by envlronmenLal sumull.
Cancer ls a consequence of unchecked prollferauon and aberranL cell deaLh , caused by lnacuvauon of 1SC and acuvauon of
oncogene, Lhey can be achleved vla geneucally or eplgeneucally.
na||marks of cancer LLSIS1L
evadlng apopLosls
llmlLless repllcauve poLenual
self sumclency ln growLh slgnal
lnsensluvlLy Lo anugrowLh slgnal
susLalned anglogenesls
ussue lnvaslon and meLasLasls
emerglng hallmarks- deregulaung cellular energeucs,avoldlng lmmune desLrucuon
enabllng characLer- genome lnsLablllLy and muLauon,Lumor promoung lnammauon
Aberranon of eplgeneuc conLrol seen ln cancer -
Lumor suppressor unA hypermeLhylauon
genome wlde unA hypomeLhylauon
dysregulauon of oLher eplgeneuc marks/ modlcauon elLher over-expresslon or muLauon
nuclear archlLecLure - dlsorganlsauon nuclear slze,nuclear shape,loldy
C||n|ca| |mp||canon of aberranL eplgeneuc conLrol ln cancer -
undersLandlng Lhe mechanlsm of eplgeneuc ln cancer gave Lherapeuuc opporLunlLy, lnvenuon and dlscovery of key paLhway
lnhlblLors responslble for Lumorlgenesls.
rognos|s -Speclc alLerauons assoclaLed wlLh ouLcome
e.g. ml8-34b/c hypermeLhylauon assoclaLed wlLh meLasLasls
D|agnosnc - eplgeneuc alLerauon as blomarkers
Lplgeneucs blomarker can be used as slngle or global prole.
ulsungulsh cancer from normal cells ln Lhe same blood sample uslng cells or Lumour unA(cell-free unA)
e.g. Lumour vs benlgn skln, Lumour vs normal prosLaLe
ldenufy a speclc feaLure of Lhe cancer deLecuon, e.g CS1 hypermeLhylauon (prosLaLe cancer)
1herapeunc lnform LreaLmenL , precllnlcal candldaLe & 1herapeuuc predlcuon
e.g. MCM1 hypermeLhylauon (glloma) suggesLs pauenLs won'L respond Lo chemoLherapeuuc agenL Lemozolomlde,
as MCM1 ls requlred Lo process Lemozolomlde (alkylaLed agenL) lnLo acuve form
urugs - unA meLhylLransferase lnhlblLor
- PuACl
Lp|genenc mod|hcanon lnCLuuL
DNA methy|anon
1ype -3'meLhylcyLoslne, 3'hydroxymeLhylcyLoslne on CpC dlnucleoude
symmeLrlcal,lL may be malnLalned Lhrough cell dlvlslon.
Lnzyme malnLalned by unA meLhylLransferase 1
Lect 8ole of DNA methy|anon ls conLexL dependenL, lL usually cause gene sllenclng, on rare occaslon lL causes acuvauon
ueleuon of unmL1 can enhance or suppress Lumorlgenesls
ulerenL Lumours have dlerenL dependencles:
1. urlven by Lumour suppressor hypermeLhylauon, Lhen
depleuon of unA meLhylauon appears Lo suppress Lumorlgenesls
2. urlven by chromosomal lnsLablllLy, Lhen depleuon of unA meLhylauon appears Lo enhance Lumorlgenesls
LecL of unA meLhylauon depleuon can be sLage speclc l.e. early vs laLe ln Lumorlgenesls
1umor suppressor gene hypermethy|anon
DNA methy|anon sllence 1SC ln cancer,and hypermeLhylaLed gene varles by Lumor Lype.
CpC lsland hypermeLhylauon - ClM (meLhylaLor phenoLype)
-
AssoclaLed wlLh cllnlcally dlsuncL Lumours
Epigenetic abnormalities, diagnosis and prognosis
-
1hey are frequenLly found ln herlLable cancer.
L.g - 88 gene ln reunoblasLoma
88CA ln breasL cancer
MCM1 ln glloma and colorecLal Lumors
CA1A4,3 ln gasLrlc cancer and oesophageal cancer
LplmuLauon more frequenL Lhan geneuc changes (eg. glloma and colon cancer)ln some cases,lL ls an early evenL ln Lumorlgenesls
(colon, gasLrlc and llver cancer)
ulagnosls: ldenucauon of Lumour Lype e.g. ClM
rognosls: PypermeLhylauon lncreases wlLh LumorlgenlclLy. ClM favourable prognosls
Plgh meLhylauon poor prognosls ln MuS, lung cancer
Genome w|de hypomethy|anon
S|te -Cccur at repeat,CpG promoters,|ntrons,gene desert (kCID)
CpC lsland shores of Lumour suppressor genes - lC8s-loss of lmprlnung
Mechan|sms
A. ConLrlbuLe Lumorlgenesls by lncreased genomlc lnsLablllLy by chromosome rearrangemenL and moblllsauon of reLroLransposons
L.g. MuLauon ln unM13b cause chromosomal lnsLablllLy
8. Acuvaung resLrlcLed no of L/s speclc genes,lmprlnLed genes and ml8nA
L.g. k8as acuvauon ln gasLrlc cancer
lCl2 -loss of meLhylauon ln Wllm's Lumor
osurans|anona| h|stone mod|hcanon
1ype hlsLone meLhylauon by lyslne and arglnlne meLhylLransferase enzymes
hlsLone aceLylauon by PA1 and PuAC
ublqulunauon by L1 ,L2 and L3
phosphorylauon by klnase and phosphorylase
SlLe 1he modlcauon usually Lake place on Lhe n-Lermlnal reglons and surface areas of core hlsLone.
P3k7 me2/3 Acuve gene P3k4me2/3 lnacuve gene 4 9 27
PlsLone aceLylauon P3k9 me2/3
P3k27 me2/3
unA meLhylauon

LecL Modled hlsLone Lall acL as a docklng slLes for oLher chromaun proLeln.
8eslde Lhe enzymes LhaL lnvolved ln hlsLone modlcauons , nucleosome and chromosome remodelllng proLeln paruclpaLe ln
eplgeneucs conLrol.
1hey aecL by lnuenclng nucleosome sLablllLy, sumulaLe or lnhlblL 1l blndlng or recrulLmenL for gene expresslon.
In cancer
1umor suppressor gene show loss of acuve marks P3k4 aceLylauon,P3k7 me3, galn of lnacuve marks P3k4 me3, P3k27 me3 .
PlsLone modlcauon collaboraLe wlLh unA meLhylauon changes. cause long range sllenclng ln cancer cells.
Mutanons |n h|stones and h|stone var|ants
MuLauons ln P3.1 (canonlcal P3) and hlsLone varlanL P3.3 very recenLly ldenued ln chlldhood hlgh grade glloma (noL adulL, noL low
grade)
unM1 lnhlblLor - lrreverslbly blnd unM1s, aer Lhey lncorporaLe lnLo unA.
anuneoplasuc eecL on low dose, LoxlclLy on hlgh dose
PuAC lnhlblLor - eecuve agalnsL lymphold mallgnancy, buL non selecuve Largeung.
1argeung on roLeln-roLelns lnLeracuon domalns :non-enzymauc eplgeneuc regulaLors (chromaun readers)
Noncod||ng kNA
long noncodlng 8nA - mosL common LranscrlpL ln cell, >200nL, acL ln cls /Lrans manner
ml8nA - 22nL 8nA blnd wlLh 3' u18 of m8nA, form 8lSC formauon, lnhlblL Lranslauon
sl8nA - 20-24 nL long and vla 8lSC/8l1S formauon cause gene sllenclng
pl8nA expresslon ls deregulaLed ln cancer
m|kNA dysregu|anon
lrequenLly mls-expressed ln cancer,oen sllenced buL s/L acuvaLed.
8ole ln cancer depend on LargeLs e.g
ml13,16 LargeL pro survlval proLeln 8CL-2 are sllenced ln CLL.
LeL 7 LargeL 8AS, sllenced ln lung Ca
ml821 LargeL 1Ln, up-regulaLed ln glloblasLoma
Lnzymes lnvolved ln ml8nA and sl8nA processlng paLhway such as u8CSPA and ulCL8 are dysregulaLed ln some cancer.
LnckNA |n cancer
PC1Al8 acL ln Lrans manner, blnd wlLh 8C2 & LSu2 (demeLhylase) over expressed ln breasL cancer.
rognosucs :PC1Al8 also poor prognosuc lndlcaLor ln esophageal cancer, also upregulaLed ln colon and llver cancer.
ulagnosucs :CA3 ln prosLaLe cancer, urlne LesL
1herapeuucs : long noncodlng 8nAs can be knocked down ln vlvo for Lherapy















Def:
Aberranon of eplgeneuc conLrol
Chromann state
Lp|genenc mod|hcanon - DNA methy|anon
osurans|anona| h|stone mod|hcanon
Noncod||ng kNA
Cancer
1umor suppressor gene hypermethy|anon -s|te,e.g.
Genome w|de hypomethy|anon -s|te,mechan|sms
n|stone mod|hcanon error
m|kNA dysregu|anon
LnckNA |n cancer
Myelodysplastic
syndrome
progressed to AML
Cutaneous T cell
lymphoma