Genetics of Colorectal Cancer (PDQ®) - Health Professional Version - National Cancer Institute

3/11/2016 GeneticsofColorectalCancer(PDQ)HealthProfessionalVersionNationalCancerInstitute
Genetics of Colorectal Cancer (PDQ)Health Professional Version

Executive Summary
ThisexecutivesummaryreviewsthetopicscoveredinthePDQsummaryonthegeneticsofcolorectalcancer(CRC),withhyperlinks
todetailedsectionsbelowthatdescribetheevidenceoneachtopic.
InheritanceandRisk
FactorssuggestiveofageneticcontributiontoCRCincludethefollowing:1)astrongfamilyhistoryofCRCand/orpolyps;2)
multipleprimarycancersinapatientwithCRC;3)theexistenceofothercancerswithinthekindredconsistentwithknown
syndromescausinganinheritedriskofCRC,suchasendometrialcancer;and4)earlyageatdiagnosisofCRC.HereditaryCRC
ismostcommonlyinheritedinanautosomaldominantpattern,althoughtwosyndromesareinheritedinanautosomal
recessivepattern(MYH-associatedpolyposisandNTHL1).Additionalfactorscoupledwithfamilyhistory,suchasdiet,useof
nonsteroidalanti-inflammatorydrugs,cigarettesmoking,alcoholconsumption,colonoscopywithremovalofadenomatous
polyps,andphysicalactivity,mayinfluencethedevelopmentofadenomatouspolypsandCRCrisk.
Atleastthreevalidatedcomputermodelsareavailabletoestimatetheprobabilitythatanindividualaffectedwithcancer
carriesapathogenicvariantinamismatchrepair(MMR)geneassociatedwithLynchsyndrome(LS),themostcommon
inheritedCRCsyndrome.TheseincludetheMMRPro,MMRPredict,andPREMM1,2,6predictionmodels.Individualswitha
quantifiedriskof5%orgreateronanyofthesemodelsareoftenreferredforgeneticevaluationandtesting.
AssociatedGenesandSyndromes
HereditaryCRChastwowell-describedforms:1)polyposis(includingfamilialadenomatouspolyposis[FAP]andattenuated
FAP(AFAP),whicharecausedbypathogenicvariantsintheAPCgene;andMYH-associatedpolyposis,whichiscausedby
pathogenicvariantsintheMYHgene);and2)LS(oftenreferredtoashereditarynonpolyposiscolorectalcancer[HNPCC]),
whichiscausedbygermlinepathogenicvariantsinDNAMMRgenes(MLH1,MSH2,MSH6,andPMS2)andEPCAM.OtherCRC
syndromesandtheirassociatedgenesincludeoligopolyposis(POLE,POLD1),NTHL1,juvenilepolyposissyndrome(BMPR1A,
SMAD4),Cowdensyndrome(PTEN),andPeutz-Jegherssyndrome(STK11).Manyofthesesyndromesarealsoassociatedwith
extracoloniccancersandothermanifestations.Serratedpolyposissyndrome,whichischaracterizedbytheappearanceof
hyperplasticpolyps,appearstohaveafamilialcomponent,butthegeneticbasisremainsunknown.Thenaturalhistoryof
someofthesesyndromesisstillbeingdescribed.ManyotherfamiliesexhibitaggregationofCRCand/oradenomas,butwith
noapparentassociationwithanidentifiablehereditarysyndrome,andareknowncollectivelyasfamilialCRC.
Genome-widesearchesareshowingpromiseinidentifyingcommon,low-penetrancesusceptibilityallelesformanycomplex
diseases,includingcolorectalcancers,buttheclinicalutilityofthesefindingsremainsuncertain.
ClinicalManagement
ItisbecomingthestandardofcareatmanycentersthatallindividualsnewlydiagnosedwithCRCandofaparticularageare
evaluatedforLSthroughmoleculardiagnostictumortestingassessingMMRdeficiency.Auniversalscreeningapproachto
tumortestingissupported,inwhichallCRCcasesareevaluatedregardlessofageatdiagnosisorfulfillmentofexistingclinical
criteriaforLS.Amorecost-effectiveapproachhasbeenreportedwherebyallpatientsaged70yearsoryoungerwithCRCand
olderpatientswhomeettherevisedBethesdaguidelinesaretestedforLS.Tumorevaluationoftenbeginswith
immunohistochemistrytestingfortheexpressionoftheMMRproteinsassociatedwithLSormicrosatelliteinstability(MSI)
testing,BRAFtesting,andMLH1hypermethylationanalyses.
ColonoscopyforCRCscreeningandsurveillanceiscommonlyperformedinindividualswithhereditaryCRCsyndromesand
hasbeenassociatedwithimprovedsurvivaloutcomes.Forexample,surveillanceofLSpatientswithcolonoscopyevery1to2
years,andinonestudyupto3years,hasbeenshowntoreduceCRCincidenceandmortality.Extracolonicsurveillanceisalso
https://www.cancer.gov/types/colorectal/hp/colorectalgeneticspdq#section/all 1/121
amainstayforsomehereditaryCRCsyndromesdependingontheothercancersassociatedwiththesyndrome.Forexample,
regularendoscopicsurveillanceoftheduodenuminFAPpatientshasbeenshowntoimprovesurvival.
Prophylacticsurgery(colectomy)hasalsobeenshowntoimprovesurvivalinpatientswithFAP.Thetimingandextentofrisk-
reducingsurgeryusuallydependsonthenumberofpolyps,theirsize,histology,andsymptomatology.ForpatientswithLS
andadiagnosisofCRC,extendedresectionisassociatedwithfewermetachronousCRCsandadditionalsurgicalprocedures
forcolorectalneoplasiathaninpatientswhoundergosegmentalresectionforCRC.Nosurvivaladvantagehasbeen
demonstratedbyundergoingamoreextendedresectionversusasegmentalresectioninLSpatientswithCRC.Thesurgical
decisionmusttakeintoaccounttheageofthepatient,comorbidities,clinicalstageofthetumor,sphincterfunction,andthe
patientswishes.InFAP,genderandfamilyhistoryofdesmoidsmustalsobeconsidered.
ChemopreventiveagentshavealsobeenstudiedinthemanagementofFAPandLS.InFAPpatients,celecoxibandsulindac
havebeenassociatedwithadecreaseinpolypsizeandnumber.Adouble-blind,randomized,controlledtrialevaluatingthe
efficacyofsulindacplusanepidermalgrowthfactorreceptorinhibitor,erlotinib,versusplaceboinFAPorAFAPpatientswith
duodenalpolypssuggestedthaterlotinibhasthepotentialtoinhibitduodenalpolypsinFAPpatients.Anongoingtrialwill
determinewhetherlowerdosesoferlotinibalonewillsignificantlyreduceduodenalpolypburden.Aspirinuse(600mgdaily)
wasshowntohaveapreventiveeffectoncancerincidenceinLSpatientsinalargerandomizedtrial;lowerdosesarebeing
examinedinanongoingstudy.
Noveltherapiesthatstimulatetheimmunesystemhavebeenevaluatedinmismatchrepairdeficienttumors,includingthose
relatedtoLS.Thedenseimmuneinfiltrationandcytokine-richenvironmentinmismatchrepairdeficienttumorsmayimprove
clinicaloutcomes.AcriticalpathwayresponsibleformediatingtumorinducedimmunesuppressionisthePD-1mediated
checkpointpathway.ArecentphaseIIstudyusedpembrolizumab,ananti-PD-1immunecheckpointinhibitor,inindividuals
withprogressivemetastaticCRCwithandwithoutMMRdeficiency.Therewasafavorableresponsewithrespectto
progression-freesurvivalandresponseratesinMSItumorsbutnotinmicrosatellitestabletumors.
PsychosocialandBehavioralIssues
Psychosocialfactorsinfluencedecisionsaboutgenetictestingforinheritedcancerriskandrisk-managementstrategies.
Uptakeofgeneticcounselingandgenetictestingvarieswidelyacrossstudies.Factorsthathavebeenassociatedwithgenetic
counselingandtestinguptakeinLSfamiliesincludehavingchildren,thenumberofaffectedrelatives,perceivedriskof
developingCRC,andfrequencyofthoughtsaboutCRC.Psychologicalstudieshaveshownlowlevelsofdistress,particularlyin
thelongterm,aftergenetictestingforLSinbothcarriersandnoncarriers.However,otherstudieshavedemonstratedthe
possibilityofincreaseddistressfollowinggenetictestingforFAP.Colonandgynecologiccancerscreeningrateshavebeen
showntoincreaseorbemaintainedamongcarriersofMMRpathogenicvariantswithintheyearafterdisclosureofresults,
whilescreeningratesdecreaseamongnoncarriers.Thelatterisexpectedasthescreeningrecommendationsforunaffected
individualsarethosethatapplytothegeneralpopulation.Studiesmeasuringquality-of-lifevariablesinFAPpatientsshow
normal-rangeresults;however,thesestudiessuggestthatrisk-reducingsurgeryforFAPmayhavenegativequality-of-life
effectsforatleastsomeproportionofthoseaffected.Patients'communicationwiththeirfamilymembersaboutaninherited
riskofCRCiscomplex;gender,age,andthedegreeofrelatednessaresomeelementsthataffectdisclosureofthis
information.Researchisongoingtobetterunderstandandaddresspsychosocialandbehavioralissuesinhigh-riskfamilies.
Introduction
[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked
term is clicked, the definition will appear in a separate window.]
[Note: Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM
appears after a gene name or the name of a condition, click on OMIM for a link to more information.]
[Note: A concerted effort is being made within the genetics community to shift terminology used to describe genetic variation. The shift is
to use the term variant rather than the term mutation to describe a genetic difference that exists between the person or group being
studied and the reference sequence. Variants can then be further classified as benign (harmless), likely benign, of uncertain significance,
likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term pathogenic variant to describe a
disease-causing mutation. Refer to the Cancer Genetics Overview summary for more information about variant classification.]
Colorectalcancer(CRC)isthethirdmostcommonlydiagnosedcancerinbothmenandwomen.
EstimatednewcasesanddeathsfromCRCin2016:[1]
Newcases:134,490.
Deaths:49,190.
About75%ofpatientswithCRChavesporadicdiseasewithnoapparentevidenceofhavinginheritedthedisorder.Theremaining
25%ofpatientshaveafamilyhistoryofCRCthatsuggestsahereditarycontribution,commonexposuresamongfamilymembers,
oracombinationofboth.Geneticpathogenicvariantshavebeenidentifiedasthecauseofinheritedcancerriskinsomecolon
cancerpronefamilies;thesepathogenicvariantsareestimatedtoaccountforonly5%to6%ofCRCcasesoverall.Itislikelythat
otherundiscoveredgenesandbackgroundgeneticfactorscontributetothedevelopmentoffamilialCRCinconjunctionwith
nongeneticriskfactors.
(RefertothePDQsummariesonColorectalCancerScreening;ColorectalCancerPrevention;ColonCancerTreatment;andRectal
CancerTreatmentformoreinformationaboutsporadicCRC.)
Natural History of CRC

Colorectaltumorspresentwithabroadspectrumofneoplasms,rangingfrombenigngrowthstoinvasivecancerandare
predominantlyepithelial-derivedtumors(i.e.,adenomasoradenocarcinomas).
Pathologistshaveclassifiedthelesionsintothefollowingthreegroups:
1.Nonneoplasticpolyps(hyperplastic,juvenile,hamartomatous,inflammatory,andlymphoidpolyps),whichhavenot
generallybeenthoughtofasprecursorsofcancer.
2.Neoplasticpolyps(adenomatouspolypsandadenomas).
3.Cancers.
Research,however,doessuggestasubstantialriskofcoloncancerinindividualswithjuvenilepolyposissyndromeandPeutz-
Jegherssyndrome,althoughthenonadenomatouspolypsassociatedwiththesesyndromeshavehistoricallybeenviewedas
nonneoplastic.[2-4]
Epidemiologicstudieshaveshownthatapersonalhistoryofcolonadenomasplacesoneatanincreasedriskofdevelopingcolon
cancer.[5]
Twocomplementaryinterpretationsofthisobservationareasfollows:
1.Theadenomamayreflectaninnateoracquiredtendencyofthecolontoformtumors.
2.Adenomasaretheprimaryprecursorlesionofcoloncancer.
Morethan95%ofCRCsarecarcinomas,andabout95%oftheseareadenocarcinomas.Itiswellrecognizedthatadenomatous
polypsarebenigntumorsthatmayundergomalignanttransformation.Theyhavebeenclassifiedintothreehistologictypes,with
increasingmalignantpotential:tubular,tubulovillous,andvillous.WhilethereisnodirectproofthatmostCRCsarisefrom
adenomas,adenocarcinomasaregenerallyconsideredtoarisefromadenomas,[6-10]baseduponthefollowingimportant
observations:
1.Benignandmalignanttissueoccurwithincolorectaltumors.[11]
2.Whenpatientswithadenomaswerefollowedfor20years,theriskofcanceratthesiteoftheadenomawas25%,arate
muchhigherthanthatexpectedinthenormalpopulation.[12]
Thefollowingthreecharacteristicsofadenomasarehighlycorrelatedwiththepotentialtotransformintocancer:[11]
1.Largersize.
2.Villouspathology.
3.Thedegreeofdysplasiawithintheadenoma.
Inaddition,removalofadenomatouspolypsisassociatedwithreducedCRCincidence.[13,14]Whilemostadenomasarepolypoid,
flatanddepressedlesionsmaybemoreprevalentthanpreviouslyrecognized.Large,flat,anddepressedlesionsmaybemore
likelytobeseverelydysplastic,althoughthisremainstobeclearlyproven.[15,16]Specializedtechniquesmaybeneededtoidentify,
biopsy,andremovesuchlesions.[17]
Molecular Events Associated With Colon Carcinogenesis

Thetransitionfromnormalepitheliumtoadenomatocarcinomaisassociatedwithacquiredmolecularevents.[18-20]Thistumor
progressionmodelwasdeducedfromcomparisonofgeneticalterationsseeninnormalcolonepithelium,adenomasof
progressivelylargersize,andmalignancies.[21,22]Atleastfivetosevenmajordeleteriousmolecularalterationsmayoccurwhena
normalepithelialcellprogressesinaclonalfashiontocarcinoma.Thereareatleasttwomajorpathwaysbywhichthesemolecular
eventscanleadtoCRC.WhilethemajorityofCRCsareduetoeventsthatresultinchromosomalinstability(CIN),20%to30%of
CRCsdisplaycharacteristicpatternsofgenehypermethylation,termedCpGislandmethylatorphenotype(CIMP),ofwhicha
portiondisplaymicrosatelliteinstability(15%ofCRCs).[20,23-27]
ThespectrumofsomaticvariantscontributingtothepathogenesisofCRCislikelytobefarmoreextensivethanpreviously
appreciated.Acomprehensivestudythatsequencedmorethan13,000genesinaseriesofCRCsfoundthattumorsaccumulatean
averageofapproximately90geneticvariants.Sixty-ninegeneswerehighlightedasrelevanttothepathogenesisofCRC,and
individualCRCsharboredanaverageofninegeneticvariantspertumor.Inaddition,eachtumorstudiedhadadistinctgenetic
signature.[28]
KeychangesinCINcancersincludewidespreadalterationsinchromosomenumber(aneuploidyandrearrangements),frequent
detectablelossesatthemolecularlevelofportionsofchromosome5q,chromosome18q,andchromosome17p,andvariantsof
theKRASoncogene.TheimportantgenesinvolvedinthesechromosomelossesareAPC(5q),DCC/MADH2/MADH4(18q),andTP53
(17p),[19,29]andchromosomelossesareassociatedwithinstabilityatthemolecularandchromosomallevel.[20]Amongthe
earliesteventsinthecolorectaltumorprogressionpathwayislossoftheAPCgene,whichappearstobeconsistentwithits
importantroleinpredisposingpersonswithgermlineAPCpathogenicvariantstocolorectaltumors.Acquiredorinheritedvariants
orhypermethylationofDNAdamage-repairgenesalsoplayaroleinpredisposingcolorectalepithelialcellstogeneticchanges.
Furthermore,thespecificgenesthatundergosomaticchangesandthespecifictypeofvariantsthetumoracquiresmayinfluence
therateoftumorgrowthortypeofpathologicchangeinthetumors.[29]Forexample,therateofadenoma-to-carcinoma
progressionappearstobefasterinmicrosatellite-unstabletumorscomparedwithmicrosatellite-stabletumors.Characteristic
histologicchangessuchasmedullarygrowthpatternorincreasedmucinproductioncanbeseeninmanytumorsthatdemonstrate
microsatelliteinstability(MSI),suggestingthatatleastsomemoleculareventscontributetothehistologicfeaturesofthetumors.
ThekeycharacteristicsofMSIcancersarethattheyaretumorswithalargelyintactchromosomecomplementandthat,asaresult
ofdefectsintheDNAmismatchrepair(MMR)system,theymorereadilyacquirevariantsinimportantcancer-associatedgenes
comparedwithcellsthathaveaproficientDNAMMRsystem.Thesetypesofcancersaredetectableatthemolecularlevelby
alterationsinrepeatingunitsofDNAthatoccurnormallythroughoutthegenome,knownasDNAmicrosatellites.
TheknowledgederivedfromthestudyofinheritedCRCsyndromeshasprovidedimportantcluesregardingthemolecularevents
thatmediatetumorinitiationandtumorprogressioninpeoplewithoutgermlineabnormalities.Amongtheearliesteventsinthe
colorectaltumorprogressionpathway(bothMSIandCIN)islossoffunctionoftheAPCgeneproduct,whichappearstobe
consistentwithitsimportantroleinpredisposingpersonswithgermlineAPCpathogenicvariantstocolorectaltumors.
Family History as a Risk Factor for CRC

SomeoftheearlieststudiesoffamilyhistoryofCRCwerethoseofUtahfamiliesthatreportedahighernumberofdeathsfromCRC
(3.9%)amongthefirst-degreerelativesofpatientswhohaddiedfromCRCthanamongsex-matchedandage-matchedcontrols
(1.2%).[30]Thisdifferencehassincebeenreplicatedinnumerousstudiesthathaveconsistentlyfoundthatfirst-degreerelativesof
affectedcasesarethemselvesatatwofoldtothreefoldincreasedriskofCRC.Despitethevariousstudydesigns(case-control,
cohort),samplingframes,samplesizes,methodsofdataverification,analyticmethods,andcountrieswherethestudiesoriginated,
themagnitudeofriskisconsistent.[31-36]
Population-basedstudieshaveshownafamilialassociationforcloserelativesofcoloncancerpatientstodevelopCRCandother
cancers.[37]Usingdatafromacancerfamilyclinicpatientpopulation,therelativeandabsoluteriskofCRCfordifferentfamily
historycategorieswasestimated(seeTable1).[38,39]
Asystematicreviewandmeta-analysisoffamilialCRCriskwasreported.[39]Of24studiesincludedintheanalysis,allbutone
reportedanincreasedriskofCRCiftherewasanaffectedfirst-degreerelative.Therelativerisk(RR)forCRCinthepooledstudy
was2.25(95%confidenceinterval[CI],2.002.53)iftherewasanaffectedfirst-degreefamilymember.In8of11studies,ifthe
indexcanceraroseinthecolon,theriskwasslightlyhigherthanifitaroseintherectum.ThepooledanalysisrevealedaRRin
relativesofcolonandrectalcancerpatientsof2.42(95%CI,2.202.65)and1.89(95%CI,1.622.21),respectively.Theanalysisdid
notrevealadifferenceinRRforcoloncancerbasedonlocationofthetumor(rightsidevs.leftside).
ThenumberofaffectedfamilymembersandageatcancerdiagnosiscorrelatedwiththeCRCrisk.Instudiesreportingmorethan
onefirst-degreerelativewithCRC,theRRwas3.76(95%CI,2.565.51).ThehighestRRwasobservedwhentheindexcasewas
diagnosedinindividualsyoungerthan45years,forfamilymembersofindexcasesdiagnosedatages45to59years,andforfamily
membersofindexcasesdiagnosedatage60yearsorolder,respectively(RR,3.87;95%CI,2.406.22vs.RR,2.25;95%CI,1.852.72
vs.RR,1.82;95%CI,1.472.25).Inthismeta-analysis,thefamilialriskofCRCassociatedwithadenomainafirst-degreerelativewas
analyzed.ThepooledanalysisdemonstratedanRRforCRCof1.99(95%CI,1.552.55)inindividualswhohadafirst-degreerelative
withanadenoma.[39]Thisfindinghasbeencorroborated.[40]Otherstudieshavereportedthatageatdiagnosisoftheadenoma
influencestheCRCrisk,withyoungerageatadenomadiagnosisassociatedwithhigherRR.[41,42]Aswithanymeta-analysis,there
couldbepotentialbiasesthatmightaffecttheresultsoftheanalysis,includingincompleteandnonrandomascertainmentof
studiesincluded;publicationbias;andheterogeneitybetweenstudiesrelativetodesign,targetpopulations,andcontrolselection.
ThisstudyisreinforcementthattherearesignificantassociationsbetweenfamilialCRCrisk,ageatdiagnosisofbothCRCand
adenomas,andmultiplicityofaffectedfamilymembers.
Table 1. Estimated Relative and Absolute Risk of Developing Colorectal Cancer (CRC)
FamilyHistory RelativeRiskofCRC[39] AbsoluteRisk(%)ofCRCbyAge79ya
Nofamilyhistory 1 4a
Onefirst-degreerelativewithCRC 2.3(95%CI,2.02.5) 9b
b
Morethanonefirst-degreerelativewith 4.3(95%CI,3.06.1) 16
CRC
Oneaffectedfirst-degreerelative 3.9(95%CI,2.46.2) 15b

diagnosedwithCRCbeforeage45y
Onefirst-degreerelativewithcolorectal 2.0(95%CI,1.62.6) 8b
adenoma
CI=confidenceinterval.
a
DatafromtheSurveillance,Epidemiology,andEndResultsdatabase.
FamilyHistory RelativeRiskofCRC[39] AbsoluteRisk(%)ofCRCbyAge79y
b
TheabsoluterisksofCRCforindividualswithaffectedrelativeswascalculatedusingtherelativerisksforCRC[39]andtheabsoluteriskofCRC
byage79yearsa.
WhenthefamilyhistoryincludestwoormorerelativeswithCRC,thepossibilityofageneticsyndromeisincreasedsubstantially.
Thefirststepinthisevaluationisadetailedreviewofthefamilyhistorytodeterminethenumberofrelativesaffected,their
relationshiptoeachother,theageatwhichtheCRCwasdiagnosed,thepresenceofmultipleprimaryCRCs,andthepresenceof
anyothercancers(e.g.,endometrial)consistentwithaninheritedCRCsyndrome.(RefertotheMajorGeneticSyndromessectionof
thissummaryformoreinformation.)YoungsubjectswhoreportapositivefamilyhistoryofCRCaremorelikelytorepresenta
high-riskpedigreethanolderindividualswhoreportapositivefamilyhistory.[43]Computermodelsarenowavailabletoestimate
theprobabilityofdevelopingCRC.Thesemodelscanbehelpfulinprovidinggeneticcounselingtoindividualsataverageriskand
highriskofdevelopingcancer.Atleastthreevalidatedmodelsarealsoavailableforpredictingtheprobabilityofcarryinga
pathogenicvariantinaMMRgene.[44-46]
Figure1showsthetypesofcoloncancercasesthatariseinvariousfamilyrisksettings.[47]
Figure1.Thefractionsofcoloncancercasesthatariseinvariousfamilyrisksettings.Reprintedfrom
Gastroenterology,Vol.119,No.3,RandallW.Burt,ColonCancerScreening,Pages837-853,Copyright(2000),
withpermissionfromElsevier.
Inheritance of CRC Predisposition

SeveralgenesassociatedwithCRCriskhavebeenidentified;thesearedescribedindetailintheColonCancerGenessectionofthis
summary.AlmostallpathogenicvariantsknowntocauseapredispositiontoCRCareinheritedinanautosomaldominantfashion.
[48]Todate,atleastoneexampleofautosomalrecessiveinheritance,MYH-associatedpolyposis(MAP),hasbeenidentified.(Refer
totheMYH-AssociatedPolyposis[MAP]sectionofthissummaryformoreinformation.)Thus,thefamilycharacteristicsthat
suggestautosomaldominantinheritanceofcancerpredispositionareimportantindicatorsofhighriskandofthepossible
presenceofacancer-predisposingpathogenicvariant.Theseincludethefollowing:
1.Verticaltransmissionofcancerpredispositioninautosomaldominantconditions.(Verticaltransmissionreferstothe
presenceofageneticpredispositioninsequentialgenerations.)
2.Inheritanceriskof50%forbothmalesandfemales.Whenaparentcarriesanautosomaldominantgeneticpredisposition,
eachchildhasa50%chanceofinheritingthepredisposition.Theriskisthesameforbothmaleandfemalechildren.
3.Otherclinicalcharacteristicsalsosuggestinheritedrisk:
Cancersinpeoplewithahereditarypredispositiontypicallyoccuratanearlieragethaninsporadic(nongenetic)
cases.[49]
ApredispositiontoCRCmayincludeapredispositiontoothercancers,suchasendometrialcancer,asdetailedin
theMajorGeneticSyndromessectionofthissummary.
Inaddition,twoormoreprimarycancersmayoccurinasingleindividual.Thesecouldbemultipleprimarycancers
ofthesametype(e.g.,twoseparateprimaryCRCs)orprimarycancerofdifferenttypes(e.g.,colorectaland
endometrialcancerinthesameindividual).
Thepresenceofnon-neoplasticextracolonicfeaturesmaysuggestahereditarycoloncancerpredisposition
syndrome(e.g.,congenitalhypertrophyoftheretinalpigmentepitheliumanddesmoidsinfamilialadenomatous
polyposis[FAP]).
Anuncommontumor(e.g.,adrenocortical,sebaceouscarcinoma,ampullary,andsmallbowel)mayserveasaclue
tothepresenceofahereditarycancersyndrome,suchasLi-FraumeniorFAP.
Thepresenceofmultiplepolypsmaysuggestahereditarycoloncancerpredispositionsyndrome.Assusceptibility
tooligopolyposis(asfewas1015polyps)hasbecomeapparent,clinicians,andGIendoscopistsinparticular,
increasinglyconsiderthepossibilityofinheritedconditions,suchasattenuatedFAP(AFAP),MYH-associated
polyposis,andPOLD1/POLE,evenwhenthefamilyhistoryappearsentirelynegative.Becauseoligopolyposisalso
involvesdiversepathology(includinghamartomas,sessileserratedpolyps,andsessileserratedadenomas),careful
attentiontopolypcountandpolyphistologieshelpstodeterminewhethergenetictestingand/orfurtherclinical
evaluationisappropriate.
HereditaryCRChastwowell-describedforms:FAP(includingAFAP),duetogermlinepathogenicvariantsintheAPCgene,[50-57]
andLynchsyndrome(LS)(alsocalledhereditarynonpolyposiscolorectalcancer[HNPCC]),whichiscausedbygermlinepathogenic
variantsinDNAMMRgenes.[58-61](Figure2depictsaclassicfamilywithLS,highlightingsomeoftheindicatorsofhighCRCrisk
thataredescribedabove.)ManyotherfamiliesexhibitaggregationofCRCand/oradenomas,butwithnoapparentassociation
withanidentifiablehereditarysyndrome,andareknowncollectivelyasfamilialCRC.[48]
Figure2.Lynchsyndromepedigree.ThispedigreeshowssomeoftheclassicfeaturesofafamilywithLynch
syndrome,includingaffectedfamilymemberswithcoloncancerorendometrialcancerandayoungerage
atonsetinsomeindividuals.Lynchsyndromefamiliesmayexhibitsomeorallofthesefeatures.Lynch
syndromefamiliesmayalsoincludeindividualswithothergastrointestinal,gynecologic,andgenitourinary
cancers,orotherextracoloniccancers.Asanautosomaldominantsyndrome,Lynchsyndromecanbe
transmittedthroughmaternalorpaternallineages,asdepictedinthefigure.
Difficulties in Identifying a Family History of CRC Risk

Theaccuracyandcompletenessoffamilyhistorydatamustbetakenintoaccountinusingfamilyhistorytoassessindividualriskin
clinicalpractice,andinidentifyingfamiliesappropriateforcancerresearch.Areportedfamilyhistorymaybeerroneous,ora
personmaybeunawareofrelativeswithcancer.[62]Inaddition,smallfamilysizesandprematuredeathsmaylimithow
informativeafamilyhistorymaybe.Also,duetoincompletepenetrance,somepersonsmaycarryageneticpredispositiontoCRC
butdonotdevelopcancer,givingtheimpressionofskippedgenerationsinafamilytree.
Accuracyofpatient-reportedfamilyhistoryofcoloncancerhasbeenshowntobegood,butitisnotoptimal.Patientreportshould
beverifiedbyobtainingmedicalrecordswheneverpossible,especiallyforreproductivetractcancersthatmayberelevantin
identifyingriskofLS.(RefertotheAccuracyoftheFamilyHistorysectioninthePDQsummaryonCancerGeneticsRiskAssessment
andCounselingformoreinformation.)
SeveralapproachesareavailabletoevaluateapatientwithnewlydiagnosedCRCwhomayormaynotbesuspectedofhavinga
cancergeneticssyndrome.Theclinicianmaysuspectapotentialinheriteddispositionbasedonthefamilyhistoryandphysical
exam,andgenetictestsareavailabletoconfirmthesesuspicions.TheAmericanCollegeofMedicalGeneticsandGenomicshas
publishedguidelinesforevaluatingpatientswithsuspectedcoloncancersusceptibilitysyndromes.[63]Theguidelinesaimto
identifyindividualswhoseclinicalfeatureswarrantreferralforgeneticsconsultation.Ifanindividualhasmultiplepolyps(>20),
dependingonthehistology,specificgene-directedtestingcanbeausefuldiagnostictool.Similarly,ifapatientsclinical
presentationissuspiciousforLS,germlinegenetictestingcanbedirectedtowardsthissyndrome.However,diagnosisismore
challengingwhentheclinicalpictureislessclear.Currently,tumorscreeningforLSisthemostcommonlyacceptedapproach.
However,increasingly,panelscharacterizingsomaticvariantsintumorsarebeingutilizedforavarietyofclinicaldecisions.
Aprioririsk-assessmenttesting(whichmodelsriskbasedonavarietyoffactors,suchasageatcanceronsetandthespectrumof
tumorsinthefamily)maybeanappropriatealternativeinmanycases.Applicationofsuchriskmodelsdoesanticipatetheuseof
multigene(panel)testing,theexactroleforwhichremainstobeestablished.
Other risk factors for CRC

OtherriskfactorsthatmayinfluencethedevelopmentofadenomatouspolypsandCRCriskincludediet,useofnonsteroidalanti-
inflammatorydrugs(NSAIDs),cigarettesmoking,colonoscopywithremovalofadenomatouspolyps,andphysicalactivity.Evenin
LS,ahereditaryformofcoloncancer,cigarettesmokinghasbeenidentifiedasariskfactorforthedevelopmentofcolorectal
adenomas.[64](RefertotheLynchSyndrome[LS]sectionofthissummaryformoreinformation).
(RefertothePDQsummaryonPreventionofColorectalCancerformoreinformation.)
Interventions
Inpracticalterms,knowingthatapersonisatanincreasedriskofCRCbecauseofagermlineabnormalityismostusefulifthe
knowledgecanbeusedtopreventthedevelopmentofcancerorcancer-relatedmorbidityandmortalityonceithasdeveloped.
Whileonecanalsousetheinformationforfamilyplanning,decisionsaboutworkandretirement,andotherimportantlife
decisions,preventionisusuallythecentralconcern.
Thissectioncoversscreening:testingintheabsenceofsymptomsforCRCanditsprecursors(i.e.,adenomatouspolyps)toidentify
peoplewithanincreasedprobabilityofdevelopingCRC.Thosewithabnormalitiesshouldundergodiagnostictestingtosee
whethertheyhaveanoccultcancer,followedbytreatmentifcanceroraprecursorisfound.Takentogether,thissetofactivitiesis
aimedateitherpreventingthedevelopmentofCRCbyfindingandremovingitsprecursor,theadenomatouspolyp,orincreasing
thelikelihoodofcurebyearlydetectionandtreatment.
Inthecontextofhigh-risksyndromessuchasLSorFAP,surveillanceimpliesexaminingpatientsinwhomadenomaorcancer
occurrenceishighlyprobable,andtheexaminationisdoneforearlydetection.Itisnotscreeninginthetraditionalsense.The
meaningofthetermsscreeningversussurveillancehasevolvedovertimeandtheirusageinthissummarymaynotbeconsistent
withotheroncologicandepidemiologiccontexts.
Primaryprevention(eliminatingthecausesofCRCinpeoplewithgeneticallyincreasedrisk)isaddressedlaterinthissection.
State of the evidence base

Currently,therearenopublishedrandomizedcontrolledtrialsofsurveillanceinpeoplewithageneticallyincreasedriskofCRCand
fewcontrolledcomparisons.Whilearandomizedtrialwithano-surveillancearmisnotfeasible,thereisaneedforwell-designed
studiescomparingvarioussurveillancemethodsordifferingperiodsoftimebetweenprocedures.Anobservationalstudythat
comparedsurveilledsubjectswithunsurveilled(bychoice)controlsevaluateda15-yearexperiencewith252relativesatriskofLS,
119ofwhomdeclinedsurveillance.Eightof133(6%)inthesurveilledgroupdevelopedCRC,comparedwith19intheunsurveilled
group(16%,P=.014).[65]Ingeneral,however,peoplewithgeneticriskhavebeenexcludedfromthetrialsofCRCscreeningthat
havebeenpublishedthusfar,soitisnotpossibletoestimateeffectivenessbysubgroupanalyses.Therefore,preventioninthese
patientscannotbebasedonstrongevidenceofeffectiveness,asisordinarilyreliedonbyexpertgroupswhensuggesting
screeningorsurveillanceguidelines.
Giventheseconsiderations,clinicaldecisionsarebasedonclinicaljudgment.Thesedecisionstakeintoaccountthebiologicand
clinicalbehaviorofeachkindofgeneticcondition,andpossibleparallelswithpatientsataveragerisk,forwhomscreeningis
knowntobeeffective.
Theevidencebasefortheeffectivenessofscreeninginaverage-riskpeople(thosewithoutapparentgeneticrisk)isthebenchmark
forconsideringanapproachtopeopleatincreasedrisk.(RefertothePDQsummaryonScreeningforColorectalCancerformore
information.)
Thefactthatscreeningofaverage-riskpersonsreducestheriskofdyingfromCRCformsthebasisforrecommendingsurveillance
inpersonsatahighergeneticriskofCRC.Aslogicalasthisapproachseems,randomizedtrialsofsurveillancehavenotbeen
performedinthisspecialpopulation,thoughobservationalstudiesperformedonfamilieswithLS[66,67]andFAP[68]supportthe
valueofsurveillance.ThesestudiesdemonstrateashifttowardsearlierstageatdiagnosisandacorrespondingreductioninCRC
mortalityamongcolonoscopy-detectedcancers.
(RefertotheMajorGeneticSyndromessectionofthissummaryformoreinformationaboutsurveillanceinhigh-riskpopulations.)
Rationale for screening

Widelyacceptedcriteria(13below)forappropriatescreeningapplyasmuchtodiseaseswithastronggeneticcomponent(more
thanoneaffectedfirst-degreerelativeoronefirst-degreerelativediagnosedatyoungerthan60years)astheydotoother
diseases.[69,70]Additionalcriteria(4and5)wereaddedbelow.[71]
1.Ahighburdenofsuffering,intermsofmorbidity,mortality,andlossoffunction.
2.Ascreeningtestthatissufficientlysensitive,specific,safe,convenient,andinexpensive.
3.Evidencethattreatingtheconditionwhenitisdetectedearly,byscreening,resultsinabetterprognosisthantreatment
afteritisdetectedbecauseofsymptoms.
4.Evidenceontheextenttowhichthescreeningtestandtreatmentdoharm.
5.Thevaluejudgmentthatthescreeningtestdoesmoregoodthanharm.
Ofthesecriteria,thefirstandsecondaresatisfiedingeneticallydeterminedCRC.Theharmsofscreening(criterion4),especially
majorcomplicationsofdiagnosticcolonoscopy(perforationandmajorbleeding),arealsoknown.Evidencethatearlyintervention
resultsinbetteroutcomes(criterion3)islimitedbutsuggestsbenefit.OnestudyinthesettingofLSfoundearlierstage/local
tumorsinthescreenedindividuals.[65]
Identification of persons at high genetic risk of CRC

Clinicalcriteriamaybeusedtoidentifypersonswhoarecandidatesforgenetictestingtodeterminewhetheraninherited
susceptibilitytoCRCispresent.Thesecriteriaincludethefollowing:
AstrongfamilyhistoryofCRCand/orpolyps(especiallyoligopolyposis).
MultipleprimarycancersinapatientwithCRC.
ExistenceofothercancerswithinthekindredconsistentwithknownsyndromescausinganinheritedriskofCRC,suchas
endometrialcancer.
EarlyageatdiagnosisofCRC.
Whensuchpersonsareidentified,optionstailoredtothepatientsituationareconsidered.(RefertotheMajorGeneticSyndromes
sectionofthissummaryforinformationonspecificinterventionsforindividualsyndromes.)
Atthistime,theuseoftestingtoidentifygeneticsusceptibilitytoCRCisnotrecommendedasascreeningmeasureinthegeneral
population.TherarityofpathogenicvariantsintheAPCtumorsuppressorgeneandLS-associatedMMRgenesandthelimited
sensitivityofcurrenttestingstrategiesrendergeneralpopulationtestingpotentiallymisleadingandnotcosteffective.
RatherdetailedrecommendationsforsurveillanceinFAPandLShavebeenprovidedbyseveralorganizationsrepresentingvarious
medicalspecialtiesandsocieties.ThefollowingguidelinesarereadilyavailablethroughtheNationalGuidelineClearinghouse:
AmericanCancerSociety.[72]
UnitedStatesMultisociety(AmericanGastroenterologicalAssociationandAmericanSocietyforGastrointestinalEndoscopy)
TaskForceonColorectalCancer.[73]
AmericanSocietyofColonandRectalSurgeons.[74]
NationalComprehensiveCancerNetwork.[75]
GeneReviews.
Theevidencebasesforrecommendationsaregenerallyincludedwithinthestatementsorguidelines.Inmanyinstances,these
guidelinesreflectexpertopinionrestingonstudiesthatarerarelyrandomizedprospectivetrials.
Primary Prevention of Familial CRC

Primary Prevention of Familial CRC
Chemoprevention
Observationalstudiesofaverage-riskpeoplehavesuggestedthattheuseofsomedrugsandsupplements(NSAIDs,estrogens,
folicacid,andcalcium)mightpreventthedevelopmentofCRC.[76](RefertothePDQsummaryonPreventionofColorectalCancer
formoreinformation.)Noneoftheevidenceisconvincingenoughtoleadexpertgroupstorecommendthesedrugsand
supplementsspecificallytopreventCRC,andfewstudiesspecificallyenrolledpeoplewithaninheritedpredispositionforCRC.
Althoughantioxidantsarehypothesizedtopreventcancer,arandomizedcontrolledtrialofantioxidantvitamins(betacarotene,
vitaminC,andvitaminE)hasshownnoeffectonCRCincidence.[77]
(RefertotheInterventionsforFAPsectionandtheChemopreventioninLSsectionintheMajorGeneticSyndromessectionofthis
summaryformoreinformationaboutchemoprevention.)
Modifying behavioral risk factors

Severalcomponentsofdietandbehaviorhavebeensuggested,withvariouslevelsofconsistency,toberiskfactorsforCRC.(Refer
tothePDQsummaryonPreventionofColorectalCancerformoreinformation.)Theselifestylefactorsmayrepresentpotential
meansofprevention.[76,78,79]Expertgroupsdifferontheinterpretationoftheevidenceforsomeofthesecomponents.
LittleisknownaboutwhetherthesesamefactorsareprotectiveinpeoplewithageneticallyincreasedriskofCRC.Inonecase-
controlstudy,lowlevelsofphysicalactivity,highcaloricintake,andlowvegetableintakeweresignificantlyrelatedtocancerriskin
peoplewithnofamilyhistoryofCRCbutshowednorelationshipinpeoplewithafamilyhistory,despiteadequatestatisticalpower
todoso.[80]
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Colon Cancer Genes

Major Genes
Majorgenesaredefinedasthosethatarenecessaryandsufficientfordiseasecausation,withimportantpathogenicvariants(e.g.,
nonsense,missense,frameshift)ofthegeneascausalmechanisms.Majorgenesaretypicallyconsideredthosethatareinvolvedin
single-genedisorders,andthediseasescausedbymajorgenesareoftenrelativelyrare.Mostpathogenicvariantsinmajorgenes
leadtoaveryhighriskofdisease,andenvironmentalcontributionsareoftendifficulttorecognize.[1]Historically,mostmajor
coloncancersusceptibilitygeneshavebeenidentifiedbylinkageanalysisusinghigh-riskfamilies;thus,thesecriteriawerefulfilled
bydefinition,asaconsequenceofthestudydesign.
Thefunctionsofthemajorcoloncancergeneshavebeenreasonablywellcharacterizedoverthepastdecade.Threeproposed
classesofcoloncancergenesaretumorsuppressorgenes,oncogenes,andDNArepairgenes.[2]Tumorsuppressorgenes
constitutethemostimportantclassofgenesresponsibleforhereditarycancersyndromesandrepresenttheclassofgenes
responsibleforbothfamilialadenomatouspolyposis(FAP)andjuvenilepolyposissyndrome(JPS),amongothers.Germline
pathogenicvariantsinoncogenesarenotanimportantcauseofinheritedsusceptibilitytocolorectalcancer(CRC),eventhough
somaticvariantsinoncogenesareubiquitousinvirtuallyallformsofgastrointestinalcancers.Stabilitygenes,especiallythe
mismatchrepair(MMR)genesresponsibleforLynchsyndrome(LS)(alsocalledhereditarynonpolyposiscolorectalcancer
[HNPCC]),accountforasubstantialfractionofhereditaryCRC,asnotedbelow.(RefertotheLynchsyndrome[LS]sectioninthe
MajorGeneticSyndromessectionofthissummaryformoreinformation).MYHisanotherimportantexampleofastabilitygene
thatconfersriskofCRCbasedondefectivebaseexcisionrepair.Table2summarizesthegenesthatconferasubstantialriskof
CRC,withtheircorrespondingdiseases.
Table 2. Genes Associated with a High Susceptibility of Colorectal Cancer
Gene Syndrome HereditaryPattern PredominantCancer
Tumorsuppressorgenes
APC(OMIM) FAP Dominant Colon,intestine,etc.
TP53(p53)(OMIM) Li-Fraumeni Dominant Multiple(includingcolon)
STK11(LKB1)(OMIM) PJS Dominant Multiple(includingintestine)
PTEN(OMIM) Cowden Dominant Multiple(includingintestine)
BMPR1A(OMIM) JPS Dominant Gastrointestinal
SMAD4(MADH/DPC4)(OMIM) JPS Dominant Gastrointestinal
Repair/stabilitygenes
MLH1(OMIM),MSH2(OMIM), LS Dominant Multiple(includingcolon,

MSH6(OMIM),PMS2 (OMIM) uterus,andothers)
Gene Syndrome HereditaryPattern PredominantCancer
EPCAM (TACSTD1)(OMIM) LS Dominant Multiple(includingcolon,

uterus,andothers)
MYH(MUTYH)(OMIM) MYH-associatedpolyposis Recessive Colon
POLD1(OMIM),POLE(OMIM) Oligopolyposis Dominant Colon,endometrial
FAP=familialadenomatouspolyposis;JPS=juvenilepolyposissyndrome;LS=Lynchsyndrome;OMIM=OnlineMendelianInheritanceinMan
database;PJS=Peutz-Jegherssyndrome.
De Novo Pathogenic Variant Rate

Untilthe1990s,thediagnosisofgeneticallyinheritedpolyposissyndromeswasbasedonclinicalmanifestationsandfamilyhistory.
Nowthatsomeofthegenesinvolvedinthesesyndromeshavebeenidentified,afewstudieshaveattemptedtoestimatethe
spontaneouspathogenicvariantrate(denovopathogenicvariantrate)inthesepopulations.Interestingly,FAP,JPS,Peutz-Jeghers
syndrome,Cowdensyndrome,andBannayan-Riley-Ruvalcabasyndromeareallthoughttohavehighratesofspontaneous
pathogenicvariants,inthe25%to30%range,[3-5]whileestimatesofdenovopathogenicvariantsintheMMRgenesassociated
withLSarethoughttobelow,inthe0.9%to5%range.[6-8]TheseestimatesofspontaneouspathogenicvariantratesinLSseemto
overlapwiththeestimatesofnonpaternityratesinvariouspopulations(0.6%to3.3%),[9-11]makingthedenovopathogenic
variantrateforLSseemquitelowincontrasttotherelativelyhighratesintheotherpolyposissyndromes.
Next-Generation Sequencing and Novel CRC Susceptibility Genes

Next-generationsequencing(NGS)involvestechnologicaladvancesoverthetraditionalcapillary-basedSangerDNAsequencing
thatwasusedintheHumanGenomeProjecttosequencethehumangenome.NGSdramaticallydecreasesthetimerequiredfor
genomicsequencingbyutilizingmassivelyparallelmultiplexingtechniques.Comparisonsofgenomicsequencingresultsbetween
individualswithandwithoutCRCaffordsyetanothermethodtoidentifyCRCsusceptibilitygenes.
Whole-genomesequencing(WGS)andwhole-exomesequencing(WES)arecurrentlybeingusedtoassesssomaticalterationsin
tumorstoinformprognosisand/ortargetedtherapeuticsandtoassessthegermlinetoidentifycancerriskalleles.(Refertothe
ClinicalSequencingsectioninthePDQCancerGeneticsOverviewsummaryformoreinformation.)
AnexampleofthesuccessofNGSinidentifyingCRCsusceptibilitygenesisthediscoveryofPOLE/POLD1germlinepathogenic
variantsinpatientswithadenomatouspolyposisbutnogermlinevariantsinknownCRCgenes.(RefertotheOligopolyposis
sectionintheMajorGeneticSyndromessectionofthissummaryformoreinformationaboutPOLE/POLD1).
WEShasalsobeenusedtoidentifynewpotentialCRCpredispositionvariants.Inone2016study,exomesequencingdataon1,006
early-onsetfamilialCRCcasesand1,609healthycontrolswereanalyzed.[12]Highlypenetrantrarepathogenicvariantswere
identifiedin16%offamilialCRCcases,ofwhichthemajoritywereknowncoloncancergeneswhilePOT1,POLE2,andMRE11were
identifiedascandidateCRCgenes.Theauthorsconcludedthatthesefindingsprobablydiscounttheexistenceoffurthermajor
high-penetrancesusceptibilityCRCgenes.
Genetic Polymorphisms and CRC Risk

Itiswidelyacknowledgedthatthefamilialclusteringofcoloncanceralsooccursoutsideofthesettingofwell-characterizedcolon
cancerfamilysyndromes.[13]Basedonepidemiologicalstudies,theriskofcoloncancerinafirst-degreerelativeofanaffected
individualcanincreaseanindividualslifetimeriskofcoloncancer2-foldto4.3-fold.[14]Therelativerisk(RR)andabsoluteriskof
CRCfordifferentfamilyhistorycategoriesisestimatedinTable1.Inaddition,thelifetimeriskofcoloncanceralsoincreasesinfirst-
degreerelativesofindividualswithcolonadenomas.[15]Themagnitudeofriskdependsontheageatdiagnosisoftheindexcase,
thedegreeofrelatednessoftheindexcasetotheat-riskcase,andthenumberofaffectedrelatives.Itiscurrentlybelievedthat
manyofthemoderate-andlow-riskcasesareinfluencedbyalterationsinsinglelow-penetrancegenesorcombinationsoflow-
penetrancegenes.Giventhepublichealthimpactofidentifyingtheetiologyofthisincreasedrisk,anintensesearchforthe
responsiblegenesisunderway.
EachlocuswouldbeexpectedtohavearelativelysmalleffectonCRCriskandwouldnotproducethedramaticfamilialaggregation
seeninLSorFAP.However,incombinationwithothercommongeneticlociand/orenvironmentalfactors,variantsofthiskind
mightsignificantlyalterCRCrisk.Thesetypesofgeneticvariationsareoftenreferredtoaspolymorphisms.Mostlocithatare
polymorphichavenoinfluenceondiseaseriskorhumantraits(benignpolymorphisms),whilethosethatareassociatedwitha
differenceinriskofdiseaseorahumantrait(howeversubtle)aresometimestermeddisease-associatedpolymorphismsor
functionallyrelevantpolymorphisms.WhensuchvariationinvolveschangesinsinglenucleotidesofDNAtheyarereferredtoas
singlenucleotidepolymorphisms(SNPs).
PolymorphismsunderlyingpolygenicsusceptibilitytoCRCareconsideredlowpenetrance,atermoftenappliedtosequence
variantsassociatedwithaminimaltomoderaterisk.Thisisincontrasttohigh-penetrancevariantsorallelesthataretypically
associatedwithmoreseverephenotypes,forexamplethoseAPCorMMRgenepathogenicvariantsleadingtoanautosomal
dominantinheritancepatterninafamily.Thedefinitionofamoderateriskofcancerisarbitrary,butitisusuallyconsideredtobein
therangeofanRRof1.5to2.0.Becausethesetypesofsequencevariantsarerelativelycommoninthepopulation,their
contributiontototalcancerriskisestimatedtobemuchhigherthantheattributableriskinthepopulationfromtherelativelyrare
syndromessuchasFAPorLS.Additionally,polymorphismsingenesdistinctfromtheMMRgenescanmodifyphenotype(e.g.,
averageageofCRC)inindividualswithLS.
Low-penetrancevariantshavebeenidentifiedinanumberofstrategies.Earlierstudiesfocusedoncandidatesgeneschosen
becauseofbiologicrelevancetocancerpathogenesis.Morerecently,genome-wideassociationstudies(GWAS)havebeenused
muchmoreextensivelytoidentifypotentialCRCsusceptibilitygenes.(RefertotheGWASsectionofthissummaryformore
information.)Anotherapproachistousemeta-analysesofexistingGWASdatasetstodiscoveradditionalnovelCRCsusceptibility
genes.
Polymorphism-modifying risk in average-risk populations
Low-penetrance candidate genes

Severalcandidategeneshavebeenidentifiedandtheirpotentialuseforclinicalgenetictestingisbeingdetermined.Candidate
Ash
allelesthathavebeenshowntoassociatewithmodestincreasedfrequenciesofcoloncancerincludeheterozygousBLM (the
allelethatisafounderpathogenicvariantinAshkenaziJewishindividualswithBloomsyndrome),theGH11663TApolymorphism
(apolymorphismofthegrowthhormonegeneassociatedwithlowlevelsofgrowthhormoneandIGF-1),andtheAPCI1307K
polymorphism.[16-18]
Ofthese,thevariantthathasbeenmostextensivelystudiedisAPCI1307K.Yet,neitheritnoranyoftheothervariantsmentioned
aboveareroutinelyusedinclinicalpractice.(RefertotheAPCI1307Ksectionofthissummaryformoreinformation.)
GWAS
AlthoughthemajorgenesforpolyposisandnonpolyposisinheritedCRCsyndromeshavebeenidentified,between20%and50%of
casesfromanygivenseriesofsuspectedFAPorLScasesfailtohaveapathogenicvariantdetectedbycurrentlyavailable
technologies.Itisestimatedthatheredityisresponsibleforapproximatelyone-thirdofthesusceptibilitytoCRC,[19]andcausative
germlinepathogenicvariantsaccountforlessthan6%ofallCRCcases.[20]Thissuggeststhattheremaybeothermajorgenes
withpathogenicvariantsthatmaypredisposetoCRCwithorwithoutpolyposis.Afewsuchgeneshavebeendetected(e.g.,MYH,
EPCAM)buttheprobabilityfordiscoveryofothersuchgenesisfairlylow.Morerecentmeasuresfornewgenediscoveryhavetaken
agenome-wideapproach.SeveralGWAShavebeenconductedwithrelativelylarge,unselectedseriesofCRCpatientsthathave
beenevaluatedforpatternsofpolymorphismsincandidateandanonymousgenesthroughoutthegenome.TheseSNPsare
chosentocapturealargeportionofcommonvariationwithinthegenome,basedontheInternationalHapMapProject.[21,22]The
goalistoidentifyallelesthat,whilenotpathogenicvariants,mayconferanincrease(orpotentialdecrease)inCRCrisk.
IdentificationofyetunknownaberrantCRCalleleswouldpermitfurtherstratificationofat-riskindividualsonageneticbasis.Such
riskstratificationwouldpotentiallyenhanceCRCscreening.Theuseofgenome-widescansinthousandsofCRCcasesandcontrols
hasledtothediscoveryofmultiplecommonlow-riskCRCSNPs,whichcanbefoundintheNationalHumanGenomeResearch
InstituteGWAScatalog.AthoroughdiscussionofGWAScanbefoundintheCancerGeneticsOverviewPDQsummary.GWASare
conductedundertheassumptionthatthegeneticunderpinningsofcomplexphenotypesaregovernedbymanyalleles,each
conferringmodestrisk.Itisveryunlikelythatanallelewithhighfrequencyinthepopulationbyitselfcontributessubstantiallyto
cancerrisk.This,coupledwiththepolygenicnatureoftumorigenesis,meansthatthecontributionbyanysinglevariantidentified
byGWAStodateisquitesmall,generallywithanoddsratio(OR)fordiseaseriskoflessthan1.5.
Meta-analysisofGWAShasallowedfortheidentificationofnovelCRC-associatedSNPsbycombiningdatafrompreviousGWAS.
[23,23-26]TheseSNPsareprovidedintheGWAScatalogreferencedabove.ThesameconsiderationsforGWASmentionedabove
applytothemeta-analysisapproach.
Genetic variation in 8q24 and SMAD7

Threeseparatestudiesshowedthatgeneticvariationat8q24.21isassociatedwithincreasedriskofcoloncancer,withRRranging
from1.17to1.27.[27-29]AlthoughtheRRismodestfortheriskallelesin8q24,theprevalence(andpopulation-attributable
fraction)oftheseriskallelesishigh.Thegenesresponsibleforthisassociationhavenotyetbeenidentified.Inaddition,common
allelesofSMAD7havealsobeenshowntobeassociatedwithanapproximately35%increaseinriskofcoloncancer.[30]
Othercandidateallelesthathavebeenidentifiedonmultiple(>3)geneticassociationstudiesincludetheGSTM1nullalleleandthe
NAT2G/Gallele.[31]Noneofthesealleleshasbeencharacterizedenoughtocurrentlysupportitsroutineuseinaclinicalsetting.
Familyhistoryremainsthemostvaluabletoolforestablishingriskofcoloncancerinthesefamilies.Similartowhathasbeen
reportedinprostatecancer,acombinationofsusceptibilitylocimayyetholdpromiseinprofilingindividualrisk.[32,33]
Variants of uncertain significance in major cancer susceptibility genes
APC I1307K
PolymorphismsinAPCarethemostextensivelystudiedpolymorphismswithregardtocancerassociation.TheAPCI1307K
polymorphismisassociatedwithanincreasedriskofcoloncancerbutdoesnotcausecolonicpolyposis.TheI1307Kpolymorphism
occursalmostexclusivelyinpeopleofAshkenaziJewishdescentandresultsinatwofoldincreasedriskofcolonicadenomasand
adenocarcinomascomparedwiththegeneralpopulation.[18,34]TheI1307KpolymorphismresultsfromatransitionfromTtoAat
nucleotide3920intheAPCgeneandappearstocreatearegionofhypermutability.[18]Althoughclinicalassaystoassessforthe
APCI1307Kpolymorphismarecurrentlyavailable,theassociatedcoloncancerriskisnothighenoughtosupportroutineuse.On
thebasisofcurrentlyavailabledata,itisnotyetknownwhethertheI1307Kcarrierstateshouldguidedecisionsregardingtheage
toinitiatescreening,thefrequencyofscreening,orthechoiceofscreeningstrategy.
Clinical implications of low-penetrance alleles

AlthoughthestatisticalevidenceforanassociationbetweengeneticvariationattheselociandCRCriskisconvincing,the
biologicallyrelevantvariantsandthemechanismsbywhichtheyleadtoincreasedriskareunknownandwillrequirefurther
geneticandfunctionalcharacterization.Additionally,theselociareassociatedwithverymodestrisk,withORsfordevelopingCRC
inheterozygouscarriersusuallyfrom1.1to1.3.Moreriskvariantswilllikelybeidentified.Risksinthisrangedonotappearto
conferenoughincreaseinage-specificriskastowarrantmodificationofotherwiseclinicallyprudentscreening.Untiltheir
collectiveinfluenceisprospectivelyevaluated,theirusecannotberecommendedinclinicalpractice.
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Major Genetic Syndromes

Introduction
Originallydescribedinthe1800sand1900sbytheirclinicalfindings,thecoloncancersusceptibilitysyndromenamesoften
reflectedthephysicianorpatientandfamilyassociatedwiththesyndrome(e.g.,Gardnersyndrome,Turcotsyndrome,Muir-Torre
syndrome,LynchIandIIsyndromes,Peutz-Jegherssyndrome[PJS],Bannayan-Riley-Ruvalcabasyndrome,andCowdensyndrome).
Thesesyndromeswereassociatedwithanincreasedlifetimeriskofcolorectaladenocarcinoma.Theyweremostlythoughttohave
autosomaldominantinheritancepatterns.Adenomatouscolonicpolypswerecharacteristicofthefirstfive,whilehamartomas
werefoundtobecharacteristicinthelastthree.
WiththedevelopmentoftheHumanGenomeProjectandtheidentificationin1990oftheadenomatous polyposis coli(APC)geneon

chromosome5q,overlapanddifferencesbetweenthesefamilialsyndromesbecameapparent.Gardnersyndromeandfamilial
adenomatouspolyposis(FAP)wereshowntobesynonymous,bothcausedbypathogenicvariantsintheAPCgene.AttenuatedFAP
(AFAP)wasrecognizedasasyndromewithlessadenomasandextraintestinalmanifestationsduetoanAPCpathogenicvarianton
the3and5endsofthegene.TurcotsyndromefamilieswereshowntobegeneticallypartofFAPwithmedulloblastomasand
Lynchsyndrome(LS)withglioblastomas.Muir-TorreandLSwereshowntohavegeneticsimilarities.MYH-associatedpolyposis
(MAP)wasrecognizedasaseparateadenomatouspolypsyndromewithautosomalrecessiveinheritance.Oncethepathogenic
variantswereidentified,theabsoluteriskofcolorectalcancer(CRC)couldbebetterassessedforcarriersofpathogenicvariants
(seeTable3).
Table 3. Absolute Risks of Colorectal Cancer for Carriers of Pathogenic Variants in Hereditary
Colorectal Cancer Syndromes
Syndrome AbsoluteRiskofCRCinCarriersofaPathogenicVariant
FAPa 90%byage45y[1]
AttenuatedFAP 69%byage80y[2]
LS 40%to80%byage75yb[3,4]
MYH-associatedpolyposis 35%to53%[5]
Syndrome AbsoluteRiskofCRCinCarriersofaPathogenicVariant
PJS 39%byage70y[6]
JPS 17%to68%byage60y[7,8]
FAP=familialadenomatouspolyposis;JPS=juvenilepolyposissyndrome;LS=Lynchsyndrome;PJS=Peutz-Jegherssyndrome.
a
Cancerriskestimatesquotedherepredatethewidespreaduseofsurveillanceandprophylacticsurgery.
b
RefertotheLynchsyndrome(LS)sectionofthissummaryforafulldiscussionofrisk.
Withthesediscoveriesgenetictestingandriskmanagementbecamepossible.Genetictestingreferstosearchingforvariantsin
knowncancersusceptibilitygenesusingavarietyoftechniques.Comprehensivegenetictestingincludessequencingtheentire
codingregionofagene,theintron-exonboundaries(splicesites),andassessmentofrearrangements,deletions,orotherchanges
incopynumber(withtechniquessuchasmultiplexligation-dependentprobeamplification[MLPA]orSouthernblot).Despite
extensiveaccumulatedexperiencethathelpsdistinguishpathogenicvariantsfrombenignvariantsandpolymorphisms,genetic
testingsometimesidentifiesvariantsofuncertainsignificance(VUS)thatcannotbeusedforpredictivepurposes.
Familial Adenomatous Polyposis (FAP)

By1900,severalreportshaddemonstratedthatpatientswithmultiplepolyps(onlylatersubclassifiedasadenomasandother
histologies)wereatveryhighriskofCRCandthatthepatternofoccurrenceinfamilieswasautosomaldominant.Inthe20th
century,theadenoma-to-carcinomaprogressionwasconfirmed,andFAPwasrecognizedasonehumanmodelforthis
progression.[9]VariouscomplicationsofFAPcametobedescribed,includinguppergastrointestinal(GI)tractadenomas;fundic
glandstomachpolyps;nonepithelialbenigntumors(osteomas,epidermalcysts,dentalabnormalities[thistriadisknown
collectivelyasGardnersyndrome]);desmoidtumors;congenitalhypertrophyofretinalpigmentepithelium(CHRPE);and
malignanttumors(thyroidandbraintumors,hepatoblastoma).
FAPisoneofthemostclearlydefinedandwellunderstoodoftheinheritedcoloncancersyndromes.[1,10,11]Itisanautosomal
dominantcondition,andthereportedincidencevariesfrom1in7,000to1in22,000livebirths,withthesyndromebeingmore
commoninWesterncountries.[12]Autosomaldominantinheritancemeansthataffectedpersonsaregeneticallyheterozygous,
suchthateachoffspringofapatientwithFAPhasa50%chanceofinheritingthediseasegene.Malesandfemalesareequallylikely
tobeaffected.
Classically,FAPischaracterizedbymultiple(>100)adenomatouspolypsinthecolonandrectumdevelopingafterthefirstdecade
oflife(seeFigure3).
Figure3.Multiplepolypsinthecolonofapatientwithfamilialadenomatouspolyposisshownendoscopically
(leftpanel)anduponsurgicalresection(rightpanel).
FAPfeaturesinadditiontothecolonicpolypsmayincludepolypsintheupperGItract,extraintestinalmanifestationssuchas
congenitalhypertrophyofretinalpigmentepithelium,osteomasandepidermoidcysts,supernumeraryteeth,desmoidformation,
andothermalignantchangessuchasthyroidtumors,smallbowelcancer,hepatoblastoma,andbraintumors,particularly
medulloblastoma(seeTable4).
Table 4. Extracolonic Tumor Risks in Familial Adenomatous Polyposis
Malignancy RelativeRisk AbsoluteLifetimeRisk(%)
Desmoid 852.0 15.0
Duodenum 330.8 5.012.0
Thyroid 7.6 2.0
Brain 7.0 2.0
Ampullary 123.7 1.7
Pancreas 4.5 1.7
Hepatoblastoma 847.0 1.6
Malignancy RelativeRisk AbsoluteLifetimeRisk(%)
Gastric 0.6a
AdaptedfromGiardielloetal.,[13]Jagelmanetal.,[14]Sturtetal.,[15]Lynchetal.,[16]Blowetal.,[17]Burtetal.,[18]andGaliatsatosetal.[19]
a
TheLeedsCastlePolyposisGroup.
FAPisalsoknownasfamilialpolyposiscoli,adenomatouspolyposiscoli(APC),orGardnersyndrome(colorectalpolyposis,
osteomas,andsofttissuetumors).GardnersyndromehassometimesbeenusedtodesignateFAPpatientswhomanifestthese
extracolonicfeatures.However,GardnersyndromehasbeenshownmolecularlytobeavariantofFAP,andthusthetermGardner
syndromeisessentiallyobsoleteinclinicalpractice.[20]
MostcasesofFAPresultfrompathogenicvariantsintheAPCgeneonchromosome5q21.Individualswhoinheritapathogenic
variantintheAPCgenehaveaveryhighlikelihoodofdevelopingcolonicadenomas;theriskhasbeenestimatedtobemorethan
90%.[1,10,11]Theageatonsetofadenomasinthecolonisvariable:Byage10years,only15%ofcarriersoftheAPCgermline
variantmanifestadenomas;byage20years,theprobabilityrisesto75%;andbyage30years,90%willhavepresentedwithFAP.
[1,10,11,21,22]Withoutanyintervention,mostpersonswithFAPwilldevelopcolonorrectalcancerbythefourthdecadeoflife.
[1,10,11]Thus,surveillanceandinterventionforcarriersofanAPCgenepathogenicvariantandat-riskpersonshaveconventionally
consistedofannualsigmoidoscopybeginningaroundpuberty.Theobjectiveofthisregimenisearlydetectionofcolonicpolypsin
thosewhohaveFAP,leadingtopreventivecolectomy.[23,24]
TheearlyappearanceofclinicalfeaturesofFAPandthesubsequentrecommendationsforsurveillancebeginningatpubertyraise
specialconsiderationsrelatingtothegenetictestingofchildrenforsusceptibilitygenes.[25]Someproponentsfeelthatthegenetic
testingofchildrenforFAPpresentsanexampleinwhichpossiblemedicalbenefitjustifiesgenetictestingofminors,especiallyfor
theanticipated50%ofchildrenwhowillbefoundnottobecarriersofpathogenicvariantsandwhocanthusbesparedthe
necessityofunpleasantandcostlyannualsigmoidoscopy.Thepsychologicalimpactofsuchtestingiscurrentlyunderinvestigation
andisaddressedinthePsychosocialIssuesinHereditaryColonCancerSyndromessectionofthissummary.
AnumberofdifferentAPCpathogenicvariantshavebeendescribedinaseriesofFAPpatients.TheclinicalfeaturesofFAPappear
tobegenerallyassociatedwiththelocationofthevariantintheAPCgeneandthetypeofvariant(i.e.,frameshiftvariantvs.
missensevariant).TwofeaturesofparticularclinicalinterestthatareapparentlyassociatedwithAPCvariantsare(1)thedensityof
colonicpolyposisand(2)thedevelopmentofextracolonictumors.
Adenomatous polyposis coli (APC)

TheAPCgeneonchromosome5q21encodesa2,843-aminoacidproteinthatisimportantincelladhesionandsignaltransduction;
beta-cateninisitsmajordownstreamtarget.APCisatumorsuppressorgene,andthelossofAPCisamongtheearliesteventsin
thechromosomalinstabilitycolorectaltumorpathway.TheimportantroleofAPCinpredispositiontocolorectaltumorsis
supportedbytheassociationofAPCgermlinepathogenicvariantswithFAPandAFAP.Bothconditionscanbediagnosed
geneticallybytestingforgermlinepathogenicvariantsintheAPCgeneinDNAfromperipheralbloodleukocytes.MostFAP
pedigreeshaveAPCalterationsthatproducetruncatingpathogenicvariants,primarilyinthefirsthalfofthegene.[26,27]AFAPis
associatedwithtruncatingpathogenicvariantsprimarilyinthe5and3endsofthegeneandpossiblymissensevariants
elsewhere.[28-31]
Morethan300differentdisease-associatedpathogenicvariantsoftheAPCgenehavebeenreported.[27]Thevastmajorityofthese
changesareinsertions,deletions,andnonsensevariantsthatleadtoframeshiftsand/orprematurestopcodonsintheresulting
transcriptofthegene.ThemostcommonAPCpathogenicvariant(10%ofFAPpatients)isadeletionofAAAAGincodon1309;no
otherpathogenicvariantsappeartopredominate.VariantsthatreduceratherthaneliminateproductionoftheAPCproteinmay
alsoleadtoFAP.[32]
MostAPCpathogenicvariantsthatoccurbetweencodon169andcodon1393resultintheclassicFAPphenotype.[28-30]Therehas
beenmuchinterestincorrelatingthelocationofthepathogenicvariantwithinthegenewiththeclinicalphenotype,includingthe
distributionofextracolonictumors,polyposisseverity,andcongenitalhypertrophyoftheretinalpigmentepithelium.Themost
consistentobservationsarethatattenuatedpolyposisandthelessclassicformsofFAPareassociatedwithpathogenicvariants
thatoccurinorbeforeexon4andinthelattertwo-thirdsofexon15,[29]andthatretinallesionsarerarelyassociatedwith
pathogenicvariantsthatoccurbeforeexon9.[30,33]Exon9pathogenicvariantshavealsobeenassociatedwithattenuated
polyposis.Additionally,individualswithexon9variantstendnottohaveduodenaladenomas.[34]
Density of colonic polyposis

Researchershavefoundthatdensecarpetingofcolonicpolyps,afeatureofclassicFAP,isseeninmostpatientswithAPC
pathogenicvariants,particularlythosevariantsthatoccurbetweencodons169and1393.Attheotherendofthespectrum,sparse
polypsarefeaturesofpatientswithpathogenicvariantsoccurringattheextremeendsoftheAPCgeneorinexon9.(Refertothe
AttenuatedFamilialAdenomatousPolyposis[AFAP]sectionofthissummaryformoreinformation.)
Extracolonic tumors
Desmoid tumors
Desmoidtumorsareproliferative,locallyinvasive,nonmetastasizing,fibromatoustumorsinacollagenmatrix.Althoughtheydo
notmetastasize,theycangrowveryaggressivelyandbelifethreatening.[35]Desmoidsmayoccursporadically,aspartofclassical
FAP,orinahereditarymannerwithoutthecolonfindingsofFAP.[16,36]DesmoidshavebeenassociatedwithhereditaryAPCgene
pathogenicvariantsevenwhennotassociatedwithtypicaladenomatouspolyposisofthecolon.[36,37]
Moststudieshavefoundthat10%ofFAPpatientsdevelopdesmoids,withreportedrangesof8%to38%.Theincidencevarieswith
themeansofascertainmentandthelocationofthepathogenicvariantintheAPCgene.[36,38,39]APCpathogenicvariants
occurringbetweencodons1445and1578havebeenassociatedwithanincreasedincidenceofdesmoidtumorsinFAPpatients.
[33,37,40,41]Desmoidtumorswithalateonsetandamilderintestinalpolyposisphenotype(hereditarydesmoiddisease)have
beendescribedinpatientswithpathogenicvariantsatcodon1924.[36]
Adesmoidriskfactorscalehasbeendescribedinanattempttoidentifypatientswhoarelikelytodevelopdesmoidtumors.[42]
Thedesmoidriskfactorscalewasbasedongender,presenceorabsenceofextracolonicmanifestations,familyhistoryof
desmoids,andgenotype,ifavailable.Byutilizingthisscale,itwaspossibletostratifyFAPpatientsintolow-,medium-,andhigh-risk
groupsfordevelopingdesmoidtumors.Theauthorsconcludedthatthedesmoidriskfactorscalecouldbeusedforsurgical
planning.Validationoftheriskfactorscomprisingthisscaleweresupportedbyalarge,multiregistry,retrospectivestudyfrom
Europe.[43]
Thenaturalhistoryofdesmoidsisvariable.Someauthorshaveproposedamodelfordesmoidtumorformationwherebyabnormal
fibroblastfunctionleadstomesentericplaque-likedesmoidprecursorlesions,whichinsomecasesoccurbeforesurgeryand
progresstomesentericfibromatosisaftersurgicaltrauma,ultimatelygivingrisetodesmoidtumors.[44]Itisestimatedthat10%of
desmoidsresolve,50%remainstableforprolongedperiods,30%fluctuate,and10%growrapidly.[45]Desmoidsoftenoccurafter
surgicalorphysiologicaltrauma,andbothendocrineandgeneticfactorshavebeenimplicated.Approximately80%ofintra-
abdominaldesmoidsinFAPoccuraftersurgicaltrauma.[46,47]
ThedesmoidsinFAPareoftenintra-abdominal,maypresentearly,andcanleadtointestinalobstructionorinfarctionand/or
obstructionoftheureters.[39]Insomeseries,desmoidsarethesecondmostcommoncauseofdeathafterCRCinFAPpatients.
[48,49]Astagingsystemhasbeenproposedtofacilitatethestratificationofintra-abdominaldesmoidsbydiseaseseverity.[50]The
proposedstagingsystemforintra-abdominaldesmoidsisasfollows:stageIforasymptomatic,nongrowingdesmoids;stageIIfor
symptomatic,nongrowingdesmoidsof10cmorlessinmaximumdiameter;stageIIIforsymptomaticdesmoidsof11to20cmor
forasymptomatic,slow-growingdesmoids;andstageIVfordesmoidslargerthan20cm,orrapidlygrowing,orwithlife-
threateningcomplications.[50]
ThesedatasuggestthatgenetictestingcouldbeofvalueinthemedicalmanagementofpatientswithFAPand/ormultiple
desmoidtumors.ThosewithAPCgenotypes,especiallythosepredisposingtodesmoidformation(e.g.,atthe3endofAPCcodon
1445),appeartobeathighriskofdevelopingdesmoidsafteranysurgery,includingrisk-reducingcolectomyandsurgical
surveillanceproceduressuchaslaparoscopy.[38,45,51]
ThemanagementofdesmoidsinFAPcanbechallengingandcancomplicatepreventionefforts.Currently,thereisnoaccepted
standardtreatmentfordesmoidtumors.Multiplemedicaltreatmentshavegenerallybeenunsuccessfulinthemanagementof
desmoids.Treatmentshaveincludedantiestrogens,nonsteroidalanti-inflammatorydrugs(NSAIDs),chemotherapy,andradiation
therapy,amongothers.Studieshaveevaluatedtheuseofraloxifenealone,tamoxifenorraloxifenecombinedwithsulindac,and
pirfenidonealone.[52-54]ThereareanecdotalreportsofusingimatinibmesylatetotreatdesmoidtumorsinFAPpatients;
however,furtherstudiesareneeded.[55]Significantdesmoidtumorregressionwasreportedinsevenpatientswhohad
symptomatic,unresectable,intra-abdominaldesmoidtumorsandfailedhormonaltherapywhentreatedwithchemotherapy
(doxorubicinanddacarbazine)followedbymeloxicam.[56]
Thirteenpatientswithintra-abdominaldesmoidsand/orunfavorableresponsetoothermedicaltreatments,whohadexpressionof
estrogenalphareceptorsintheirdesmoidtissues,wereincludedinaprospectivestudyofraloxifene,givenindosesof120mg
daily.[52]Sixofthepatientshadbeenontamoxifenorsulindacbeforetreatmentwithraloxifene,andsevenpatientswere
previouslyuntreated.All13patientswithintra-abdominaldesmoiddiseasehadeitherapartialoracompleteresponse7monthsto
35monthsafterstartingtreatment,andmostdesmoidsdecreasedinsizeat4.71.8monthsaftertreatment.Responseoccurred
inpatientswithdesmoidplaquesandwithdistinctlesions.Studylimitationsincludesmallsamplesize,andtheclinicalevaluationof
responsewasnotconsistentinallpatients.Severalquestionsremainconcerningpatientswithdesmoidtumorsnotexpressing
estrogenalphareceptorswhohavereceivedraloxifeneandtheiroutcomeandwhichpatientsmaybenefitfromthispotential
treatment.
Asecondstudyof13patientswithFAP-associateddesmoids,whoweretreatedwithtamoxifen120mg/dayorraloxifene120
mg/dayincombinationwithsulindac300mg/day,reportedthattenpatientshadeitherstabledisease(n=6)orapartialor
completeresponse(n=4)formorethan6monthsandthatthreepatientshadstablediseaseformorethan30months.[53]These
resultssuggestthatthecombinationoftheseagentsmaybeeffectiveinatleastslowingthegrowthofdesmoidtumors.However,
thenaturalhistoryofdesmoidsisvariable,withbothspontaneousregressionandvariablegrowthrates.
Athirdstudyreportedmixedresultsin14patientswithFAP-associateddesmoidtumorstreatedwithpirfenidonefor2years.[54]In
thisstudy,somepatientshadregression,somepatientshadprogression,andsomepatientshadstabledisease.
ThesethreestudiesillustratesomeoftheproblemsencounteredinthestudyofdesmoiddiseaseinFAPpatients:
Thedefinitionofdesmoiddiseasehasbeenusedinconsistently.
Insomepatients,desmoidtumorsdonotprogressorareveryslowgrowingandmaynotneedtherapy.
Thereisnoconsistent,systematicwaytoevaluatetheresponsetotherapy.
Thereisnosingleinstitutionthatwillenrollenoughpatientstoperformarandomizedtrial.
Norandomizedclinicaltrialsusingtheseagentshavebeenperformedandtheiruseinclinicalpracticeisbasedonanecdotal
experienceonly.
Levelofevidence:4
Becauseofthehighratesofmorbidityandrecurrence,ingeneral,surgicalresectionisnotrecommendedinthetreatmentofintra-
abdominaldesmoidtumors.However,somehaveadvocatedaroleforsurgerygiventheineffectivenessofmedicaltherapy,even
whenthepotentialhazardsofsurgeryareconsidered,andrecognizingthatnotalldesmoidsareresectable.[57]Arecentreviewof
onehospital'sexperiencesuggestedthatsurgicaloutcomeswithintra-abdominaldesmoidsmaybebetterthanpreviously
believed.[57,58]Issuesofsubjectselectionarecriticalinevaluatingsurgicaloutcomedata.[58]Abdominalwalldesmoidscanbe
treatedwithsurgicalresection,buttherecurrencerateishigh.
Stomach tumors
ThemostcommonFAP-relatedgastricpolypsarefundicglandpolyps(FGPs).FGPsareoftendiffuseandnotamenableto
endoscopicremoval.TheincidenceofFGPshasbeenestimatedtobeashighas60%inpatientswithFAP,comparedwith0.8%to
1.9%inthegeneralpopulation.[17,19,59-63]Thesepolypsconsistofdistortedfundicglandscontainingmicrocystslinedwith
fundic-typeepithelialcellsorfoveolarmucouscells.[64,65]
Thehyperplasticsurfaceepitheliumis,bydefinition,nonneoplastic.Accordingly,FGPshavenotbeenconsideredprecancerous;in
WesternFAPpatientstheriskofstomachcancerisminimallyincreased,ifatall.However,casereportsofstomachcancer
appearingtoarisefromFGPshaveledtoareexaminationofthisissue.[19,66]InoneFAPseries,focaldysplasiawasevidentinthe
surfaceepitheliumofFGPsin25%ofpatientsversus1%ofsporadicFGPs.[65]InaprospectivestudyofpatientswithFAP
undergoingsurveillancewithesophagogastroduodenoscopy,FGPsweredetectedin88%ofthepatients.Low-gradedysplasiawas
detectedin38%ofthesepatients,whereashigh-gradedysplasiawasdetectedin3%ofthesepatients.Intheauthor'sview,ifa
polypwithhigh-gradedysplasiaisidentified,polypectomycanbeconsideredwithrepeatendoscopicsurveillancein3to6months.
Considerationfortreatmentwithdailyproton-pumpinhibitors(PPIs)alsomaybegiven.[67]
Complicatingtheissueofdifferentialdiagnosis,FGPshavebeenincreasinglyrecognizedinnon-FAPpatientsconsumingPPIs.
[65,68]FGPsinthissettingcommonlyshowaPPIeffectconsistingofcongestionofsecretorygranulesinparietalcells,leadingto
irregularbulgingofindividualcellsintothelumenofglands.Tothetrainedeye,thepresenceofdysplasiaandtheconcomitant
absenceofacharacteristicPPIeffectcanbeconsideredhighlysuggestiveofthepresenceofunderlyingFAP.ThenumberofFGPs
tendstobegreaterinFAPthanthatseeninpatientsconsumingPPIs,althoughthereissomeoverlap.
GastricadenomasalsooccurinFAPpatients.TheincidenceofgastricadenomasinWesternpatientshasbeenreportedtobe
between2%and12%,whereasinJapan,ithasbeenreportedtobebetween39%and50%.[69-72]Theseadenomascanprogressto
carcinoma.FAPpatientsinKoreaandJapanarereportedtohaveathreefoldtofourfoldincreasedgastriccancerriskcompared
withtheirgeneralpopulation,afindingnotobservedinWesternpopulations.[73-76]Therecommendedmanagementforgastric
adenomasisendoscopicpolypectomy.Themanagementofadenomasinthestomachisusuallyindividualizedbasedonthesizeof
theadenomaandthedegreeofdysplasia.
Levelofevidence:5
Duodenum/small bowel tumors

Whereastheincidenceofduodenaladenomasisonly0.4%inpatientsundergoingupperGIendoscopy,[77]duodenaladenomas
arefoundin80%to100%ofFAPpatients.Thevastmajorityarelocatedinthefirstandsecondportionsoftheduodenum,
especiallyintheperiampullaryregion.[59,60,78]Thereisa4%to12%lifetimeincidenceofduodenaladenocarcinomainFAP
patients.[14,75,79,80]Inaprospectivemulticentersurveillancestudyofduodenaladenomasin368northernEuropeanswithFAP,
65%hadadenomasatbaselineevaluation(meanage,38years),withcumulativeprevalencereaching90%byage70years.In
contrasttoearlierbeliefsregardinganindolentclinicalcourse,theadenomasincreasedinsizeanddegreeofdysplasiaduringthe
8yearsofaveragesurveillance,thoughonly4.5%developedcancerwhileunderprospectivesurveillance.[17]Whilethisstudyisthe
largesttodate,itislimitedbytheuseofforward-viewingratherthanside-viewingendoscopyandthelargenumberof
investigatorsinvolvedinthestudy.AnothermodalitythroughwhichintestinalpolypscanbeassessedinFAPpatientsiscapsule
endoscopy.[81-83]Onestudyofcomputedtomography(CT)duodenographyfoundthatlargeradenomasizecouldbeaccurately
measuredbutsmaller,flatteradenomascouldnotbeaccuratelycounted.[84]
AretrospectivereviewofFAPpatientssuggestedthattheadenoma-carcinomasequenceoccurredinatemporalfashionfor
periampullaryadenocarcinomaswithadiagnosisofadenomaatameanageof39years,high-gradedysplasiaatameanageof47
years,andadenocarcinomaatameanageof54years.[85]Adecisionanalysisof601FAPpatientssuggestedthatthebenefitof
periodicsurveillancestartingatage30yearsledtoanincreasedlifeexpectancyof7months.[79]Althoughpolypsintheduodenum
canbedifficulttotreat,smallseriessuggestthattheycanbemanagedsuccessfullywithendoscopybutwithpotentialmorbidity
primarilyfrompancreatitis,bleeding,andduodenalperforation.[86,87]
FAPpatientswithparticularlysevereduodenalpolyposis,sometimescalleddensepolyposis,orwithhistologicallyadvanced
duodenaladenomasappeartobeatthehighestriskofdevelopingduodenaladenocarcinoma.[17,80,88,89]Becausetheriskof
duodenaladenocarcinomaiscorrelatedwiththenumberandsizeofpolyps,andtheseverityofdysplasiaofthepolyps,a
stratificationsystembasedonthesefeatureswasdevelopedtoattempttoidentifythoseindividualswithFAPathighestriskof
developingduodenaladenocarcinoma.[89]Accordingtothissystem,knownastheSpigelmanClassification(seeTable5),36%of
patientswiththemostadvancedstagewilldevelopcarcinoma.[80]
Table 5. Spigelman Classification
Points PolypNumber PolypSize(mm) Histology Dysplasia
1 14 14 Tubular Mild
2 520 410 Tubulovillous Moderate
3 >20 >10 Villous Severe
StageI,14points;StageII,56points;StageIII,78points;StageIV,912points[89]
Abaselineupperendoscopy,includingside-viewingduodenoscopy,shouldbeperformedbetweenages25and30yearsinFAP
patients.[76]Thesubsequentintervalsbetweenendoscopyvaryaccordingtothefindingsofthepreviousendoscopy,often,based
onSpigelmanstage.Recommendedintervalsarebasedonexpertopinionalthoughtherelativelyliberalintervalsforstage0-II
diseasearebasedinpartonthenaturalhistorydatageneratedbytheDutch/Scandinavianduodenalsurveillancetrial(seeTable
6).[17]
ThemainadvantagesoftheSpigelmanClassificationareitslong-standingfamiliaritytoandusagebythoseinthefield,which
allowsreasonablestandardizationofoutcomecomparisonsacrossstudies.[72,90]However,thereareseverallimitationson
attemptedapplicationoftheSpigelmanClassification:
Mostpathologistsdonotcurrentlyemploythetermmoderatedysplasia,preferringasimplerlow-versushigh-grade
dysplasiasystem.
Becauseofthevillousnatureofnormalduodenalepithelium,pathologistscommonlydisagreeovertheclassificationof
tubular,tubulovillous,andvillous.
Spigelmanstagingrequiresbiopsy,whichisnotalwaysessentialwhenonlyafewsmallplaquesarepresent;conversely,for
largeradenomas,samplingvariationleadstounderstaging.[91,92]
Table 6. Recommended Screening Intervals by Spigelman Stage
SpigelmanStage NCCN(2015)[93] Grovesetal.(2002)[80]
0(nopolyps) Endoscopyevery4y Endoscopyevery5y
I Endoscopyevery23y Endoscopyevery5y
II Endoscopyevery13y Endoscopyevery3y
CP+ET
III Endoscopyevery612mo Endoscopyevery12y
CP+ET(+/-GA)
SpigelmanStage NCCN(2015)[93] Grovesetal.(2002)[80]
IV Surgicalreferral Surgicalresection
Completemucosectomyor
duodenectomy,orWhippleprocedureif
duodenalpapillaisinvolved OR
Expertendoscopicsurveillanceevery36 Endoscopyevery12y
mo
CP+ET(+/-GA)
CP=chemoprevention;ET=endoscopictherapy;GA=generalanesthetic;NCCN=NationalComprehensiveCancerNetwork.
RefertotheInterventionsforFAPsectionintheMajorGeneticSyndromessectionofthissummaryformoreinformationaboutchemoprevention.
SeebelowforadditionalinformationabouttheuseofsurgicalresectioninSpigelmanstageIVdisease.
Theresultsoflong-termduodenaladenomasurveillanceofFAPpatientsinNordiccountriesandtheNetherlandsrevealed
significantduodenalcancerriskinFAPpatients.[94]Perprotocol,biennialfrontal-viewingendoscopywasperformedfrom1990
through2000.Subsequently,patientswerefollowedupwithsurveillanceaccordingtointernationalguidelines.The261of304
patients(86%)whohadmorethanoneendoscopycomprisedthestudygroup.Medianfollow-upwas14years(range,917years).
Thelifetimeriskofduodenaladenomatosiswas88%.Forty-fourpercentofpatientshadworseningSpigelmanstageovertime,
whereas12%improvedand34%remainedunchanged.Twentypatients(7%)developedduodenalcanceratamedianageof56
years(range,4482years).Thecumulativecancerincidencewas18%atage75years(95%CI,828).Survivalinpatientswith
symptomaticcancerswasworsethanthosediagnosedatsurveillanceendoscopy.
Levelofevidence(screeningforduodenum/smallboweltumors):3
Manyfactors,includingseverityofpolyposis,comorbiditiesofthepatient,patientpreferences,andavailabilityofadequately
trainedphysicians,determinewhethersurgicalorendoscopictherapyisselectedforpolypmanagement.Endoscopicresectionor
ablationoflargeorhistologicallyadvancedadenomasappearstobesafeandeffectiveinreducingtheshort-termriskof
developingduodenaladenocarcinoma;[86,87,95]however,patientsmanagedwithendoscopicresectionofadenomasremainat
substantialriskofdevelopingrecurrentadenomasintheduodenum.[91]Themostdefinitiveprocedureforreducingtheriskof
adenocarcinomaissurgicalresectionoftheampullaandduodenum,thoughtheseproceduresalsohavehighermorbidityand
mortalityassociatedwiththemthandoendoscopictreatments.Duodenotomyandlocalresectionofduodenalpolypsor
mucosectomyhavebeenreported,butinvariably,thepolypsrecuraftertheseprocedures.[96]Inaseriesof47patientswithFAP
andSpigelmanstageIIIorstageIVdiseasewhounderwentdefinitiveradicalsurgery,thelocalrecurrenceratewasreportedtobe
9%atameanfollow-upof44months.Thislocalrecurrencerateisdramaticallylowerthananylocalendoscopicorsurgical
approachfromthesamestudy.[91]Pancreaticoduodenectomyandpancreas-sparingduodenectomyareappropriatesurgical
therapiesthatarebelievedtosubstantiallyreducetheriskofdevelopingperiampullaryadenocarcinoma.[92,96-98]Ifsuchsurgical
optionsareconsidered,preservationofthepylorusisofparticularbenefitinthisgroupofpatientsbecausemostwillhave
undergoneasubtotalcolectomywithileorectalanastomosisortotalcolectomywithilealpouchanalanastomosis(IPAA).Asnoted
inaNorthernEuropeanstudy,[17]andothers,[99,100]thevastmajorityofpatientswithduodenaladenomaswillnotdevelop
cancerandcanbefollowedwithendoscopy.However,individualswithadvancedadenomas(SpigelmanstageIIIorstageIV
disease)generallyrequireendoscopicorsurgicaltreatmentofthepolyps.Chemopreventionstudiesforduodenaladenomasin
FAPpatientsarecurrentlyunderwayandmayofferanalternatestrategyinthefuture.
Theendoscopicapproachtolargerand/orflatteradenomasoftheduodenumdependsonwhethertheampullaisinvolved.
Endoscopicmucosalresection(EMR)aftersubmucosalinjectionofsaline,withorwithoutepinephrineand/ordye,suchasindigo
carmine,canbeemployedfornonampullarylesions.Ampullarylesionsrequireevengreatercareincludingendoscopicultrasound
evaluationforevidenceofbileorpancreaticductinvolvement.Stentingofthepancreaticductiscommonlyperformedtoprevent
stricturingandpancreatitis.Thestentsrequireendoscopicremovalatanintervalof1to4weeks.Becausetheampullaistethered
attheductalorifices,ittypicallydoesnotuniformlyliftwithinjection,soinjectioniscommonlynotused.Anyconsiderationof
EMRorampullectomyrequiresgreatexperienceandjudgment,withcarefulconsiderationofthenaturalhistoryofuntreated
lesionsandanappreciationofthehighrateofadenomarecurrencedespiteaggressiveendoscopicintervention.[87,91,92,97,101-
104]TheliteratureuniformlysupportsduodenectomyforSpigelmanstageIVdisease.ForSpigelmanstageIIandIIIdisease,there
isaroleforendoscopictreatmentinvariablyfocusingontheoneortwoworstlesionsthatarepresent.
Reluctancetoconsidersurgicalresectionhastodowithshort-termmorbidityandmortalityandlong-termcomplicationsrelatedto
surgery.Althoughtheseconcernsarelikelyoverstated,[91,92,98,101,105-111]fearofsurgicalinterventioncanleadtoaggressive
andsomewhatill-advisedendoscopicinterventions.Insomecircumstances,endoscopicresectionofampullaryand/orother
duodenaladenomascannotbeaccomplishedcompletelyorsafelybyendoscopicmeans,andduodenectomycannotbe
accomplishedwithoutriskingashort-gutsyndromeorcannotbedoneatallbecauseofmesentericfibrosis.Insuchcases,surgical
transduodenalampullectomy/polypectomycanbeperformed.Thisis,however,associatedwithahighriskoflocalrecurrence
similartothatofendoscopictreatment.
Levelofevidence(treatmentofduodenum/smallboweltumors):4
Other tumors
ThespectrumoftumorsarisinginFAPissummarizedinTable4.
Papillarythyroidcancerhasbeenreportedtoaffect1%to2%ofpatientswithFAP.[112]However,arecentstudy[113]ofpapillary
thyroidcancersinsixfemaleswithFAPfailedtodemonstratelossofheterozygosity(LOH)orpathogenicvariantsofthewild-type
alleleincodons545and1061to1678ofthesixtumors.Inaddition,fouroutoffiveofthesepatientshaddetectablesomatic
RET/PTCchimericgenes.Thispathogenicvariantisgenerallyrestrictedtosporadicpapillarythyroidcarcinomas,suggestingthe
involvementofgeneticfactorsotherthanAPCpathogenicvariants.Furtherstudiesareneededtoshowwhetherothergenetic
factorssuchastheRET/PTCchimericgeneareindependentlyresponsiblefororcooperativewithAPCvariantsincausingpapillary
thyroidcancersinFAPpatients.Althoughlevel1evidenceislacking,aconsensusopinionrecommendsannualthyroid
examinationsbeginninginthelateteenageyearstoscreenforpapillarythyroidcancerinpatientswithFAP.Thesamepanel
suggestsclinicianscouldconsidertheadditionofannualthyroidultrasoundstothisscreeningroutine.[93,114,115]
Levelofevidence(thyroidcancerscreening):4
AdrenaltumorshavebeenreportedinFAPpatients,andonestudydemonstratedLOHinanadrenocorticalcarcinoma(ACC)inan
FAPpatient.[116]Inastudyof162FAPpatientswhounderwentabdominalCTforevaluationofintra-abdominaldesmoidtumors,
15patients(11females)werefoundtohaveadrenaltumors.[117]Ofthese,twohadsymptomsattributabletocortisol
hypersecretion.ThreeofthesepatientsunderwentsubsequentsurgeryandwerefoundtohaveACC,bilateralnodularhyperplasia,
oradrenocorticaladenoma.Theprevalenceofanunexpectedadrenalneoplasiainthiscohortwas7.4%,whichcompareswitha
prevalenceof0.6%to3.4%(P<.001)innon-FAPpatients.[117]Nomoleculargeneticanalyseswereprovidedforthetumors
resectedinthisseries.
Hepatoblastomaisarare,rapidlyprogressive,andusuallyfatalchildhoodmalignancythat,ifconfinedtotheliver,canbecuredby
radicalsurgicalresection.MultiplecasesofhepatoblastomahavebeendescribedinchildrenwithanAPCpathogenicvariant.[118-
127]SomeserieshavealsodemonstratedLOHofAPCinthesetumors.[119,121,128]Nospecificgenotype-phenotypecorrelations
havebeenidentifiedinFAPpatientswithhepatoblastoma.[129]Althoughlackinglevel1evidence,aconsensuspanelhas
suggestedthatabdominalexamination,abdominalultrasound,andmeasurementofserumalphafetoproteinevery3to6months
forthefirst5yearsoflifeinchildrenwithapredispositiontoFAPbeconsidered.[93,130]
Levelofevidence(hepatoblastomascreening):5
TheconstellationofCRCandbraintumorshasbeenreferredtoasTurcotsyndrome;however,Turcotsyndromeismolecularly
heterogeneous.Molecularstudieshavedemonstratedthatcolonpolyposisandmedulloblastomaareassociatedwithpathogenic
variantsinAPC,whilecoloncancerandglioblastomaareassociatedwithpathogenicvariantsinmismatchrepair(MMR)genes.
[131]
ThereareseveralreportsofotherextracolonictumorsassociatedwithFAP,butwhetherthesearesimplycoincidenceoractually
shareacommonmoleculargeneticoriginwiththecolonictumorsisnotalwaysevident.Someofthesereportshavedemonstrated
LOHoravariantofthewild-typeAPCalleleinextracolonictumorsinFAPpatients,whichstrengthenstheargumentfortheir
inclusionintheFAPsyndrome.
Genetic testing for FAP

APCgenetestingisnowcommerciallyavailableandhasledtochangesinmanagementguidelines,particularlyforthosewhose
testsindicatetheyarenotcarriersofpathogenicvariants.PresymptomaticgeneticdiagnosisofFAPinat-riskindividualshasbeen
feasiblewithlinkage[22]anddirectdetection[132]ofAPCpathogenicvariants.Thesetestsrequireasmallsample(<10cc)ofblood
inwhichthelymphocyteDNAistested.Ifoneweretouselinkageanalysistoidentifygenecarriers,ancillaryfamilymembers,
includingmorethanoneaffectedindividual,wouldneedtobestudied.Withdirectdetection,fewerfamilymembersblood
samplesarerequiredthanforlinkageanalysis,butthespecificpathogenicvariantmustbeidentifiedinatleastoneaffected
personbyDNAvariantanalysisorsequencing.Thedetectionrateisapproximately80%usingsequencingalone.[133]
Studieshavereportedwholeexondeletionsin12%ofFAPpatientswithpreviouslynegativeAPCtesting.[134,135]Forthisreason,
deletiontestinghasbeenaddedasanoptionaladjuncttosequencingofAPC.Furthermore,pathogenicvariantdetectionassays
thatuseMLPAarebeingdevelopedandappeartobeaccuratefordetectingintragenicdeletions.[136]MYHgenetestingmaybe
consideredinAPCpathogenicvariantnegativeaffectedindividuals.[137](RefertotheAdenomatous polyposis coli [APC]sectionof
thissummaryformoreinformation.)
Patientswhodevelopfewerthan100colorectaladenomatouspolypsareadiagnosticchallenge.Thedifferentialdiagnosisshould
includeAFAPandMYH-associatedcolorectalneoplasia(alsoreportedasMYH-associatedpolyposisorMAP).[138]AFAPcanbe
diagnosedbytestingforgermlineAPCgenepathogenicvariants.(RefertotheAttenuatedFamilialAdenomatousPolyposis[AFAP]
sectionintheMajorGeneticSyndromessectionofthissummaryformoreinformation.)MYH-associatedneoplasiaiscausedby
germlinehomozygousrecessivepathogenicvariantsintheMYHgene.[139]
Presymptomaticgenetictestingremovesthenecessityofannualscreeningofat-riskindividualswhodonothavethefamilialgene
pathogenicvariant.Forat-riskindividualswhohavebeenfoundtobedefinitivelypathogenicvariantnegativebygenetictesting,
thereisnoclearconsensusontheneedfororfrequencyofcolonscreening,[21]thoughallexpertsagreethatatleastoneflexible
sigmoidoscopyorcolonoscopyexaminationshouldbeperformedinearlyadulthood(byage1825years).[21,22]Colonadenomas
willdevelopinnearly100%ofpersonswhoareAPCpathogenicvariantpositive;risk-reducingsurgerycomprisesthestandardof
caretopreventcoloncancerafterpolypshaveappearedandaretoonumerousorhistologicallyadvancedtomonitorsafelyusing
endoscopicresection.
Interventions for FAP

IndividualsatriskofFAP,becauseofaknownAPCpathogenicvariantineitherthefamilyorthemselves,areevaluatedforonsetof
polyposisbyflexiblesigmoidoscopyorcolonoscopy.OnceanFAPfamilymemberisfoundtomanifestpolyps,theonlyeffective
managementtopreventCRCiseventualcolectomy.ProphylacticsurgeryhasbeenshowntoimprovesurvivalinpatientswithFAP.
[140]Iffeasible,thepatientandhis/herfamilymembersshouldbeincludedinaregistrybecauseithasbeenshownretrospectively
thatregistrationandsurveillancereduceCRCincidenceandmortality.[141]InpatientswithclassicFAPidentifiedveryearlyintheir
course,thesurgeon,endoscopist,andfamilymaychoosetodelaysurgeryforseveralyearsintheinterestofachievingsocial
milestones.Inaddition,incarefullyselectedpatientswithAFAP(thosewithminimalpolypburdenandadvancedage),deferringa
decisionaboutcolectomymaybereasonablewithsurgeryperformedonlyinthefaceofadvancingpolypburdenordysplasia.
Therecommendedageatwhichsurveillanceforpolyposisshouldbegininvolvesatrade-off.Ontheonehand,someonewhowaits
untilthelateteenstobeginsurveillancefacesaremotepossibilitythatacancerwillhavedevelopedatanearlierage.Althoughitis
rare,CRCcandevelopinateenagerwhocarriesanAPCpathogenicvariant.Ontheotherhand,itispreferabletoallowpeopleat
risktodevelopemotionallybeforetheyarefacedwithamajorsurgicaldecisionregardingthetimingofcolectomy.Therefore,
surveillanceisusuallybegunintheearlyteenageyears(age1015years).Surveillancehasconsistedofeitherflexible
sigmoidoscopyorcolonoscopyeveryyear.[93,142,143]Ifflexiblesigmoidoscopyisutilizedandpolypsarefound,colonoscopy
shouldbeperformed.Historically,sigmoidoscopymayhavebeenareasonableapproachatthetimeinidentifyingearlyadenomas
inamajorityofthepatients.However,colonoscopymustbeconsideredthetoolofchoiceinlightof(a)improvedinstrumentation
forfullcolonoscopy,(b)sedation,(c)recognitionofAFAP,inwhichthediseaseistypicallymostmanifestintherightcolon,and(d)
thegrowingtendencytodefersurgeryforanumberofyears.Individualswhohavetestednegativeforanotherwiseknownfamily
pathogenicvariantdonotneedFAP-orientedsurveillanceatall.Theyarerecommendedtoundergoaverage-riskpopulation
screening.Inthecaseoffamiliesinwhichnofamilyvarianthasbeenidentifiedinanaffectedperson,clinicalsurveillanceis
warranted.ColonsurveillanceshouldnotbestoppedinpersonswhoareknowntocarryanAPCpathogenicvariantbutwhodonot
yetmanifestpolyps,sinceadenomasoccasionallyarenotmanifestuntilthefourthandfifthdecadesoflife.(Refertothe
AttenuatedFamilialAdenomatousPolyposis[AFAP]sectionofthissummaryformoreinformation.)(RefertothePDQsummaryon
ColorectalCancerScreeningformoreinformationonthesemethods.)
Insomecircumstances,fullcolonoscopymaybepreferredoverthemorelimitedsigmoidoscopy.Amongpediatric
gastroenterologists,tolerabilityofendoscopicproceduresingeneralhasbeenregardedasimprovedwiththeuseofdeeper
intravenoussedation.
Table7summarizestheclinicalpracticeguidelinesfromdifferentprofessionalsocietiesregardingdiagnosisandsurveillanceof
FAP.
Table 7. Clinical Practice Guidelines for Diagnosis and Colon Surveillance of Familial Adenomatous
Polyposis (FAP)
Organization APCGeneTest AgeScreening Frequency Method Comment

Recommended Initiated
American Yes NA NA NA
SocietyofColon
andRectal
Surgeons(2001,
2003)[144-146]
American NA Puberty NA Endoscopy Referraltoa

CancerSociety center
(2002)[147] specializingin
FAPscreening
suggested.
GISocieties Yes 1012y Annual FS

(2003)a[142]
Organization APCGeneTest AgeScreening Frequency Method Comment

Recommended Initiated
NCCN(2015) Yes 1015y Annual FSorC Ifanat-risk

[93] individualis
foundtonot
carrytheAPC
gene
pathogenic
variant
responsiblefor
familial
polyposisinthe
family,
screeningasan
average-risk
individualis
recommended.
C=colonoscopy;FS=flexiblesigmoidoscopy;GI=gastrointestinal;NA=notaddressed;NCCN=NationalComprehensiveCancerNetwork.
a
GISocietiesAmericanAcademyofFamilyPractice,AmericanCollegeofGastroenterology,AmericanCollegeofPhysicians-AmericanSocietyof
InternalMedicine,AmericanCollegeofRadiology,AmericanGastroenterologicalAssociation,AmericanSocietyofColorectalSurgeons,and
AmericanSocietyforGastrointestinalEndoscopy.
OnceanFAPfamilymemberisfoundtomanifestpolyposis,colectomyistheonlyeffectivemanagement.Patientanddoctorshould
enterintoanindividualizeddiscussiontodecidewhensurgeryshouldbeperformed.Itisusefultoincorporateintothediscussion
theriskofdevelopingdesmoidtumorsaftersurgery.Timingofrisk-reducingsurgeryusuallydependsonthenumberofpolyps,
theirsize,histology,andsymptomatology.[148]Oncenumerouspolypshavedeveloped,surveillancecolonoscopyisnolonger
usefulintimingthecolectomybecausepolypsaresonumerousthatitisnotpossibletobiopsyorremoveallofthem.Atthistime,
itisappropriateforpatientstoconsultwithasurgeonwhoisexperiencedwithavailableoptions,includingtotalcolectomyand
postcolectomyreconstructiontechniques.[149]Rectum-sparingsurgery,withsigmoidoscopicsurveillanceoftheremainingrectum,
isareasonablealternativetototalcolectomyinthosecompliantindividualswhounderstandtheconsequencesandmakean
informeddecisiontoaccepttheresidualriskofrectalcanceroccurringdespiteperiodicsurveillance.[150]
SurgicaloptionsincluderestorativeproctocolectomywithIPAA,subtotalcolectomywithileorectalanastomosis(IRA),ortotal
proctocolectomywithileostomy(TPC).TPCisreservedforpatientswithlowrectalcancerinwhichthesphinctercannotbespared
orforpatientsonwhomanIPAAcannotbeperformedbecauseoftechnicalproblems.Thereisnoriskofdevelopingrectalcancer
afterTPCbecausethewholemucosaatriskisremoved.WhetheracolectomyandanIRAorarestorativeproctocolectomyis
performed,mostexpertssuggestthatperiodicandlifelongsurveillanceoftherectumortheilealpouchbeperformedtoremove
orablateanypolyps.ThisisnecessitatedbycaseseriesofrectalcancersarisingintherectumofFAPpatientswhohadsubtotal
colectomieswithanIRAinwhichtherewasanapproximately25%cumulativeriskofrectaladenocarcinoma20yearsafterIRAand
bycasereportsofadenocarcinomaintheileoanalpouchandanalcanalafterrestorativeproctocolectomy.[151-154]The
cumulativeriskofrectalcancerafterIRAmaybelowerthanthatreportedintheliterature,inpartbecauseofbetterselectionof
patientsforthisprocedure,suchasthosewithminimalpolypburdenintherectum.[149]Otherfactorsthathavebeenreportedto
increasetherectalcancerriskafterIRAincludethepresenceofcoloncanceratthetimeofIRA,thelengthoftherectalstump,and
thedurationoffollow-upafterIRA.[155-161]AnabdominalcolectomywithIRAastheprimarysurgeryforFAPdoesnotpreclude
laterconversiontoanIPAAforuncontrolledrectalpolypsand/orrectalcancer.IntheDanishPolyposisRegistry,themorbidityand
functionalresultsofasecondaryIPAA(afterapreviousIRA)in24patientswerereportedtobesimilartothoseof59patientswho
underwentprimaryIPAA.[162]
Inmostcases,theclinicalpolypburdenintherectumatthetimeofsurgerydictatesthetypeofsurgicalintervention,namely
restorativeproctocolectomywithIPAAversusIRA.Patientswithamildphenotype(<1,000colonicadenomas)andfewerthan20
rectalpolypsmaybecandidatesforIRAatthetimeofprophylacticsurgery.[163]Insomecases,however,thepolypburdenis
equivocal,andinsuchcases,investigatorshaveconsideredtheroleofgenotypeinpredictingsubsequentoutcomeswithrespect
totherectum.[164]PathogenicvariantsreportedtoincreasetherectalcancerriskandeventualcompletionproctectomyafterIRA
includevariantsinexon15codon1250,exon15codons1309and1328,andexon15variantsbetweencodons1250and1464.
[160,151,161,165]InpatientswhohaveundergoneIPAA,itisimportanttocontinueannualsurveillanceoftheilealpouchbecause
thecumulativeriskofdevelopingadenomasinthepouchhasbeenreportedtobeupto75%at15years.[166,167]Althoughthey
arerare,carcinomashavebeenreportedintheilealpouchandanaltransitionzoneafterrestorativeproctocolectomyinFAP
patients.[168]Ameta-analysisofqualityoflifeafterrestorativeproctocolectomyandIPAAhassuggestedthatFAPpatientsdo
marginallybetterthaninflammatoryboweldiseasepatientsintermsoffistulaformation,pouchitis,stoolfrequency,andseepage.
[169]
Celecoxib,aspecificcyclooxygenaseII(COX-2)inhibitor,andnonspecificCOX-2inhibitors,suchassulindac,havebeenassociated
withadecreaseinpolypsizeandnumberinFAPpatients,suggestingaroleforchemopreventiveagentsinthetreatmentofthis
disorder.[170,171]AlthoughcelecoxibhadbeenapprovedbytheU.S.FoodandDrugAdministration(FDA),itslicensewas
voluntarilywithdrawnbythemanufacturer.Currently,therearenoFDA-approveddrugsforchemopreventioninFAP.Nevertheless,
agentssuchascelecoxibandsulindacareinsufficientlywidespreadusethatchemopreventiveclinicaltrialstypicallyutilizeoneof
theseagentsasthecontrolarm.Arandomizedtrialshowedpossiblemarginalimprovementinpolypburdenwiththecombination
ofcelecoxibanddifluoromethylornithine,comparedwithcelecoxibalone.[172]
Asmall,randomized,placebo-controlled,dose-escalationtrialofcelecoxibinapediatricpopulation(aged1014years)
demonstratedthesafetyofcelecoxibatalldosinglevelswhenadministeredovera3-monthperiod.[173]Thisstudyfoundadose-
dependentreductioninadenomatouspolypburden.Atadoseof16mg/kg/day,whichapproximatestheapproveddoseof400mg
twicedailyinadults,thereductioninpolypburdenparalleledthatdemonstratedwithcelecoxibinadults.
Omega-3-polyunsaturatedfattyacideicosapentaenoicacidinthefreefattyacidformhasbeenshowntoreducerectalpolyp
numberandsizeinasmallstudyofpatientswithFAPpostsubtotalcolectomy.[174]Althoughnotdirectlycomparedina
randomizedtrial,theeffectappearedtobesimilarinmagnitudetothatpreviouslyobservedwithcelecoxib.
ItisunclearatpresenthowtoincorporateCOX-2inhibitorsintothemanagementofFAPpatientswhohavenotyetundergonerisk-
reducingsurgery.Adouble-blind,placebo-controlledtrialin41childandyoungadultcarriersofAPCpathogenicvariantswhohad
notyetmanifestedpolyposisdemonstratedthatsulindacmaynotbeeffectiveasaprimarytreatmentinFAP.Therewereno
statisticallysignificantdifferencesbetweenthesulindacandplacebogroupsover4yearsoftreatmentinincidence,number,orsize
ofpolyps.[171]
ConsistentwiththeeffectsofCOX-2inhibitorsoncolonicpolyps,inarandomized,prospective,double-blind,placebo-controlled
trial,celecoxib(400mg,administeredorallytwicedaily)reduced,butdidnoteliminate,thenumberofduodenalpolypsin32
patientswithFAPaftera6-monthcourseoftreatment.Ofimportance,astatisticallysignificanteffectwasseenonlyinindividuals
whohadmorethan5%oftheduodenuminvolvedwithpolypsatbaselineandwithanoraldoseof400mg,giventwicedaily.[175]
Apreviousrandomizedstudyof24FAPpatientstreatedwithsulindacfor6monthsshowedanonsignificanttrendinthereduction
ofduodenalpolyps.[176]ThesameissuessurroundingtheuseofCOX-2inhibitorsforthetreatmentofcolonicpolypsapplytotheir
useforthetreatmentofduodenalpolyps(e.g.,onlypartialeliminationofthepolyps,complicationssecondarytotheCOX-2
inhibitors,andlossofeffectafterthemedicationisdiscontinued).[175]
Becauseofthecommonclusteringofadenomatouspolypsaroundtheduodenalpapilla(wherebileenterstheintestine)and
preclinicaldatasuggestingthatursodeoxycholateinhibitsintestinaladenomasinmicethatharboranApcgermlinevariant,[177]
twotrialsthatemployursodeoxycholatehavebeenperformed.[178,179]Inbothstudies,ursodeoxycholatedidnothavea
significantchemopreventiveeffectonduodenalpolyps;paradoxically,inonestudy,ursodeoxycholateincombinationwith
celecoxibappearedtopromotepolypdensityinpatientswithFAP.
Becauseofreportsdemonstratinganincreaseincardiac-relatedeventsinpatientstakingrofecoxibandcelecoxib,[180-182]itis
unclearwhetherthisclassofagentswillbesafeforlong-termuseforpatientswithFAPandinthegeneralpopulation.Also,
becauseoftheshort-term(6months)natureofthesetrials,thereiscurrentlynoclinicalinformationaboutcardiaceventsinFAP
patientstakingCOX-2inhibitorsonalong-termbasis.
Levelofevidence(celecoxib):1b
Onecohortstudyhasdemonstratedregressionofcolonicandrectaladenomaswithsulindac(anNSAID)treatmentinFAP.The
reportedoutcomeofthistrialwasthenumberandsizeofpolyps,asurrogatefortheclinicaloutcomeofmaininterest,CRC
incidence.[183]
Levelofevidence(sulindac):1b
min/+
Preclinicalstudiesofasmall-moleculeepidermalgrowthfactorreceptor(EGFR)inhibitorandlow-dosesulindacintheApc
mousediminishedintestinaladenomadevelopmentby87%[184]suggestingthatEGFRinhibitorshadthepotentialtoinhibit
duodenalpolypsinFAPpatients.A6-monthdouble-blind,randomized,placebo-controlledtrialtestedtheefficacyofsulindac,150
mgtwicedaily,anderlotinib,75mgdaily,versusplaceboinFAPorAFAPpatientswithduodenalpolyps.[185]Ninety-twopatients
withFAPorAFAPwererandomlyassignedtoreceivestudydrugsorplaceboandunderwentpretreatmentandposttreatment
upperendoscopiestodeterminethechangesinthesumdiameterofthepolypsandnumberofpolypsina10cmsegmentof
proximalduodenum.Thetrialwasterminatedprematurelybecausetheprimaryendpointwasmet.Theintent-to-treatanalysis
demonstratedamediandecreaseinduodenalpolypburden(sumofdiameters)of8.5mminthesulindac/erlotinibarmwhilethere
wasan8mmincreaseintheplaceboarm(P<.001).Significantlyhigherratesofgrade1andgrade2adverseeventsoccurredin
thetreatmentarmthanintheplaceboarm:inthetreatmentarm,60.9%developedanacneiformrashand32.6%developedoral
mucositis;intheplaceboarm,19.6%developedanacneiformrashand10.9%developedoralmucositis.Basedonthepreviously
modesteffectsofsulindacandcelecoxibonduodenalpolypsinFAPpatients[171,183]andthedramaticeffectofgeneticEGFR
inhibitiononintestinaladenomadevelopmentintheApcmin/+mouse,[186]itislikelythaterlotinibwasresponsibleforthesuccess
ofthistrial.Anongoingclinicaltrialisdeterminingwhetherlowerdosesoferlotinibalonearesufficientforsignificantlyreducing
duodenalpolypburdeninFAPandAFAPpatients.
Levelofevidence(sulindac+erlotinib):1b
PatientswhocarryAPCgermlinepathogenicvariantsareatincreasedriskofothertypesofmalignancies,includingthyroidcancer,
smallbowelcancer,hepatoblastoma,andbraintumors.Theriskofthesetumors,however,ismuchlowerthanthatforcolon
cancer,andtheonlysurveillancerecommendationbyexpertsinthefieldisupperendoscopyofthegastricandduodenalmucosa.
[10,23]Theseverityofduodenalpolyposisdetectedappearstocorrelatewithriskofduodenaladenocarcinoma.[80](Refertothe
Duodenum/smallboweltumorssectionandtheOthertumorssectionintheMajorGeneticSyndromessectionofthissummaryfor
moreinformationaboutscreeningforextracolonicmalignanciesinpatientswithFAP.)
Attenuated Familial Adenomatous Polyposis (AFAP)

AFAPisaheterogeneousclinicalentitycharacterizedbyfeweradenomatouspolypsinthecolonandrectumthaninclassicFAP.It
wasfirstdescribedclinicallyin1990inalargekindredwithavariablenumberofadenomas.Theaveragenumberofadenomasin
thiskindredwas30,thoughtheyrangedinnumberfromafewtohundreds.[187]AdenomasinAFAParebelievedtoforminthe
mid-twentiestolatetwenties.[66]SimilartoclassicFAP,theriskofCRCishigherinindividualswithAFAP;theaverageageat
diagnosis,however,isolderthanclassicFAPat56years.[28,29,188]ExtracolonicmanifestationssimilartothoseinclassicFAPalso
occurinAFAP.ThesemanifestationsincludeupperGIpolyps(FGPs,duodenaladenomas,andduodenaladenocarcinoma),
osteomas,epidermoidcysts,anddesmoids.[66]
AFAPisassociatedwithparticularsubsetsofAPCpathogenicvariants,includingmissensechanges.Threegroupsofsite-specific
APCpathogenicvariantscausingAFAPhavebeencharacterized:[28-31,189,190]
Pathogenicvariantsassociatedwiththe5endofAPCandexon4inwhichpatientscanmanifest2tomorethan500
adenomas,includingtheclassicFAPphenotypeandupperGIpolyps.
Exon9associatedphenotypesinwhichpatientsmayhave1to150adenomasbutnoupperGImanifestations.
3regionpathogenicvariantsinwhichpatientshaveveryfewadenomas(<50).
APCgenetestingisanimportantcomponentoftheevaluationofpatientssuspectedofhavingAFAP.[191]Ithasbeen
recommendedthatthemanagementofAFAPpatientsincludecolonoscopyratherthanflexiblesigmoidoscopybecausethe
adenomascanbepredominantlyright-sided.[191]Theroleforandtimingofrisk-reducingcolectomyinAFAPiscontroversial.[192]
IfgermlineAPCpathogenicvarianttestingisnegativeinsuspectedAFAPindividuals,genetictestingforMYHpathogenicvariants
maybewarranted.[134]
Patientsfoundtohaveanunusuallyorunacceptablyhighadenomacountatanage-appropriatecolonoscopyposeadifferential
diagnosticchallenge.[193,194]Intheabsenceoffamilyhistoryofsimilarlyaffectedrelatives,thedifferentialdiagnosismayinclude
AFAP(includingMAP),LS,oranotherwiseunclassifiedsporadicorgeneticproblem.AcarefulfamilyhistorymayimplicateAFAPor
LS.
Table8summarizestheclinicalpracticeguidelinesfromdifferentprofessionalsocietiesregardingsurveillanceofAFAP.
Table 8. Clinical Practice Guidelines for Colon Surveillance of Attenuated Familial Adenomatous
Polyposis (AFAP)
Organization Condition Screening Screening AgeScreening Comment

Method Frequency Initiated
EuropeMallorca AFAP Colonoscopy Every2y;every 1820y

Group(2008) 1yifadenomas
[195] aredetected
NCCN(2015) Personalhistory Colonoscopy Every12y Ifpatienthad

[93] ofAFAPwith colectomywith
smalladenoma IRA,endoscopic
burdena evaluationevery
612mo
dependingon
polypburden.
Colectomyand
IRAmaybe
consideredin
patientsaged
21y
NCCN(2015) Personalhistory Notapplicable Notapplicable Notapplicable Colectomywith

[93] ofAFAPwith IRApreferred.
significant Consider
polyposis proctocolectomy
withIPAAif
denserectal
polyposis.

NCCN(2015) Unaffected,at- Colonoscopy Every23y Lateteens

[93] riskfamily
member;family
pathogenic
variant
unknown;APC
pathogenic
variantstatus
unknownor
positive
IPAA=ilealpouchanalanastomosis;IRA=ileorectalanastomosis;NCCN=NationalComprehensiveCancerNetwork.
a
Fewerthan20adenomasthatareeach<1cmindiameterandwithoutadvancedhistologysothatcolonoscopywithpolypectomycanbeusedto
effectivelyeliminatethepolyps.
MYH-Associated Polyposis (MAP)

MAPisanautosomalrecessiveinheritedpolyposissyndrome.TheMYHgenewasfirstidentifiedin2002inthreesiblingswith
multiplecolonicadenomasandCRCbutnoAPCpathogenicvariant.[139]MAPhasabroadclinicalspectrum.Mostoftenit
resemblestheclinicalpictureofAFAP,butithasbeenreportedinindividualswithphenotypicresemblancetoclassicalFAPandLS.
[196]MAPpatientstendtodevelopfeweradenomasatalateragethanpatientswithAPCpathogenicvariants[137,197]andalso
carryahighriskofCRC(35%63%).[5,198]A2012studyofcolorectaladenomaburdenin7,225individualsreportedaprevalenceof
biallelicMYHpathogenicvariantsof4%(95%confidenceinterval[CI],3%5%)amongthosewith10to19adenomas,7%(95%CI,
6%8%)amongthosewith20to99adenomas,and7%(95%CI,6%8%)amongthosewith100to999adenomas.[199]Thisbroad
clinicalpresentationresultsfromtheMYHgene'sabilitytocausediseaseinitshomozygousorcompoundheterozygousforms.
BasedonstudiesfrommultipleFAPregistries,approximately7%to19%ofpatientswithaFAPphenotypeandwithoutadetectable
APCgermlinepathogenicvariantcarrybiallelicvariantsintheMYHgene.[5,137,200,201]
Adenomas,serratedadenomas,andhyperplasticpolypscanbeseeninMAPpatients.TheCRCstendtoberight-sidedand
synchronousatpresentationandseemtocarryabetterprognosisthansporadicCRC.[202]Clinicalmanagementguidelinesfor
biallelicMAPrangebetweenonceayeartoevery3yearsforcolonoscopicsurveillancebeginningatage18to30years,[93,195,198]
withupperendoscopicsurveillancebeginningatage25to30years.[195](RefertoTable9formoreinformationaboutavailable
clinicalpracticeguidelinesforcolonsurveillanceinbiallelicMAPpatients.)Therecommendedupperendoscopicsurveillance
intervalcanbebasedontheburdenofinvolvementaccordingtoSpigelmancriteria.[195]Totalcolectomywithileorectal
anastomosisorsubtotalcolectomymaybeappropriateforpatientswithMYH-associatedpolyposis,providedthattheyhaveno
rectalcancerorsevererectalpolyposisatpresentationandthattheyundergoyearlyendoscopicsurveillancethereafter.[198,203]
Table9summarizestheclinicalpracticeguidelinesfromdifferentprofessionalsocietiesregardingcolonsurveillanceofbiallelic
MAP.
Table 9. Clinical Practice Guidelines for Colon Surveillance of Biallelic MYH-Associated Polyposis
(MAP)

EuropeMallorca Carrierof Colonoscopy Every2y 1820y

Group(2008) biallelicMYH
[195] pathogenic
variants
Nieuwenhuiset Carrierof Colonoscopy Every12y

al.(2012)[198] biallelicMYH
pathogenic
variants
NCCN(2015) Personalhistory Colonoscopy Every12y Ifpatienthad

[93] ofMAP,small colectomywith
adenoma IRA,endoscopic
a
burden evaluationevery
612mo
dependingon
polypburden.
Colectomyand
IRAmaybe
consideredin
patientsaged
21y
NCCN(2015) Personalhistory Notapplicable Notapplicable Notapplicable Colectomywith

[93] ofMAPwith IRApreferred.
significant Consider
polyposis proctocolectomy
withIPAAif
denserectal
polyposis.If
patienthad
colectomywith
IRA,then
endoscopic
evaluationof
rectumevery6
12mo
dependingon
polypburden.
NCCN(2015) Unaffected,at- Colonoscopy Every23y 2530y Ifpositivefora

[93] riskfamily singleMYH
member;family pathogenic
pathogenic variant,follow
variant average-risk
unknown;MYH colorectal
pathogenic screening.
variantstatus
unknownor
positive
(biallelic)
IPAA=ilealpouchanalanastomosis;IRA=ileorectalanastomosis;NCCN=NationalComprehensiveCancerNetwork.
a
Fewerthan20adenomasthatareeach<1cmindiameterandwithoutadvancedhistologysothatcolonoscopywithpolypectomycanbeusedto
effectivelyeliminatethepolyps.
ManyextracoloniccancershavebeenreportedinpatientswithMAPincludinggastric,smallintestinal,endometrial,liver,ovarian,
bladder,thyroid,andskincancersincludingmelanoma,squamousepithelial,andbasalcellcarcinomas.[204,205]Additionally,
extracolonicmanifestationshavebeenreportedinafewMAPpatientsincludinglipomas,congenitalhypertrophyoftheretinal
pigmentepithelium,osteomas,anddesmoidtumors.[137,205-207]FemaleMAPpatientshaveanincreasedriskofbreastcancer.
[208]TheseextracolonicmanifestationsseemtooccurlessfrequentlyinMAPthaninFAP,AFAP,orLS.[209,210]
BecauseMAPhasanautosomalrecessiveinheritancepattern,siblingsofanaffectedpatienthavea25%chanceofalsocarrying
biallelicMYHpathogenicvariantsandshouldbeofferedgenetictesting.Similarly,testingcanbeofferedtothepartnerofan
affectedpatientsothattheriskintheirchildrencanbeassessed.
TheclinicalphenotypeofmonoallelicMYHpathogenicvariantsislesswellcharacterizedwithrespecttoincidenceandassociated
clinicalphenotypes,anditsroleinpathogenesisofpolyposiscoliandcolorectalcarcinomaremainsindispute.Approximately1%to
2%ofthegeneralpopulationcarryapathogenicvariantinMYH.[5,137,139]A2011meta-analysisfoundthatcarriersofmonoallelic
MYHpathogenicvariantsareatmodestlyincreasedriskofCRC(oddsratio[OR],1.15;95%CI,0.981.36);however,giventherarity
ofcarriersofmonoallelicpathogenicvariants,theyaccountforonlyatrivialproportionofallCRCcases.[211]Althoughsome
studieshavesuggestedscreeningtheseindividualsonthebasisofthismodestincreaseinrisk,[197,212]othershavesuggested
followingscreeningrecommendationsforthegeneralpopulation.[93]
MMRgenesmayinteractwithMYHandincreasetheriskofCRC.AnassociationbetweenMYHandMSH6hasbeenreported.Both
proteinsinteracttogetherinbaseexcisionrepairprocesses.AstudyreportedasignificantincreaseofMSH6pathogenicvariantsin
carriersofmonoallelicMYHpathogenicvariantswithCRCcomparedtononcarriers(11.5%vs.0%;P=.037).[213]
Mut Y homolog
TheMut Y homologgene,whichisalsoknownasMUTYHandMYH,islocatedonchromosome1p34.3-32.1.[202]Theproteinencoded
byMYHisabaseexcisionrepairglycosylase.Itrepairsoneofthemostcommonformsofoxidativedamage.Over100unique
sequencevariantsofMYHhavebeenreported(LeidenOpenVariationDatabase).Afounderpathogenicvariantwithethnic
differentiationisassumedforMYHpathogenicvariants.InCaucasianpopulationsofnorthernEuropeandescent,twomajor
variants,Y179CandG396D(formerlyknownasY165CandG382D),accountfor70%ofbiallelicpathogenicvariantsinMYH-
associatedpolyposispatients,and90%ofthesepatientscarryatleastoneofthesepathogenicvariants.[214]Othercausative
variantsthathavebeenfoundincludeP405L(formerlyknownasP391L)(Netherlands),[215,216]E480X(India),[200]Y104X
(Pakistan),[217]1395delGGA(Italy),[206]1186-1187insGG(Portugal),[218]andp.A359V(Japan,Korea).[219-221]BiallelicMYH
pathogenicvariantsareassociatedwitha93-foldexcessriskofCRC,withnearcompletepenetrancebyage60years.[222]
NTHL1
Astudyutilizingwhole-exomesequencingin51individualswithmultiplecolonicadenomasfrom48familiesidentifieda
homozygousgermlinenonsensepathogenicvariantinsevenaffectedindividualsfromthreeunrelatedfamiliesinthebase-excision
repairgeneNTHL1.[223]TheseindividualshadCRC,multipleadenomas(850),noneofwhichwereeitherhyperplasticorserrated,
andinthreeaffectedfemales,therewaseitherendometrialcancerorendometrialcomplexhyperplasia.Thereweretwoother
individualswhodevelopedduodenaladenomasandduodenalcancer.Allpedigreeswereconsistentwithautosomalrecessive
inheritance.Uponexaminingthreecancersandfiveadenomasfromdifferentaffectedindividuals,noneshowedmicrosatellite
instability(MSI).Theseneoplasmsdidshowenrichmentofcytosinetothyminetransitions.Additionalstudiesareneededtofurther
definethephenotype.
Oligopolyposis
Oligopolyposisisapopulartermusedtodescribetheclinicalpresentationofapolypcountorburdenthatisgreaterthan
anticipatedinthecourseofscreeninginaverage-riskpatientsbutthatfallsshortoftherequirementforadiagnosisofFAP.Thus,
oligo-,Greekforfew,canmeandifferentthingstodifferentobservers.Whileconcedingalackofconsensusonthematter,the
NationalComprehensiveCancerNetwork(NCCN)committeeonCRCscreeningsuggestsanAFAPdiagnosisisworthconsidering
when10to100adenomasarepresent.[93]Itwillbeusedheretodescribethecircumstanceinwhichthepolypcount(generally
adenoma)islargeenough,withorwithoutanyattendantfamilyhistory,toraiseinthemindoftheendoscopistthepossibilityofan
inheritedsusceptibility.
InthesettingofknownorsuspectedLS,thedetectionofonetotenadenomasisstillinkeepingwiththediagnosis.Asimilar
adenomacountinayoungpatientundergoingcolonoscopyforsymptomsorinascreeningpatientoverage50yearscouldraise
thequestionofLS.Intheappropriateclinicalsettingearlyonsetandpositivefamilyhistorythedetectionofanynumberof
adenomasmaysupportthetestinganddiagnosisofapatientforunderlyingLSpathogenicvariants,consistentwithguidelines
suchasthoseofferedbytheNCCN.SomecontroversyexistsovertheutilityoftestingadenomatissueforMSI,astheyieldislower
thanininvasivecancer.[224]Ingeneral,andsubjecttotheabovecaveats,LSisnotroutinelyconsideredinadiscussionof
oligopolyposis.
Onestudyconsideredaseriesofpolyps(37adenomas)from21patientswithknownMMRpathogenicvariants,performingMSI
andimmunohistochemistry(IHC)forMMRproteinexpression.[225]Overall,MSI-high(MSI-H)wasseenin41%andin100%of
adenomaslargerthan1cm.Adenomasmeasuringsmallerthan1cmyieldedMSIabout30%ofthetime.CorrelationbetweenMSI
andlossofstainingonIHCwasfairlyhigh,althoughthediscordancerate(17%)washigherthaninotherseriesthatevaluated
invasivecancersfromknowncarriersofMMRpathogenicvariants.AhigherMSIlikelihoodwasobservedinsubjectsolderthan50
years.IHCstaininginrelationtogeneshowed8of12MLH1adenomastohavelostproteinexpression,with10of20adenomas
fromMSH2patientstohavelossofexpression.Incontrast,none(0of6)oftheadenomasfromcarriersofMSH6pathogenic
variantshadlossofassociatedproteinexpression.TheauthorsconcludedthatwhilenormalMSI/IHCwassimplynotinformative,
abnormalMSI/IHCwasaslikelyinlarger(>8mm)polypsasincancersandthusareasonabletesttoconsider.
AFAPisfoundattheotherendoftheoligopolyposisspectrum.Mostcaseswillhavemorethan100adenomas,albeitatalaterage
andoftenwithapredominanceofmicroadenomasoftherightcolonandwithfewer,largerpolypsintheleftcolon.Caseswitha
positivefamilyhistoryandanAPCpathogenicvariantareclearlyvariantcasesofFAP,asthetermAFAPimplies.[226]However,
patientswithnoimmediatefamilyhistoryandalesseradenomaburdenmaynotbefoundtohaveanAPCpathogenicvariant.The
lowerthepolypcountthelowertheprobabilityofhavinganAPCpathogenicvariant.Someofthesecasesarenowknowntocarry
biallelicMYHpathogenicvariants,althoughevenhere,thelowertheadenomacountthelowerthevariantlikelihood.[227]
Anotherstudyevaluated152patientswith3to100adenomasandanother107APCpathogenicvariantnegativepatientswitha
classicFAPpolypburdenforevidenceofMYHpathogenicvariants.[137]Sixpatientswithmultipleadenomasandeightwitha
classicFAPburdenhadbiallelicMYHpathogenicvariants.Theauthorsconcludedthatacut-pointofabout15adenomaswasa
thresholdabovewhichMYHtestingwasreasonable,andmanyinsurancecompaniesintheUnitedStateshaveadoptedapolicy
basedonthiscumulativeadenomacount.SimilarratesforMYHbiallelicpathogenicvariantswerefoundbyothersusing20
adenomasasthethresholdforconsideringtesting.[227]
PathogenicvariantsinrelatedDNApolymerasegenesPOLEandPOLD1havebeendescribedinfamilieswitholigopolyposisand
endometrialcancer.[228,229]Anelegantapproachwasemployedusingwhole-genomesequencingin15selectedpatientswith
morethantenadenomasbeforeage60years.Severalhadacloserelativewithatleastfiveadenomaswhocouldalsohavewhole-
genomesequencingperformed.AlltestedpatientshadCRCorafirst-degreerelativewithCRC.AllhadnegativeAPC,MYH,and
MMRgenepathogenicvarianttestresults.Novariantswerefoundtobeincommonamongtheevaluatedfamilies.Inonefamily,
however,linkagehadestablishedsharedregions,inwhichonesharedvariantwasfound(POLEp.Leu424Val;c.1270C>G),witha
predictedmajorderangementinproteinstructureandfunction.Inavalidationphase,nearly4,000affectedcasesenrichedforthe
presenceofmultipleadenomasweretestedforthisvariantandcomparedwithnearly7,000controls.Inthisexercise,12additional
unrelatedcaseswerefoundtohavetheL424Vvariant,withnoneofthecontrolshavingthevariant.Intheaffectedfamilies,
inheritanceofmultiple-adenomariskappearedtobeautosomaldominant.Somaticvariantsintumorsweregenerallyconsistent
withtheotherwisetypicalchromosomeinstability(CIN)pathway,asopposedtoMSIorCIMP.Noextracolonicmanifestationswere
seen.Asimilarapproach,whole-genometestingforsharedvariants,withfurtherfilteringbylinkageanalysisidentifiedavariant
inthePOLD1gene(p.Ser478Asn;c.1433G>A).ThisS478Nvariantwasidentifiedintwooftheoriginallyevaluatedfamilies,
suggestingevidenceofcommonancestry.Thevalidationexerciseshowedonepatientwithpolypswiththevariantbutnocontrols
withthevariant.SomaticvariantpatternsweresimilartothePOLEvariant.Severalcasesofearly-onsetendometrialcancerwere
seen.ThemechanismunderlyingadenomaandcarcinomaformationresultingfromthePOLEL424Vvariantappearedtobea
decreaseinthefidelityofreplication-associatedpolymeraseproofreading.Thisinturnappearedtoleadtovariantsrelatedtobase
substitution.AsubsequentstudyconfirmedthatPOLEpathogenicvariantsareararecauseofoligopolyposisandearly-onsetCRC.
[230]AllindividualsinthisstudywerenegativeforgermlinepathogenicvariantsinAPC,MYH,andtheMMRgenes.ThePOLEvariant
L424Vwasfoundin3of485indexcaseswithcolorectalpolyposisandearly-onsetCRC.TumorswereMSIanddeficientofoneor
moreMMRproteinsintwoofthreeindexcases.SomaticvariantsinMMRgenes,possiblytheresultofhypermutabilitysecondary
toPOLEdeficiency,weredetectedinthesetwocases.
ThestudyauthorsrecommendconsiderationofPOLEandPOLD1testinginpatientswithmultipleorlargeadenomasinwhom
alternativepathogenicvarianttestingisuninformativeandsurveillanceakintothataffordedpatientswithLSorMAP.[228,229]
POLEandPOLD1pathogenicvarianttestingisbeingincorporatedintothenewmultiple-gene(panel)testsforCRCsusceptibility
offeredcommercially.
Amajorityofpatientswitholigopolyposisinvolvingadenomasarecurrentlynotfoundtohaveanunderlyingpredispositionwhen
evaluatedforpathogenicvariantsinknownpredispositiongenes.Suchcasesaregenerallymanagedasiftheyareatanincreased
riskofrecurrentadenomasevenwhenthecoloncanbeclearedofpolypsendoscopically.
Oligopolyposiscausedbyjuvenilepolyposissyndrome(JPS)orPJScanbedistinguishedfromadenomatouspolyposisonsimple
endoscopicandhistologicgrounds.Serratedpolyposiscanpresentinhighlyvariablefashion.TheWorldHealthOrganization
(WHO)criteriaforserratedpolyposis(=5serratedpolypsproximaltosigmoidwith2=1cm,oranynumberofpolypsproximalto
sigmoidifthereisarelativewithserratedpolyposis,or>20serratedpolypsanywhereinthecolon)haveneverbeenvalidated.
Furthermore,nogeneticbasishasbeenestablished,evenintheuncommonfamilialcases.Butcasesofoligopolyposisofthe
serratedvarietycaninitiallybechallengingtodistinguishfromoligoadenomatosis,particularlywhenthereisanadmixtureof
adenomas.Consequently,suchpatientsareincreasinglybeingreferredforgeneticcounselingandforconsiderationofgenetic
testing.OccasionalcasesofMYHbiallelicpathogenicvariantshavebeenfoundinpatientswithatleastsomefeaturesofserrated
polyposisandserratedpolypscanbeseeninLS.Generallythough,thegeneticworkupofserratedpolyposisisunrewarding.[231-
235]
Lynch Syndrome (LS)

Between1900and1990,numerouscasereportsoffamilieswithapparentincreasesinCRCwerereported.Asseriesofsuchreports
accumulated,certaincharacteristicclinicalfeaturesemerged:earlyageatonset;highriskofsecondprimarytumors;preferential
involvementoftherightcolon;improvedclinicaloutcome;andarangeofassociatedextracolonicsitesincludingtheendometrium,
ovaries,othersitesintheGItract,uroepithelium,brain,andskin(sebaceoustumors).TermssuchasLynch1(familieswithCRC
only),Lynch2(familieswithCRCandextracolonictumors),cancerfamilysyndrome,andlater,hereditarynonpolyposis
colorectalcancer(HNPCC),werecommonlyemployed.
By1990,theneedforenhancedsurveillance(colonoscopyatanearlyageandrepeatedfrequently)wasrecognized.However,the
needtolimitthisaggressiveregimentofamiliesmostlikelytohaveaninheritedsusceptibilityortrueHNPCCledtodevelopment
oftheso-calledAmsterdamcriteria:threeormorecasesofCRCovertwoormoregenerations,withatleastonediagnosedbefore
age50years,andnoevidenceofFAP.
Ataboutthissametime,achromosomalabnormalityon5qledtodetectinggeneticlinkagebetweenFAPandthisgenomicregion,
fromwhichtheAPCgenewaseventuallycloned.ThisledtosearchesforsimilarlinkageinHNPCC.TheAPCgenewasoneofseveral
genes(alongwithDCCandMCC)evaluatedandtowhichnoHNPCClinkagewasfound.Anextendedgenome-widesearchresulted
intherecognitionofacandidatechromosome2susceptibilitylocusinlargeHNPCCfamiliesin1993.OnceMSH2,thefirstHNPCC
gene,wassequenced,itwasevident(fromthesomaticvariantpatternsinthetumors)thattheMMRfamilyofgeneswaslikely
involved.Shortlythereafter,additionalMMRgeneswereidentified,includingMLH1,MSH6,andPMS2.TheseMMRgeneswere
formerlyreferredtoashMSH2,hMLH1,hMSH6,andhPMS2,withthehdesignatingthemashumanhomologs;forsimplicity,the
hwasdropped.
Concurrentwiththelinkagestudies,somaticgeneticstudiesofHNPCCtumorsshowedevidenceofcharacteristicvariantsin
microsatelliteregionsofnumerousgenes,whichappearedtobeamolecularmarkerofMMRdeficiency.Thiswascharacterized
withsynonymssuchasubiquitoussomaticvariants,replicationerrors,andeventually,thecurrentlyemployedterm
microsatelliteinstability(MSI).InHNPCC-relatedtumorsshowingMSI,thereistypicallylossofimmunohistochemicalexpression
foroneormoreoftheproteinsassociatedwiththeMMRgenes.SinceIHCisrelativelyeasytoperform,itcanservetocomplement
orevensupplantMSIscreeningofsuspectedHNPCCcases.AlthoughMSIcharacterizesnearlyallHNPCCtumors,itcanalsooccur
sporadicallyinabout12%ofCRCs.ThesecasesclearlydonothavetheinheriteddisorderHNPCC,sincefurtherstudieshaveshown
thattheMSIiscausedbysomaticinactivationoftheMLH1proteinbyhypermethylationoftheMLH1promoter.Inmostinstances,
thesporadicnatureofthesecasescanbeconfirmedbyconcurrentdetectionofsomaticBRAFvariantsinCRCtumortissue.
Genetictestingforgermlinealterationshasbeensomewhatdisappointing,asnomorethanhalfofsuspectedHNPCCcaseshave
detectablepathogenicvariants.Becauseofthis,andthelackofsufficientlyspecificclinicalfeatures,variousgeneticscreening
strategieshaveemergedtoimprovetheyieldofgenetictesting.Asufficientlycompellingfamilyhistory,ideallycomplementedby
thepresenceofMSI,warrantsgenetictesting,andmostclinicalpracticeguidelinesprovideforsuchanapproach.TheBethesda
guidelinesareacombinationofclinical,pathologic,andfamilyhistoryfeaturesthataresufficientlypredictivetowarrantMSI/IHC
screening.Computerrisk-assessmentprofileshavebeendevelopedtodothissameworkmorequantifiablyandcanestimate
variantrisklikelihoodwithorwithouttheintermediatestepofusingMSI/IHC.
Againstthisbackgroundofpotentialclinicalselectioncriteriaforgenetictesting,populationstudieshaveemergedthatcan
estimateHNPCCfrequency(1%3%)anddeterminetheperformancecharacteristicsofthesesameselectiontoolswhen
implementedinotherwiseunselectedcases.
Thecombinationofgeneticcounseling/testingstrategieswithclinicalscreening/treatmentmeasureshasledtothedevelopment
ofconsensusclinicalpracticeguidelines.Theseguidelinescanbeusedbyprovidersandpatientsaliketobetterunderstandthe
availableoptionsandkeydecision-pointsthatexist.(RefertoTable11formoreinformationaboutpracticeguidelinesfordiagnosis
andcolonsurveillanceinLS.)
TerminologyrelatedtofamilialCRChascertainlyevolved.MostinthefieldusethetermLynchsyndrome(LS)asapreferred
synonymoverHNPCC,sinceHNPCCisbothexcessivelywordyandmisleadingmanypatientshavepolypsandmanyhavetumors
otherthanCRC.Inaddition,entitiessuchasMuir-TorresyndromearenowrecognizedasphenotypicvariantsofLS.EvenTurcot
syndrome,whichwasinitiallythoughttoonlybeanFAPvariant,isnowknowntobeanLSvariantwhenitpresentswith
glioblastomasandanFAPvariantwhenitpresentswithmedulloblastomas.IthasbeensuggestedthatthetermLSbeappliedto
casesinwhichthegeneticbasiscanbeconfidentlylinkedtoagermlinepathogenicvariantinaDNAMMRgene(eitheragermline
pathogenicvariantispresentorcanbeconfidentlyinferredbasedontheclinicalpresentationcombinedwithMSI/IHC).[236]
Theterm"familialcolorectalcancertypeX"or"FCCX"wascoinedtorefertofamilieswhomeetAmsterdamcriteriabutlack
MSI/IHCabnormalities.[237]SomerefertoFCCXasLynch-likesyndrome.Complicatingtheterminologyfurther,thetermLynch-
likehasalsobeenusedincaseswithMSI-HtumorsandpresumedunderlyingMMRgermlinepathogenicvariant,butinwhichno
suchvariantisdetected.
InLS,[238-240]unlikeFAP,mostpatientsdonothaveanunusualnumberofpolyps.LSaccountsforabout1%to3%ofallCRCs.
[241]LSisanautosomaldominantsyndromecharacterizedbyanearlyageofonsetofCRC,excesssynchronousand
metachronouscolorectalneoplasms,right-sidedpredominance,andextracolonictumors.LSiscausedbypathogenicvariantsin
theDNAMMRgenes,namelyMLH1,MSH2,MSH6,andPMS2.EPCAMgenepathogenicvariantsthatresultinhypermethylationand
silencingofMSH2havealsobeendescribed.(RefertotheMSIsectionintheMajorGeneticSyndromessectionofthissummaryfor
moreinformation.)TheaverageageofCRCdiagnosisincarriersofLSpathogenicvariantsis44to52years[241-243]versus71
yearsinsporadicCRC.[244]Inpathogenicvariantpositivefamilieswhenprobandswereexcludedandbothaffectedand
unaffectedrelativeswereascertained,theaverageageatdiagnosisofCRCwasreportedtobe61years,[245]suggesting
ascertainmentbiasinearlyreports.
ThelifetimeriskofCRCincarriersofMLH1andMSH2pathogenicvariantswas68.7%inmalesand52%infemales.[245]However,in
ameta-analysisofthreepopulation-basedstudiesandoneclinic-basedstudy,thelifetimeriskofCRCincarriersofMLH1andMSH2
pathogenicvariantswasreportedtobe53%inmalesand33%infemales.[246,247]Inastudyof113familieswithcarriersofMSH6
pathogenicvariants,theestimatedcumulativeriskofCRCinmaleswas22%and10%infemales.[248]PMS2lifetimeCRCrisktoage
70yearshasbeenreportedtobe20%inmalesand15%infemales.[249]Alargeregistry-basedstudyfromFranceestimatedCRC
riskatage70yearstobe41%forcarriersofMLH1pathogenicvariants,48%forcarriersofMSH2pathogenicvariants,and12%for
carriersofMSH6pathogenicvariants.[250]
Thesedatahavebeenlargelyretrospectiveandpotentiallyincludesomebiasesforthatreason.Someprospectivedataexist,
however.TheColonCancerFamilyRegistryprogramfollowed446carriersprospectivelyandfounda10-yearriskofCRCof8%.[251]
PatientswithLScanhavesynchronousandmetachronouscolorectalneoplasmsandotherprimaryextracolonicmalignancies.
CarriersofLSpathogenicvariantshaveanincreasedriskofdevelopingcolonadenomas(hazardratio[HR],3.4),andtheonsetof
adenomasappearstooccuratayoungeragethaninpathogenicvariantnegativeindividualsfromthesamefamilies.[252]Unlike
patientswithsporadiccancers,whosecancerdevelopsmostoftenintheleftsideofthecolon,approximatelytwo-thirdsofLS
cancersdevelopintherightsideofthecolon,definedasproximaltothesplenicflexure.
ThemostcommonextracolonicmalignancyinLSisendometrialadenocarcinoma,whichaffectsatleastonefemalememberin
about50%ofLSpedigrees.FiftypercentofwomenwithanMMRgenepathogenicvariantwillpresentwithendometrialcanceras
theirfirstmalignancy.[253]
Thelifetimeriskofendometrialcancerhasbeenestimatedtobefrom44%incarriersofMLH1pathogenicvariantsto71%in
carriersofMSH2pathogenicvariants.[245-248,254]FamilieswithanMSH6pathogenicvarianthavebeenreportedtohavean
endometrialcancerpredominance.LifetimeriskofendometrialcancerincarriersofMSH6pathogenicvariantsin113familieswas
estimatedtobe26%atage70yearsand44%atage80years.[248]IncarriersofPMS2pathogenicvariants,theendometrialcancer
riskatage70yearshasbeenreportedtobe15%.[249]ThesameprospectivedatacollectionintheColonCancerFamilyRegistry
programyielded5-yearendometrialcancerrisksofabout3%and10-yearendometrialcancerrisksofabout10%inwomenfrom
thiscohort.[251]WomenwithlossofMSH2proteinexpressioncausedbyanEPCAMpathogenicvariantarealsoatriskof
endometrialcancer.Onestudyfounda12%(95%CI,0%27%)cumulativeriskofendometrialcancerinEPCAMdeletioncarriers.
[255]Astudyof127womenwithLSwhohadendometrialcancerastheirindexcancerwerefoundtobeatsignificantlyincreased
riskofothercancers.Thefollowingelevatedriskswerereported:CRC,48%(95%CI,27.2%58.3%);kidney,renalpelvis,andureter
cancer,28%(95%CI,11.9%48.6%);urinarybladdercancer,24.3%(95%CI,8.56%42.9%;andbreastcancer,2.51%(95%CI,1.17%
4.14%).[256]
LS-associatedendometrialcancerisnotlimitedtotheendometrioidsubtype.Itmostcommonlyarisesfromtheloweruterine
segment.Endometrialadenocarcinoma,clearcellcarcinoma,uterinepapillaryserouscarcinoma,andmalignantmixedMllerian
tumorsarepartofthespectrumofuterinetumorsinLS.[257]Threecasesofendometrialcancerarisingfromendometriosisin
womenwithLShavebeenreported.[258](RefertotheScreeningforendometrialcancerinLSfamiliessectionofthissummaryfor
informationaboutscreeningmethods.)
Cancer risk in LS beyond CRC and endometrial cancer

Asillustratedintheprevioussection,multiplestudieshaveconfirmedasubstantiallyincreasedriskofCRCandendometrialcancer
inLS.Severalstudieshavealsodemonstratedanincreasedriskofadditionalmalignancies,mostcommonlytransitionalcell
carcinomaoftheuretersandrenalpelvisandcancersofthestomach,pancreas,ovary,smallintestine,andbrain.[259-264]In
addition,somestudieshavesuggestedanassociationwithbreast,prostate,adrenalcortex,liver,andbiliarytractcancers.
[251,262,265-267]Thestrengthoftheassociationformanyofthesemalignanciesislimitedbysmallsamplesize(andconsequently,
wideCIsassociatedwithrelativerisk[RR]),theretrospectivenatureoftheanalyses,andbias.
Thelargestprospectivestudytodateisof446unaffectedcarriersofpathogenicvariantsfromtheColonCancerFamilyRegistry.
[251]Participantswhowerefollowedforupto10yearsdemonstratedanincreasedstandardizedincidenceratio(SIR)forCRC(SIR,
20.48;95%CI,11.7133.27;P<.01),endometrialcancer(SIR,30.62;95%CI,11.2466.64;P<.001),ovariancancer(SIR,18.81;95%CI,
3.8854.95;P<.001),gastriccancer(SIR,9.78;95%CI,1.1835.30;P=.009),renalcancer(SIR,11.22;95%CI,2.3132.79;P<.001),
bladdercancer(SIR,9.51;95%CI,1.1534.37;P=.009),pancreaticcancer(SIR,10.68;95%CI,2.6847.70;P=.001),andfemale
breastcancer(SIR,3.95;95%CI,1.598.13;P=.001).[251]
TheissueofbreastcancerriskinLShasbeencontroversial.Retrospectivestudieshavebeeninconsistent,butseveralhave
demonstratedmicrosatelliteinstabilityinaproportionofbreastcancersfromindividualswithLS;[268-271]oneofthesestudies
evaluatedbreastcancerriskinindividualswithLSandfoundthatitisnotelevated.[271]However,thelargestprospectivestudyto
dateof446unaffectedcarriersofpathogenicvariantsfromtheColonCancerFamilyRegistry[251]whowerefollowedforupto10
yearsreportedanelevatedSIRof3.95forbreastcancer(95%CI,1.598.13;P=.001).[251]Thesamegroupsubsequentlyanalyzed
dataon764carriersofMMRgenepathogenicvariantswithapriordiagnosisofcolorectalcancer.Resultsshowedthatthe10-year
riskofbreastcancerfollowingcolorectalcancerwas2%(95%CI,1%4%)andthattheSIRwas1.76(95%CI,1.072.59).[272]Aseries
fromtheUnitedKingdomcomposedofclinicallyreferredLSkindreds,witheffortstocorrectforascertainment,showedatwofold
increasedriskofbreastcancerinMLH1familiesbutnotinfamilieswithotherMMRvariants.[273]However,furtherstudiesare
neededtodefineabsoluterisksandagedistributionbeforesurveillanceguidelinesforbreastcancercanbedevelopedforcarriers
ofMMRpathogenicvariants.
ProstatecancerwasfoundtobeassociatedwithLSinastudyof198familiesfromtwoU.S.LSregistriesinwhichprostatecancer
hadnotoriginallybeenpartofthefamilyselectioncriteria.ProstatecancerriskinrelativesofcarriersofMMRgenepathogenic
variantswas6.3%atage60yearsand30%atage80years,versusapopulationriskof2.6%atage60yearsand18%atage80
years,withanoverallHRof1.99(95%CI,1.313.03).[265]A2014meta-analysissupportsthisassociation,findinganestimatedRRof
3.67(95%CI,2.326.67)forprostatecancerinmenwithaknownMMRpathogenicvariant.[274]Thisriskispossiblyincreasedin
thosewithMSH2pathogenicvariants.[267,274]Notwithstandingprevalentcontroversysurroundingroutineprostate-specific
antigen(PSA)screening,theauthorssuggestedthatscreeningbymeansofPSAanddigitalrectalexambeginningatage40years
inmaleMMRgenecarrierswouldbereasonabletoconsider.[265]Currently,molecularandepidemiologicevidencesupports
prostatecancerasoneoftheLScancers.Aswithbreastcancer,[274]additionalstudiesareneededtodefineabsoluterisksandage
distributionbeforesurveillanceguidelinesforprostatecancercanbedevelopedforcarriersofMMRpathogenicvariants.(Referto
theMMRGenessectioninthePDQsummaryonGeneticsofProstateCancerformoreinformationaboutprostatecancerandLS.)
Anotherstudyassessedaseriesof114ACCs.Of94patientswhohadadetailedfamilyhistoryassessmentandinwhomLi-
Fraumenisyndrometestingwasnondiagnostic,threepatientshadfamilyhistoriesthatweresuggestiveofLS.Theprevalenceof
MMRgenepathogenicvariantsin94familieswas3.2%,similartotheproportionofLSamongunselectedcolorectaland
endometrialcancerpatients.Inaretrospectivereviewof135MMRgenepathogenicvariantpositiveLSfamiliesfromthesame
program,twoprobandswerefoundtohavehadahistoryofACC.OfthefourACCsinwhichMSItestingcouldbeperformed,all
weremicrosatellitestable(MSS).ThesedatasuggestthatifLSisotherwisesuspectedinanACCindexcase,aninitialevaluationof
theACCusingMSIorIHCtestingmaybemisleading.[266]
Muir-TorresyndromeisconsideredavariantofLSandincludesaphenotypeofmultiplecutaneousneoplasms(including
sebaceousadenomas,sebaceouscarcinomas,andkeratoacanthomas).TheskinlesionsandCRCdefinethephenotype,[275,276]
andclinicalvariabilityiscommon.PathogenicvariantsintheMSH2andMLH1geneshavebeenfoundinMuir-Torrefamilies.[277-
279]Astudyof1,914MSH2andMLH1unrelatedprobandsfoundMSH2tobemorecommoninindividualswiththeMuir-Torre
syndromephenotype.[280](RefertotheSebaceousCarcinomasectioninthePDQsummaryonGeneticsofSkinCancerformore
informationaboutcutaneousneoplasmsinMuir-Torresyndrome.)
Historical criteria for defining LS families

TheresearchcriteriafordefiningLSfamilieswereestablishedbytheInternationalCollaborativeGroup(ICG)meetingin
Amsterdamin1990andareknownastheAmsterdamcriteria.[281]ThesecriteriawerelimitedtoCRC.In1999,theAmsterdam
criteriawererevisedtoincludesomeextracoloniccancers.[282]ThesecriteriaprovideageneralapproachtoidentifyingLSfamilies,
buttheyarenotconsideredcomprehensive;anumberoffamilieswhodonotmeetthesecriteria,buthavegermlineMMRgene
pathogenicvariants,havebeenreported.
Amsterdam criteria I (1990):
1.OnememberdiagnosedwithCRCbeforeage50years.
2.Twoaffectedgenerations.
3.Threeaffectedrelatives,oneofthemafirst-degreerelativeoftheothertwo.
4.FAPshouldbeexcluded.
5.Tumorsshouldbeverifiedbypathologicalexamination.
Amsterdam criteria II (1999):
SameasAmsterdamcriteriaI,buttumorsoftheendometrium,smallbowel,ureter,orrenalpelviscanbeusedtosubstitute
anotherwisequalifyingCRC.
Althoughthesecriteriaarethemoststringentusedtoidentifypotentialcandidatesformicrosatelliteandgermlinetesting,itmust
becautionedthatbydefinition,FCCXincludesfamiliesmeetingAmsterdamcriteriabutinwhomthereisnoevidenceofMSI.(Refer
totheFamilialcolorectalcancertypeX[FCCX]sectionintheMajorGeneticSyndromessectionofthissummaryformore
information.)
RecognizingboththerelativeinsensitivityoftheAmsterdamcriteriaandtheincreasingimportanceoftumor-basedtestingfor
detectingLS,theBethesdaguidelinesweredeveloped.TheBethesdaguidelinesandasubsequentrevisionwereformulatedto
improvesensitivitybytargetingpatientswhosetumorswouldbemostlikelytoshowMSI.[283,284](RefertotheGenetic/molecular
TestingforLSsectionintheMajorGeneticSyndromessectionofthissummaryformoreinformationabouttestingforMSIand
IHC.)
Bethesda guidelines (1997):
1.CancerinfamiliesthatmeettheAmsterdamcriteria.
2.ThepresenceoftwoLS-relatedcancers,includingsynchronousandmetachronousCRCsorassociatedextracoloniccancers.
[Note: Endometrial, ovarian, gastric, hepatobiliary, or small-bowel cancer or transitional cell carcinoma of the renal pelvis or
ureter.]
3.ThepresenceofCRCandafirst-degreerelativewithCRCand/orLS-relatedextracoloniccancerand/oracolorectal
adenoma;oneofthecancersdiagnosedbeforeage45years,andtheadenomadiagnosedbeforeage40years.
4.CRCorendometrialcancerdiagnosedbeforeage45years.
5.Right-sidedCRCwithanundifferentiatedpattern(solid/cribriform)onhistopathologydiagnosedbeforeage45years.[Note:
Solid/cribriform defined as poorly differentiated or undifferentiated carcinoma composed of irregular, solid sheets of large
eosinophilic cells and containing small gland-like spaces.]
6.Signet-ring-cell-typeCRCdiagnosedbeforeage45years.[Note: Composed of more than 50% signet ring cells.]
7.Adenomasdiagnosedbeforeage40years.
Revised Bethesda Guidelines (2004)*:
1.CRCdiagnosedinanindividualyoungerthan50years.
2.Presenceofsynchronous,metachronouscolorectal,orotherLS-associatedtumors.**
3.CRCwithMSI-Hpathologicassociatedfeaturesdiagnosedinanindividualyoungerthan60years.[Note: Presence of tumor-
infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern.]
4.CRCorLS-associatedtumor**diagnosedinatleastonefirst-degreerelativeyoungerthan50years.
5.CRCorLS-associatedtumor**diagnosedatanyageintwofirst-degreeorsecond-degreerelatives.
*OnecriterionmustbemettoconsiderthetumorforMSItesting.
**LS-associatedtumorsincludecolorectal,endometrial,stomach,ovarian,pancreatic,ureterandrenalpelvis,biliarytract,and
braintumors;sebaceousglandadenomasandkeratoacanthomasinMuir-Torresyndrome;andcarcinomaofthesmallbowel.
[284,285]
ResearchhasincludedCRCfamilieswhodonotmeetAmsterdamcriteriaforLSand/orinwhomthecolorectaltumorsareMSS.A
numberofthesefamilieshavebeenfoundtohavepathogenicvariantsinMSH6.[286-290]Whiletheclinicalsignificanceand
implicationsofthesefindingsarenotclear,theseobservationssuggestthatgermlinepathogenicvariantsinMSH6maypredispose
tolate-onsetfamilialCRCsthatdonotmeetAmsterdamcriteriaforLSandtumorsthatmightnotnecessarilydisplayMSI.
Currently,thereisamovetowarduniversaltestingofcolorectalandendometrialtumors.[291](RefertotheDiagnosticstrategies
forallindividualsdiagnosedwithCRC[universaltesting]sectionformoreinformation.)
Genetic/molecular testing for LS

GeneticriskassessmentofLSgenerallyconsidersthecancerfamilyhistoryandageatdiagnosisofCRCand/orotherLS-associated
cancersinthepatient.StudiesofgenetestingusingDNAsequencinginsuspectedLSprobandsfromacancerriskassessment
clinicalsettingfoundthatapproximately25%testpositiveforaninformativeMSH2orMLH1pathogenicvariant,allowinggenetically
informedmanagementstrategiestobedevelopedforthefamily.[292,293]ComputermodelsanalogoustoBRCAPROpredictthe
probabilityofaMMRgenepathogenicvariant.PREMM1,2,6andtheMMRpromodelsareeasytouseandhavebeenvalidated.[294-
297]AlthoughthesemodelscanpredictpathogenicvariantsevenintheabsenceofMSIorIHCinformation,theycanincorporate
thosedataasavailable.Allthreecomputerpredictionmodelstakefamilyhistoryofendometrialcancerintoaccount.The
pathogenicvariantdetectionrateishigherforpatientswithmorestrikingfamilyhistoriesorwithinformativetumortesting.
IntheabsenceofadditionalfamilyorpersonalhistorysuggestiveofLS,isolatedcasesofCRCdiagnosedbeforeage36yearsare
uncommonlyassociatedwithMMRgenepathogenicvariants.OnestudyfoundMMRpathogenicvariantsinonly6.5%ofsuch
individuals.[298]Therefore,isolatedcasesofveryearly-onsetCRCshouldbeofferedtumorscreeningwithMSI/IHCratherthan
proceedingdirectlytogermlinepathogenicvariantanalysis.
MSI/IHC in adenomas
Currentpracticeistooffercolonoscopysurveillancetothosewithstrongfamilyhistoriesbutnopriorgeneticortumortesting.At
times,adenomasaredetectedduringthesecolonoscopies.Intheinstancewhenanadenomaisdetected,thequestionofwhether
totesttheadenomaforMSI/IHCisraised.OnestudyofpatientswithpriorCRCandknownMMRpathogenicvariantsfound8of12
adenomastohavebothMSIandIHCproteinloss.[299]However,thestudyauthorsemphasizedthatnormalMSI/IHCtestinginan
adenomadoesnotexcludeLS.
MSI
Microsatellitesareshort,repetitivesequencesofDNA(oftenmononucleotides,dinucleotides,ortrinucleotides)locatedthroughout
thegenome,primarilyinintronicsequences.[300,301]Thetermmicrosatelliteinstability(MSI)isusedwhentumorDNAshows
alterationsinmicrosatelliteregionswhencomparedwithnormaltissue.MSIindicatesprobabledefectsinMMRgenes,whichmay
beduetosomaticorgermlinevariantsorepigeneticalterations.[302]Inmostinstances,MSIisassociatedwithabsenceofprotein
expressionofoneormoreoftheMMRproteins(MSH2,MLH1,MSH6,andPMS2).However,lossofproteinexpressionmaynotbe
seeninallMSI-Htumors.
CertainhistopathologicfeaturesarestronglysuggestiveofMSIphenotypeincludingthepresenceoftumorinfiltrating
lymphocytes,Crohn-likereaction,mucinoushistology,absenceofdirtynecrosis,andhistologicheterogeneity.Thesehistologic
featureshavebeencombinedintocomputationalscoresthathavehighpredictivevalueinidentifyingMSICRCs.[303,304]
Becausemanycoloncancersdemonstrateframeshiftvariantsatasmallpercentageofmicrosatelliterepeats,thedesignationofan
adenocarcinomashowingMSIdepends,inpart,onthedetectionofaspecifiedpercentageofvariantlocifromapanelof
dinucleotideandmononucleotiderepeatsthatwereselectedataNationalInstitutesofHealth(NIH)ConsensusConference.[305]If
morethan30%ofatumor'smarkersareunstable,itisscoredasMSI-H;ifatleastone,butfewerthan30%ofmarkersare
unstable,thetumorisdesignatedMSI-low(MSI-L).Ifnolociareunstable,thetumorisdesignatedMSS.Mosttumorsarisinginthe
settingofLSwillbeMSI-H.[305]TheclinicalrelevanceofMSI-Ltumorsremainscontroversial.Theprobabilityoffindingagermline
pathogenicvariantinaMMRgeneinthissettingisverysmall.Onedistinctionisthatpeoplewithgermlinepathogenicvariantsin
MSH6donotnecessarilymanifesttheMSI-Hphenotype.OnestudypresentedevidencethatMSH6pathogenicvariantswere
associatedwithcancershavinganMSI-Lphenotype.[288]However,asecondstudyfoundthat86%(18of21)ofCRCsinMSH6
carriersshowedMSI-H.[306]Inaddition,insporadiccancerswithMSI-Lphenotype,MSH6pathogenicvariantswerenotfound.[307]
(RefertotheDiagnosticstrategiesforallindividualsdiagnosedwithCRC[universaltesting]sectionofthissummaryfor
informationabouttheutilizationofMSIstatusinthediagnosticwork-upofapatientwithsuspectedLS.)
(RefertotheUniversalMSI/IHCcolorectalcancerscreeninginclinicalpracticesectionofthissummaryforinformationaboutthe
practiceandfeasibilityofuniversaltestingandissuesrelatedtoinformedconsentforMSIandIHCtesting.)
The complexity of aberrant methylation of MMR genes

Aberrant MLH1 methylation in sporadic CRC
Aberrant MLH1 methylation in sporadic CRC
ThepresenceofanMSI-HtumorassociatedwithlossofMSH2,MSH6,orPMS2proteinexpressionstronglysupportsadiagnosisof
LS.However,MSI-HtumorswithabsentMLH1proteinexpressionpresentamorecomplexscenario.MSIoccursinapproximately
10%to15%ofsporadicCRC(generally,patientsaged>50yearsandwithlittleornofamilyhistory).InsporadicCRC,absentMLH1
proteinexpressionisaconsequenceofaberrantMLH1methylation,asomaticeventconfinedtothetumorthatinthevastmajority
ofcasesisnotheritable.SincelossofMLH1proteinexpressionoccursinbothLSandsporadictumors,itsspecificityforpredicting
germlineMMRgenepathogenicvariantsislowerthanfortheotherMMRproteins.
Becauseofthisuncertainty,additionalmoleculartestingisoftennecessarytoclarifytheetiologyofMLH1absenceinthesecases.
Othersomaticchangesincoloncancersthatappeartohavenegativepredictivevalueforidentifyingindividualswithgermline
pathogenicvariantsinoneoftheMMRgenesareBRAFpathogenicvariantsandMLH1promoterhypermethylation.
AberrantmethylationofMLH1isresponsibleforcausingapproximately90%ofsporadicMSIcoloncancers.[308]Othermechanisms
suchassomaticMLH1variantsmayberesponsiblefortheminorityofcaseswhereaberrantMLH1methylationisabsent.[308]In
moststudies,aberrantMLH1methylationhasbeendetectedinonlyasmallpercentageofLScoloncancersinindividualswith
germlinepathogenicvariantsinMLH1.[308-311]Thus,detectionofaberrantlymethylatedMLH1incoloncancerismoresuggestive
ofasporadicMSItumor.Sinceassaysofmethylationarecomplexandresource-intensive,surrogatemarkersofMLH1methylation
havebeenexamined.Onestudyfoundthatlossofimmunohistochemicalstainingforp16correlatedstronglywithbothMLH1
methylationandBRAFV600Epathogenicvariants(BRAFpathogenicvariantsarediscussedindetailinthefollowingparagraphs).
However,only30%ofsporadictumorsexaminedinthisstudyexhibitedlossofp16expression,limitingtheutilityofthisassay.[312]
BRAFpathogenicvariantshavebeendetectedpredominantlyinsporadicMSItumors.[313-316]ThissuggeststhatsomaticBRAF
V600Epathogenicvariantsmaybeusefulinexcludingindividualsfromgermlinevarianttesting.MLH1hypermethylationand/or
BRAFpathogenicvarianttestingareincreasinglyutilizedinuniversalLStestingalgorithmsinanattempttodistinguishbetweenan
absenceofMLH1proteinexpressioncausedbyhypermethylationandgermlineMLH1pathogenicvariants.
(RefertotheDiagnosticstrategiesforallindividualsdiagnosedwithCRC[universaltesting]sectionofthissummaryformore
informationabouttheclinicalroleofBRAFandhypermethylationtesting.)
Germline MLH1 hypermethylation

ReportsofpatientswithgermlineMLH1hypermethylationshouldnotbeconfusedwithEPCAMvariant-inducedhypermethylationof
MSH2,asdescribedbelow.Priorparagraphshaveemphasizedtheissuesassociatedwiththecommon,acquiredsomatic
hypermethylationoftheMLH1promoter.However,examplesofhypermethylationoftheMLH1promoterdescribedinthegermline
havegenerallynotbeenassociatedwithastableMendelianinheritance.
AcomprehensivereviewofMLH1constitutionalepigeneticalterationsinvolvinghypermethylationofoneMLH1allelehasbeen
published.[317]Suchepigeneticvariantsareseeninpatientswithearly-onsetLSand/ormultipletumorsoftheLStype.Germline
sequencevariationsorrearrangementsarenotseeninthesepatients,althoughthetumorsshowMSI-H,lossofMLH1protein
expression,andanabsenceofBRAFV600Epathogenicvariants.ThesepatientscommonlyhavenofamilyhistoryofLS-liketumors.
Interestingly,inheritanceappearstobematernal,andthereforenon-Mendelian.Theconstitutionalmonoallelichypermethylation
mayappearasamosaic,involvingdifferenttissuestoavaryingextent.Inaddition,theconstitutionalepigeneticvariantistypically
reversibleinthecourseofmeiosis,suchthatoffspringareusuallyunaffected.Becauseinheritancehasbeendemonstratedinvery
fewfamilies,performinggeneticcounselingandgenetictesting(whichrequiresspecializedresearchtechniques)isparticularly
challenging.
EPCAM/TACSTD1
TumorswithMSIandlossofMSH2proteinexpressionaregenerallyindicativeofanunderlyingMSH2germlinevariant(inferred
MSH2pathogenicvariant).UnlikethecasewithMLH1,MSIwithMSH2lossisrarelyassociatedwithsomatichypermethylationofthe
promoter.Nevertheless,inatleast30%to40%ofthesecasesofinferredMSH2pathogenicvariant,nogermlinevariantcanbe
detectedwithstate-of-the-arttechnology.OneChinesefamilywithtumorsshowingMSH2losswasfoundtohaveallele-specific
hypermethylationthatappearedtohavebeenaninheritedphenomenon.[318]AnotherstudyofafamilywithMSH2-deficientMSI-
hightumorsemployedthecommonlyuseddiagnosticMLPAanalysisofMSH6andalsoshowedreducedexpressionofMSH6.In
doingso,adecreaseinsignalwasobservedforexon9oftheEPCAM (TACSTD1)gene,whichisnearMSH2.UseofadditionalMLPA
probeslocatedbetweenexon3ofEPCAMandexon1ofMSH2demonstratedthatthedeletionspannedmost3exonsofEPCAM,but
sparedtheMSH2promoter.[319]TheEPCAMvariantwasfoundtoinducetheobservedmethylationoftheMSH2promoterby
transcriptionacrossaCpGislandwithinthepromoterregion.ThepresenceofEPCAMpathogenicvariantsshowingsimilar
methylation-mediatedMSH2losswasfoundataboutthesametimeinfamiliesfromHungary.[320].Onthestrengthofthese
observations,EPCAMtestinghasalreadybeenintroducedclinicallyforpatientswithlossofMSH2proteinexpressionintheirCRCs
wholackadetectableMSH2germlinepathogenicvariant.OnestudyoftwofamilieswiththesameEPCAMdeletionfoundfew
extracoloniccancersandnoendometrialcancers.[321]However,asubsequentstudydemonstratedthatwomenwithMSH2protein
expressionlosscausedbyEPCAMvariantsarealsoatriskofendometrialcancer.[255]
IHC
AcomplementaryandperhapsevenalternativeapproachtoMSIistotestthetumorbyIHCforproteinexpressionusing
monoclonalantibodiesfortheMSH2,MLH1,MSH6,andPMS2proteins.Lossofexpressionoftheseproteinsappearstocorrelate
withthepresenceofMSIandmaysuggestwhichspecificMMRgeneisalteredinaparticularpatient.[322-325]
(RefertotheUniversalMSI/IHCcolorectalcancerscreeninginclinicalpracticesectionofthissummaryforinformationaboutissues
relatedtoinformedconsentforMSIandIHCtesting.)
Tumor testing for suspected LS

ItappearsthatclinicalpracticehasshiftedfromrelianceonMSIintheearlydaysoftumortestingtoincreasing,andinmanycases
exclusive,relianceonIHCcurrently.Usingbothtestsincreasesthesensitivityoftheinitialscreenandimprovesqualityassurance;
therefore,manylaboratoriesassessbothMSIandIHCinitially.However,becausethesetestsarecommonlyregardedassimple
alternatives,cost-effectivenessconsiderationsseemtosupportIHCandaccountforitspreferentialuse.Partofthisrationaleisthat
theinformationprovidedbyIHCmaydirecttestingtowardonespecificMMRgene(theonewithlossofproteinexpression)as
opposedtocomprehensivetestingthatwouldbenecessitatedbytheuseofMSIalone.[241,242,326-329]Argumentsfora
sequentialapproachtoincreaseefficiencyhavebeenmade.AGermanconsortiumhasproposedanalgorithmsuggestinga
sequentialapproach;thisislikelytodependonthedifferentcostsofMSIandIHCandthepriorprobabilityofapathogenicvariant.
[330]DatafromalargeU.S.studysupportIHCanalysisastheprimaryscreeningmethod,emphasizingitseaseofperformancein
routinepathologylaboratories.[242]Toidentifyamoreefficientscreeningapproach,thestrategyofperformingIHCstainingonly
forPMS2andMSH6hasbeenconsidered,ontheassumptionthatnegativestainingofeitherofthesewould,inmostinstances,
detectthemajorityofcasesofLS.[331]Thisapproachmaybemoreappropriatewhenalltumorsarebeingscreened(universal
testing).Althoughthisstrategyappearsattractivefromthestandpointofefficiency,stainingforallfourMMRproteinsremainsthe
currentstandardofcare.Furtherstudiesarenecessarytovalidatetheutilityofthetwo-proteinapproach.(RefertotheDiagnostic
strategiesforallindividualsdiagnosedwithCRC[universaltesting]sectionofthissummaryformoreinformation.)
EvenincentersthatrelyexclusivelyonIHCtesting,theremaybearoleforsubsequentMSItestingincasesinwhichtheclinical
picturesuggestsLS,notwithstandingtheresultsofIHC.
Ifgreatestweightisgiventoclinicalselectionconsiderations(i.e.,Bethesdaguidelinesbeingmet),thenIHCcombinedwithMSI
maybeappropriate.Infact,inatrulyhigh-riskpopulation(Amsterdamcriteriabeingmet),anystrategymaybeacceptable,
includinggermlinetestingwithoutthebenefitoftumortestingfirst.(RefertotheGenetic/molecularTestingforLSsectionofthis
summaryforinformationaboutmodels.)However,asmoreinstitutionsareadoptinguniversaltestingusingMSIorIHC,perhapsin
partbasedonsomeoftheoutlier(older,familyhistory-negative)casesreported[242,326,330]orinpartbasedonprognostic
considerations(MSI-Hhavingbetterprognosis),concernsaboutcosteffectivenessofscreeningcommonlydictateamore
truncatedapproach.Thus,inarelativelylow-riskpopulationofpatientswithCRC,ascreenwithIHCorMSIalonemaybeadequate
incasesofnormalstainingorMSStumor.
(RefertotheUniversalMSI/IHCcolorectalcancerscreeninginclinicalpracticesectionofthissummaryforinformationaboutissues
relatedtoinformedconsentforMSIandIHCtesting.)
Other techniques
IninstancesinwhichtumortissueisnotavailablefromindividualstotestforMSIand/orMMRproteinIHC,germlinevariant
analysisofMLH1,MSH2,andMSH6maybeconsidered.Thisapproachis,however,timeconsumingandexpensive.Strategiesto
screenforpathogenicvariantsusingheteroduplexanalysis-basedtechniqueshavebeenexplored.Thesetechniquesarelimitedby
theneedtoperformDNAsequencingasasubsequentsteponallaberrantsamplesdetectedinscreening.Additionally,such
techniquesfrequentlydetectnumerousVUS.Theycannot,therefore,berecommendedforroutineclinicaluseatthistime.[332]
Genetic testing
GenetictestingforgermlinepathogenicvariantsinMLH1,MSH2,MSH6,andPMS2canhelpformulateappropriateintervention
strategiesfortheaffectedpathogenicvariantpositiveindividualandat-riskfamilymembers.
Ifapathogenicvariantisidentifiedinanaffectedperson,thentestingforthatsamepathogenicvariantcouldbeofferedtoat-risk
familymembers(referredtoaspredictivetesting).Familymemberswhotestnegativeforthefamilialpathogenicvariantare
generallynotatincreasedriskofCRCorotherLS-associatedmalignanciesandcanfollowsurveillancerecommendationsapplicable
tothegeneralpopulation.Familymemberswhocarrythefamilialpathogenicvariantshouldfollowsurveillanceandmanagement
guidelinesforLS.(RefertotheInterventionsforLSsectionofthissummaryformoreinformation.)
Ifnopathogenicvariantisidentifiedintheaffectedfamilymember,thentestingisconsidereduninformativefortheindividualand
at-riskfamilymembers.Thiswouldnotexcludeaninheritedsusceptibilitytocoloncancerinthefamilybutrathercouldindicate
thatcurrentgenetestingtechnologyisnotsensitiveenoughtodetectthepathogenicvariantinthegenestested.Thecurrent
sensitivityoftestingisbetween50%and95%,dependingonthemethodologyused.Varianttestingutilizingsequencingalonewill
notdetectlargegenomicrearrangementsinMSH2orMLH1thatmaybepresentinasignificantnumberofLSprobands.[333-335]
Anassessmentof365probandswithsuspectedLSshowed153probandswithgermlinepathogenicvariantsinMLH1orMSH2,12of
67(17.9%)and39of86(45.3%)ofwhichwerelargegenomicalterationsinMLH1andMSH2,respectively.[336]Suchvariantscanbe
detectedbyMLPAorSouthernblotting(MLPAhaslargelyreplacedSouthernblotting).[337,338]MLPAanalysisofMLH1,MSH2,and
MSH6iscommerciallyavailableandshouldbeperformedincasesinwhichnovariantisdetectedbysequenceanalysis.
Alternatively,thefamilycouldhaveavariantinayet-unidentifiedgenethatcausesLSorapredispositiontocoloncancer.Another
explanationforanegativevarianttestisthat,bychance,theindividualtestedinthefamilyhasdevelopedcoloncancerthrougha
nongeneticmechanism(i.e.,itisasporadiccase),whiletheothercasesinthefamilyarereallytheresultofagermlinevariant.If
thisscenarioissuspected,testinganotheraffectedindividualisrecommended.Finally,failuretodetectapathogenicvariantcould
meanthatthefamilytrulyisnotatgeneticriskdespiteaclinicalpresentationthatsuggestsageneticbasis.Ifnovariantcanbe
identifiedinanaffectedfamilymember,testingshouldnotbeofferedtoat-riskmembers.Theywouldremainatincreasedriskof
CRCbyvirtueoftheirfamilyhistoryandshouldcontinuewithrecommendedintensivescreening.(RefertotheInterventionsforLS
sectionofthissummaryformoreinformation.)
DNA MMR genes

LSiscausedbyagermlinepathogenicvariantofoneofseveralDNAMMRgenes.[339-345]Thefunctionofthesegenesisto
maintainthefidelityofDNAduringreplication.ThegenesthathavebeenimplicatedinLSincludeMSH2(mutS homolog 2)on
chromosome2p22-21;[342,343]MLH1(mutL homolog 1)onchromosome3p21;[341]PMS2(postmeiotic segregation 2)on
chromosome7p22;[345,346]andMSH6onchromosome2p16.ThegenesMSH2andMLH1arethoughttoaccountformost
pathogenicvariantsoftheMMRgenesfoundinLSfamilies.[347,348]
AvarietyofLS-associatedpathogenicvariantsinMSH2andMLH1havebeenidentified.Theseincludefounderpathogenicvariants
intheAshkenaziJewish,Finnish,Portuguese,andGermanAmericanpopulations.[334,348-353]Thewidedistributionofthe
pathogenicvariantsinthetwogenesprecludesimplegenetestingassays(i.e.,assaysthatwouldidentifyonlyafewpathogenic
variants).CommercialtestingisavailabletosearchforpathogenicvariantsinMSH2,MLH1,MSH6,andmostrecentlyforPMS2.
Clinicalandcostconsiderationsmayguidetestingstrategies.MostcommercialgenetictestingforMSH2andMLH1isdonebygene
sequencing.BecausesequencingfailstodetectgenomicdeletionsthatarerelativelycommoninLS,methodssuchasSouthernblot
orMLPA,[354]fordetectionoflargedeletions,arebeingused.[355](RefertotheGenetic/moleculartestingforLSsectionofthis
summaryformoreinformationaboutissuestobeconsideredintestingforthesepathogenicvariants.)
MLH1
Prevalence
MLH1andMSH2makeupthemajorityofLSpathogenicvariants.Upto50%ofpathogenicvariant-positiveLSfamiliesharboran
MLH1pathogenicvariant,withsomegeographicvariation.[356]
Genotype-phenotype correlations
MLH1pathogenicvariantshavebeenassociatedwiththeentirespectrumofmalignanciesassociatedwithLS.[356]Thelifetimerisk
ofCRCincarriersofMLH1pathogenicvariantsisestimatedtobe41%to68%.[245,250,357]Thelifetimeriskofendometrialcancer
isestimatedtobeapproximately40%.[3,250]Muir-TorresyndromeislesscommonlyassociatedwithMLH1pathogenicvariants
thanareMSH2pathogenicvariants.[280]
Practices and pitfalls in testing

IncontrasttothescenarioofMSIassociatedwithlossofexpressionofMSH2,MSH6orPMS2,absenceofMLH1expressionisnot
specifictoLS.MostinstancesofabsenceofMLH1expressionarecausedbythesporadichypermethylationoftheMLH1promoter.
Therefore,absentMLH1expressionislessspecificforLSthanabsenceoftheotherMMRproteins.Inaddition,rareinstancesof
inheritedgermlineMLH1methylationhaveaddedfurthercomplexitytotheinterpretationofMSIassociatedwithabsenceofMLH1
expression.(RefertotheMSIsectionformoreinformationaboutgermlineMLH1hypermethylation.)
MSH2
Prevalence
TheprevalenceofMSH2pathogenicvariantsinindividualsorfamilieswithLShasvariedacrossstudies.MSH2pathogenicvariants
werereportedin38%to54%ofLSfamiliesinstudiesincludinglargecancerregistries,cohortsofearly-onsetCRC(<55years),and
registriesaroundtheworld.[247,295]
ThelifetimeriskofcoloncancerassociatedwithMSH2pathogenicvariantsisestimatedtobebetween48%and68%.[245,250,357]
InacaseseriesofLSpatients,thosecarryinggermlineMSH2pathogenicvariants(49individuals,45%females)hadalifetime
(cutoffofage60years)riskofextracoloniccancersof48%comparedwith11%forMLH1carriers(56individuals,50%females).[358]
Inaddition,thesamegroupreportedasignificantlyhigherprevalenceofpoorlydifferentiatedCRCs(44%forMSH2carriersvs.14%
forMLH1carriers;P=.002)andCrohn-likereaction(49%forMSH2carriersvs.27%forMLH1carriers;P=.049).Anotherstudy
reportednosignificantdifferencesbetweentheprevalenceofcolorectalandextracoloniccancersin22familieswithgermline
MLH1pathogenicvariantsandin12familieswithgermlineMSH2pathogenicvariants.[359]
MultiplegroupshavereportedthatMSH2andMSH6carriershaveagreaterchanceofpresentingwithendometrialcancersbefore
CRCsthandoMLH1carriers.[3,286,360]Theaverageageatdiagnosisofendometrialcancersdifferedwithgenotypeintwostudies:
age41yearsforMSH2,age49yearsforMLH1,andage55yearsforMSH6carriers.[361,362]Incontrastwithearlydataindicating
noincreasedriskofendometrialcancer,a2011studysuggeststhattheremaybeanincreasedriskinpatientswithEPCAMvariants.
[255]

InpatientswithabsenceofMSH2andMSH6proteinexpressionwhohaveundergonegenetictestingwithnopathogenicvariant
foundbythecurrentlyavailablestandardtechniques,germlinepathogenicvarianttestingforEPCAM/TACSTD1shouldbe
considered.Approximately20%ofpatientswithabsenceofMSH2andMSH6proteinexpressionbyIHCandnoMSH2orMSH6
pathogenicvariantidentifiedwillhavegermlinedeletionsinEPCAM/TACSTD1.[363]Thelattermechanismaccountsfor
approximately5%ofallLScases.[363](RefertotheEPCAM/TACSTD1sectionofthissummaryformoreinformation.)
MSH6
Prevalence
MostseriesshowaprevalenceofgermlineMSH6pathogenicvariantsinapproximately10%ofLSfamilies.However,thereported
range(5%52%)islarge.[286,289,290,364-367]Thiswidevariationislikelyaresultofsmallsamplesizes,referralbias,and
ascertainmentbias.
ThelifetimeriskofcoloncancerassociatedwithMSH6pathogenicvariantsisestimatedtobebetween12%and22%.[248,250]The
lifetimeriskofCRCmightbelowerinMSH6carriersthaninMSH2andMLH1carriers.Initialstudieshavesuggestedthatinactivating
germlinepathogenicvariantsofMSH6mightbemorefrequentinpersonswithalateraverageageatonsetofCRCwhosetumors
exhibitanon-MSI-Hphenotype.
Onestudyreportedon146MSH6carriers(59menand87women)from20families,allofwhomhadtruncatingpathogenicvariants
inMSH6.WhiletheprevalenceofCRCsbyage70yearswasnotsignificantlydifferentbetweenMSH6andMLH1orMSH2carriers(P=
.0854),themeanageatdiagnosisforcolorectalcarcinomainmalecarriersofMSH6pathogenicvariantswas55years(n=21;
range,2684years)versus43yearsand44yearsincarriersofMLH1andMSH2pathogenicvariants,respectively.Theprevalenceof
CRCwassignificantlylowerinwomenwithMSH6germlinepathogenicvariantsthanincarriersofMLH1orMSH2pathogenic
variants(P=.0049).ThemeanageatdiagnosisforcolorectalcarcinomainfemalecarriersofMSH6pathogenicvariantswas57
years(n=15;range,4181years)versus43yearsand44yearsincarriersofMLH1andMSH2pathogenicvariants,respectively.[306]
Inaddition,endometrialcancerhasbeenreportedtobemorecommoninMSH6families.Inthesamestudy,thecumulativeriskof
uterinecancerwassignificantlyhigherincarriersofMSH6pathogenicvariants(71%)thanincarriersofMLH1(27%)andMSH2
(40%)pathogenicvariants(P=.02).Themeanageatdiagnosisofendometrialcarcinomawas54yearsincarriersofMSH6
pathogenicvariants(n=29;range,4365years)versus48yearsand49yearsincarriersofMLH1andMSH2pathogenicvariants,
respectively.[306]AgroupofresearchersreportedontenMSH6kindredswithLSinwhich70%offemaleshadbeendiagnosedwith
endometrialcancercomparedwith31%and29%inMLH1andMSH2carriers,respectively.[360]Onestudyfoundtheprevalenceof
endometrialcarcinomatobe58%in12MSH6familieswithameanageatdiagnosisof57years.[365]
OnegroupofresearchersassembledthelargestseriesofcarrierfamiliesofMSH6pathogenicvariantstoestimatepenetranceof
cancers.[248]Atotalof113familiesofcarriersofMSH6pathogenicvariantsfromfivecountrieswereascertainedthroughfamily
cancerclinicsandpopulation-basedcancerregistries.Thefamiliescontainedanestimated1,043carriersofpathogenicvariants.By
age70years,22%(95%CI,14%32%)ofmalecarriersofMSH6pathogenicvariantsdevelopedCRCcomparedwith10%(95%CI,5%
17%)offemalecarriersofMSH6pathogenicvariants.Byage80years,44%(95%CI,28%62%)ofmalecarriersofMSH6pathogenic
variantswerediagnosedwithCRC,comparedwith20%(95%CI,11%35%)offemalecarriersofMSH6pathogenicvariants.Forall
carriersofMSH6pathogenicvariants,theincreasedriskofCRC,relativetothatofthegeneralpopulation,acrossallagegroupswas
statisticallysignificantlyelevated(HR,7.6;95%CI,5.410.8;P<.001).Byages70yearsand80years,26%(95%CI,18%36%)and
44%(95%CI,30%58%),respectively,ofwomenwouldbediagnosedwithendometrialcancer.FemalecarriersofMSH6pathogenic
variantshadanendometrialcancerriskthatwasabout25timeshigherthanwomeninthegeneralpopulation(HR,25.5;95%CI,
16.838.7;P<.001).
Inthesamestudy,femalecarriersofMSH6pathogenicvariantshadacumulativeriskofotherLynchcancers(i.e.,ovarian,stomach,
smallintestine,kidney,ureter,orbrain)of11%(95%CI,6%19%)byage70yearsand22%(95%CI,12%38%)byage80years.[248]
TheriskofLScancers,excludingcolorectalandendometrialcancers,wassixtimesthatofthegeneralpopulation(HR,6.0;95%CI,
3.410.7;P<.001).MalecarriersofMSH6pathogenicvariantsshowednoevidenceofanincreasedriskofthesecancers(HR,0.8;
95%CI,0.18.8;P=.9).Theauthorsestimatedthat24%(95%CI,16%37%)ofmenand40%(95%CI,32%52%)ofwomenharboring
MSH6pathogenicvariantswouldbediagnosedwithanyLScancerbyage70yearsandthatthesevalueswillincreaseto47%(95%
CI,2%66%)ofmenand65%(95%CI,53%78%)ofwomenbyage80years.

Onestudyreportedthatof42population-basedprobandsharboringdeleteriousMSH6germlinepathogenicvariantswhowere
ascertainedindependentoftheirfamilycancerhistory,30(71%)hadafamilycancerhistorythatdidnotmeettheAmsterdamII
criteria.[248]
MSH6colorectaltumorscanbeMSI-H,MSI-L,orMSS.ThispitfallillustratestheutilityofIHCfortheMMRproteinexpression.
Eighteenof21(86%)ofthecolorectaltumorsshowedanMSI-Hphenotype.Ofthe16endometrialtumorstested,11wereMSI-H
(69%);fourwereMSI-L(25%),andonewasMSS(6%).[306]
InendometrialcancerswithgermlineMSH2pathogenicvariants,lossofMSH6frequentlyoccurswithlossofMSH2.[362,368]
PMS2
Prevalence
PMS2wasthelastofthegenesintheMMRfamilyofgenestobeidentified.Itwasthoughttobedifficulttoevaluatebecauseof
pseudogeneinterferenceanditslowpenetrance.ThePMS2monoallelicpathogenicvariantstillappearstobetheleastpenetrantof
alltheMMRgenes,butgrowingevidencesuggeststhatitisacommonvariant.Themostsevereexpressionappearstobein
bialleliccarriers.
Oneregistrystudyreportedanincidenceof2.2%forPMS2pathogenicvariantsin184patientswithsuspectedLS.[369]A
population-basedstudyreportedaprevalenceofapproximately5%(1of18).[241]Germlinevariantanalysisutilizingnext-
generationsequencing(NGS)in1,260patientswhohadpreviouslyundergoneclinicalgenetictestingforLSrevealed114probands
withgermlinepathogenicvariantsinMLH1(27%),MSH2(35%),MSH6(23%),EPCAM(3%),andPMS2(12%).[370]Thus,the
contributionofPMS2toLSappearstobegreaterthanpreviouslyappreciated.Inaddition,anIHC-basedsurveyof1,000
consecutivelycollectedCRCsinSwitzerlandfoundisolatedabsenceofPMS2expressionin1.5%ofthetumors.Ifthisfrequencyof
PMS2-deficientCRCswererepresentativeofallPMS2-associatedLS,PMS2wouldbethemostcommongeneassociatedwithLS.
[371]BecauseoflowerpenetranceinPMS2-associatedLS,affectedfamiliesaremoredifficulttoidentify.[372]
Ameta-analysisofthreepopulation-basedstudiesandoneclinic-basedstudyestimatedthatforcarriersofPMS2pathogenic
variants,theriskofCRCtoage70yearswas20%amongmenand15%amongwomen,andtheriskofendometrialcancerwas15%.
[246]
Inonestudy,patientswithPMS2pathogenicvariantspresentedwithCRC7to8yearslaterthandidthosewithMLH1andMSH2
pathogenicvariants.However,thesefamiliesweresmallanddidnotfulfillAmsterdamcriteria.[369]AEuropeanconsortiumof
clinic-basedregistries,takingcaretocorrectforascertainmentbias,foundacumulativelifetime(toage70years)CRCriskofonly
19%inmenand11%inwomenwithPMS2pathogenicvariants.Endometrialcancerriskwasestimatedat12%.[373]Onthebasisof
thesefigures,thisconsortiummadeaclinicalrecommendationfordelayingtheonsetofcolorectalandendometrialcancer
screeningtoage30years,inlinewiththeirrecommendationforlaterinitiationofscreeningforcarriersofMSH6pathogenic
variants.NotethattheNCCNguidelinedevelopersconsideredbutdidnotadoptthesemore-liberalguidelines.[93]Additionally,a
2015reviewbyanadhocAmericanvirtualworkgroupinvolvedinthecareofLSpatientsandfamiliesconcludedthatdespite
multiplestudiesindicatingreducedpenetranceinmonoallelicPMS2carriers,theycouldnotrecommendanychangestoLScancer
surveillanceguidelinesforthisgroup.[372]

ThepresenceofthepseudogenePMS2CLandfrequentsequenceexchangebetweenPMS2andPMS2CLhavemadedetectionof
germlinePMS2pathogenicvariantsdifficult.AcombinatorialapproachutilizingMLPA,long-rangepolymerasechainreaction,and
NGSisbeingemployedtoincreasethediagnosticyieldinindividualswithsuspectedgermlinevariantsinPMS2.[374]
PMS2andMLH2functionasastableheterodimer.ThemostcommonabnormalIHCpatternforDNAMMRproteinsincolorectal
adenocarcinomasislossofexpressionofMLH1andPMS2.AfunctionaldefectinMLH1resultsindegradationofbothMLH1and
PMS2,whileadefectinPMS2onlyaffects(negatively)PMS2expression.Thus,alossofMLH1andPMS2indicatesanalterationin
MLH1(promoterhypermethylationorgermlinevariant),whilelossofPMS2expressionindicatesagermlinePMS2variant.However,
among88individualswithPMS2-deficientCRC,PMS2germlinepathogenicvarianttestingfollowedbyMLH1germlinepathogenic
varianttestingrevealedpathogenicPMS2variantsin49(74%)individualsandMLH1pathogenicvariantsin8(12%)individuals.[375]
Eighty-threepercentofthealterationsinMLH1weremissensevariants,buttworelativescarriedidenticalMLH1variants,andone
individual,whodevelopedtwotumorswithretainedMLH1expression,carriedanintronicvariantthatledtoskippingofexon8.
[375]Therefore,inCRCswithsolitarylossofPMS2expression,anMLH1germlinepathogenicvariantshouldbesoughtifnoPMS2
germlinevariantisfound.
Polymorphisms in unrelated genes affecting expression in LS

PolymorphismspotentiallyaffectingexpressioninMMRgenesfallintotwocategories:thosewhosemechanismsarealready
suspectedtohaveaneffectoncancer-relatedpathways,andthosethataretrulyanonymous.Severalcandidategeneshavebeen
studied.Anonymousgeneshavealsobeenevaluated.
Studieshavedemonstratedthatapolymorphisminthepromoterregionoftheinsulin-like growth factor 1(IGF1)genemodifiesage

ofonsetofCRCinLS.[376,377]ThepolymorphismisavariablenumberofCA-dinucleotiderepeatsapproximately1kbupstreamof
thetranscriptionstartsiteofIGF1.Thereissignificantvariabilitybetweenindividualsandpopulationswithrespecttorepeatlength.
Carriersofshorterrepeatlengths(shortestallele=17repeats)developCRConaverage12yearsearlierthanthosewithlonger
repeatlengths.Itisunclearwhetherthispolymorphisminfluencesextracolonicmalignancies.Additionally,thecyclinD1
polymorphismG870AmaybeassociatedwithearlierageofonsetofCRCinLS,[378,379]althoughtheassociationappearstobe
morereproducibleincarriersofMSH2pathogenicvariantsthanincarriersofMLH1pathogenicvariants.[379,380]
Twosinglenucleotidepolymorphisms(SNPs)identifiedingenome-wideassociationstudies(GWAS)havebeenreportedto
increaseCRCriskincarriersofMMRgenepathogenicvariants.(RefertotheGWASsectionofthissummaryformoreinformation.)
HavingtheC-alleleofeitherSNPincreasedtheriskofCRCinadose-dependentfashion(withhomozygotesatahigherriskthan
heterozygotes).ThefirstSNPin8q23.3increasedCRCrisk2.16-foldforhomozygotecarriersoftheSNP.ThesecondSNP,locatedin
11q23.1,increasedCRCriskonlyinfemaleSNPcarriersby3.08forhomozygotesand1.49forheterozygoteSNPcarriers.[381]
Inastudyof684carriersofMMRpathogenicvariantsfrom298AustralianandPolishfamilies,nineSNPswithinsixpreviousCRC
susceptibilitylociweregenotypedtoinvestigatetheirpotentialasmodifiersofdiseaseriskinLS.[382]TwoSNPs,rs3802842
(11q23.1)andrs16892766(8q23.3),wereassociatedwithCRCsusceptibilityinMLH1pathogenicvariantpositiveLSpatients.
However,asubsequentstudyof748FrenchcarriersofMMRpathogenicvariantsdidnotreplicatetheassociationbetweentheIGF1
CArepeatandageofCRConsetortheassociationbetweenSNPsin8q23.3and11q23.1andCRCrisk.[383]
Giventheinconsistentresultsofthesestudies,genetictestingforthesepolymorphismshasnoclinicalutilityatpresent.
Diagnostic strategies for all individuals diagnosed with CRC (universal testing)
TheEvaluationofGenomicApplicationsinPracticeandPrevention(EGAPP),aprojectdevelopedbytheOfficeofPublicHealth
GenomicsattheCentersforDiseaseControlandPrevention,formedaworkinggrouptosupportarigorous,evidence-based
processforevaluatinggenetictestsandothergenomicapplicationsthatareintransitionfromresearchtoclinicalandpublichealth
practice.TheWorkingGroupwascommissionedtoaddressthefollowingquestion:DoriskassessmentandMMRgenevariant
testinginindividualswithnewlydiagnosedCRCleadtoimprovedoutcomesforthepatientorrelatives,oraretheyusefulin
medical,personal,orpublichealthdecision-making?[384,385]TheWorkingGroupconstructedeconomicmodelstoassistin
analyzingavailableevidenceonclinicalutilityinestimatinghowvarioustestingstrategiesmightfunctioninpractice.These
includedvariantfrequency,sensitivityandspecificityofbothIHCandMSItesting,andthecostofthesetests.Theperformanceof
thesetestsisbasedontheriskofcarryingapathogenicvariantincludingfamilyhistory,ageatdiagnosis,andextracoloniccancers.
In2009,theWorkingGroupreportedthattherewassufficientevidencetorecommendofferinggenetictestingforLStoindividuals
withnewlydiagnosedCRCtoreducemorbidityandmortalityinrelatives.Theyconcludedthattherewasinsufficientevidenceto
recommendaspecificgene-testingstrategyamongthefollowingfourstrategiestested:[384,385]
1.AllindividualswithCRCtestedforgermlinepathogenicvariantsinMSH2,MLH1,andMSH6.TheaveragecostperLSdetected
wasestimatedtobe$111,825.
2.AlltumorstestedforMSI,followedbygermlinetestingofMSH2,MLH1,andMSH6offeredtothosewithMSI-Htumors.The
averagecostperLSdetectedwasestimatedtobe$47,268.
3.AlltumorstestedforabsenceofproteinexpressionofMSH2,MLH1,MSH6,andPMS2,followedbytargetedgermlinetesting
ofMSH2,MLH1,orMSH6offereddependingonwhichproteinwasabsent.TheaveragecostperLSdetectedwasestimatedto
be$21,315.
4.AlltumorstestedforabsenceofproteinexpressionofMSH2,MLH1,MSH6,andPMS2followedbytargetedgermlinetesting
ofMSH2,MLH1,orMSH6offereddependingonwhichproteinwasabsent.IftherewasabsenceofMLH1,testingwasoffered
forBRAFvariant-negativetumors.TheaveragecostperLSdetectedwasestimatedtobe$18,863.[385]
TheEGAPPanalysismadeseveralassumptions,including(1)IHCandMSIwillnotdetectallLSpatientsand(2)notallpatientswith
CRCwilloptfortesting.
ResultsareavailablefromaMarkovmodelthatincorporatedtherisksofcolorectal,endometrial,andovariancancerstoestimate
theeffectivenessandcost-effectivenessofstrategiestoidentifyLSamongpersonswithnewlydiagnosedCRC.[386]Thestrategies
incorporatedinthemodelwerebasedonclinicalcriteria,predictionalgorithms,andtumortestingorup-frontgermlinepathogenic
varianttestingfollowedbydirectedscreeningandrisk-reducingsurgery.SimilartotheEGAPPworkinggroup,IHCfollowedbyBRAF
pathogenicvarianttestingwasthepreferredstrategyinthisstudy.Anincrementalcost-effectivenessratioof$36,200perlifeyear
gainedresultedfromthisstrategy.Inthismodel,thenumberofrelativestested(3to4)perprobandwasacriticaldeterminantof
botheffectivenessandcost-effectiveness.
Adifferentapproachbasedonriskassessmentsof100,000simulatedindividualsrepresentativeoftheU.S.populationwhowere
trackedfromage20andexposedto20differentscreeningstrategieshasbeenreported.[387]Inthisstudy,thestrategiesinvolved
riskassessmentatdifferentagesutilizingthePREMM1,2,6modelfollowedbypathogenicvariantanalysisforMLH1,MSH2,MSH6,
andPMS2inindividualswhosepathogenicvariantriskthresholdexceeded0%,2.5%,5%,or10%.Inindividualswhoserisk
assessment(startingatage25,30,or35years)forcarryingapathogenicvariantexceeded5%,colorectalandendometrialcancers
incarrierswerereducedby12.4%and8.8%,respectively.Inthewholepopulation,thisstrategyincreasedthequalityadjustedlife-
yearsby135yearsper100,000individualswithanaveragecost-effectivenessratioof$26,000.Theauthorssuggestedthatthe
outlinedstrategywasmorecosteffectivethancurrentpracticeandcouldimprovehealthcareoutcomes.
RecognizingthecontroversialconclusionsoftheEGAPPworkinggroup,theCentersforDiseaseControlandPreventionconveneda
specialmeetingofcancergeneticsexpertstocritiquetheserecommendations.Thegroupconcludedthatgeneticscreeningofall
newlydiagnosedCRCcasesforLS(universalLSscreening)cantheoreticallyresultinpopulationhealthbenefits,andfeasibilityhas
beendemonstrated."[388]
Universal MSI/IHC colorectal cancer screening in clinical practice
Universal MSI/IHC colorectal cancer screening in clinical practice
Universalscreeninghasbeenadoptedbymanyinstitutionsinrecentyears.A2011surveyoftheNationalSocietyofGenetic
Counselorsrevealedthatmorethan25%ofrespondentshadsomeformofuniversalscreeningimplementedattheircenter.
Tumorscreeningmethodsvaried;34of53(64.2%)startedwithIHC,11of53(20.8%)startedwithMSItesting,and8of53(15.1%)
performedbothtestsonnewlydiagnosedcolorectaltumors.[389]A2012surveysuggestedthatsomeformofuniversalscreening
wasbeingroutinelyperformedat71%oftheNationalCancerInstitute(NCI)comprehensivecancercentersbutthatutilization
droppedto15%amongarandomsampleofcommunityhospitalcancerprograms.[390]NCCN2015guidelinessupportIHCor
sometimesMSItestingofallCRCsdiagnosedinpatientsyoungerthan70yearsiftumorisavailableandinpatients70yearsor
olderwhomeetBethesdaguidelines.[93]Universalscreeninginallindividualsirrespectiveofagewasassociatedwithadoublingof
incrementalcostperlife-yearsavedcomparedwithscreeningonlythoseyoungerthan70years.[386]Theauthorsofthisanalysis
concludethatscreeningindividualsyoungerthan70yearsappearsreasonable,whilescreeningallindividualsregardlessofage
mightalsobeacceptable,dependingonsocieties'willingnesstopay.
SeveralstudieshavedemonstratedthefeasibilityandusefulnessofuniversalscreeningforLS.Initialexperiencefromone
institutionfoundthatamong1,566patientsscreenedusingMSIandIHC,44(2.8%)patientshadLS.Foreachproband,anaverage
ofthreeadditionalfamilymembersweresubsequentlydiagnosedwithLS.[241]Asubsequentpooledanalysisof10,206incident
CRCpatientstestedwithMSI/IHCaspartoffourlargestudiesrevealedapathogenicvariantdetectionrateof3.1%.[391]Thisstudy
comparedfourstrategiesfortumortestingforthediagnosisofLS.[391]Thestrategyoftumortestingallindividualsdiagnosed
withCRCatage70yearsoryoungerandtestingolderindividualswhometoneoftherevisedBethesdaguidelinesyieldeda
sensitivityof95.1%,aspecificityof95.5%,andadiagnosticyieldof2.1%.Thisstrategymissed4.9%ofLScases,but34.8%fewer
casesrequiredIHC/MSItesting,and28.6%fewercasesunderwentgermlinetestingthanintheuniversalapproach.
AnimportantimplicationofuniversalscreeningforLSistherealitythatitdoesnotresultinautomaticgermlinetestingin
appropriateindividuals.Subsequentgeneticcounselingrequirescoordinationbetweenthepathologist,thereferringsurgeonor
oncologist,andacancergeneticsservice.Inaddition,patientconsentandcompliancewithsubsequenttestingmaysignificantly
influenceuptakeofgeneticcounseling.Asanillustration,apopulation-basedscreeningstudyfoundthatonly54%ofpatientswith
anIHC-deficienttumor(thatwasBRAFpathogenicvariantnegative)ultimatelyconsentedtoandproceededwithgermlineMMR
testing.[392]Oneinstitutionfound21pathogenicvariantsamong1,100patientswhounderwentroutineMSIandIHCtestingafter
adiagnosisofCRC.ThisstudyfoundmarkedlyincreaseduptakeofgeneticcounselingandgermlineMMRgenetestingwhenboth
thesurgeonandageneticcounselorreceivedacopyofabnormalMSI/IHCresults,especiallywhenthegeneticcounselorplayedan
activeroleinpatientfollow-up.[393]
TosimplifytheprocessofIHCtestingandtohelpdecreasecost,astrategythatemploysIHCtestingforPMS2andMSH6alonehas
beensuggested.ThisstrategyreliesonthebindingpropertiesoftheMMRheterodimercomplexes,bywhichgenevariantandloss
ofMLH1andMSH2invariablyresultinthedegradationofPMS2andMSH6,respectively,buttheconverseisnottrue.[331]The
authorsdonotsuggestadefinitivealgorithmafterthefindingofanIHC-deficienttumor.However,giventhepredominanceof
MLH1andMSH2pathogenicvariantsinLS,theauthorssuggestthataPMS2-deficienttumorshouldbeinvestigatedforeitherMLH1
hypermethylation(utilizingBRAFpathogenicvariantstatusasaproxy)orgermlineMLH1pathogenicvariantanalysis.Similarly,
MSH6deficiencywouldgenerallyresultinMSH2germlinetestingasafirststep.Thisstrategyhasnotbeenvalidatedorwidely
adoptedinclinicalpractice.
Thereisanongoingdiscussionaboutbestpracticesfortheinformedconsentprocessforthistumortesting.[394]Identificationof
geneticpredispositiontocancergenerallymandatesexplicitinformedconsentbecauseofconcernsforthepossibilityofinsurance
discrimination(irrespectiveoftheGeneticInformationNondiscriminationActof2008),adversepsychologicaloutcomes,andcosts
associatedwithfurthertesting.[395,396]TheEGAPPworkinggroupspecificallyrecommendsobtaininginformedconsentforMSI
orIHCtesting.[384]Nevertheless,debateaboutthisissuecontinues,partiallybecauseofpragmaticconcernssurroundingthe
feasibilityofobtainingsuchconsentbeforetheprocedure.Oneproposedapproachsuggestsapreparatoryconversationinforming
patientsbeforetheirprocedurethatCRCrunsinfamiliesandthatiftheirtumorhasfeaturescharacteristicofaheritabletype,they
willbecontactedbyagenetichealthcareproviderforfurtherassessmentofthegeneticbasisoftheircancer.[394]Across-
sectionalsurveyofU.S.cancerprograms(20NCIdesignatedcomprehensivecancercentersand49communityhospitalcancer
programs)foundthat,ofthosethatperformedMSIand/orIHCtestingaspartofstandardpathologicevaluationatthetimeof
coloncancerdiagnosisinallorselectcases,nonerequiredwritteninformedconsentbeforetumortesting.[390]
(RefertotheInformedConsentsectioninthePDQsummaryonCancerGeneticsRiskAssessmentandCounselingformore
information.)
Cost-effectiveness of genetic testing
Cost-effectiveness of genetic testing
Asgenetictestingbecomesroutineratherthantheexception,questionsregardingthecostoftestingwillalwaysarise.Historically,
utilizingacost-effectivenessratio(costperquality-adjustedlifeyears[QALY])of$50,000hasbeenutilizedforthebenchmarkasa
goodvalueforcare.[397]Overtimeithasbeensuggestedthatthisthresholdistoolowandthatotherthresholdssuchas$100,000
or$150,000beutilized.[397]Tworecentpaperstriedtoaddressthisissuewithregardstoapproachestogenetictesting.
Onestudyevaluatedthecost-effectivenessofNGSpanelsforthediagnosisofCRCandpolyposissyndromesinpatientsreferredto
acancergeneticsclinic.[398]Theseauthorsdevelopedadecisionmodeltoestimatetheimmediateanddownstreamcostsfor
patientsreferredforevaluationandofCRCsurveillanceinfamilymembersidentifiedascarriersofpathogenicvariants.Thecosts
wereestimatedonthebasisofpublishedmodelsfromtheCentersforDiseaseControlandPreventionandfromanacademic
moleculargeneticslaboratory.TheyclassifiedthesyndromesonthebasisofinheritancepatternandpenetranceofCRC.Four
panelswerecomparedwiththestandardofcare.ThefirstpanelconsistedofsequencingonlyLS-associatedgenes.Thecostofthis
strategywasabout$144,235perQALY.ThesecondpanelconsistedofLS-associatedgenesandgenesassociatedwithautosomal
dominantinheritanceandhighCRCpenetrance.Thecostofthisstrategywas$37,467perQALY.ThethirdpanelconsistedofLS-
associatedgenesandgenesassociatedwithautosomaldominantandautosomalrecessiveinheritanceandhighCRCpenetrance.
Thecostofthisstrategywas$36,500perQALY.Thefourthpanelincludedthegenesinthefirstthreepanelsandthoseassociated
withautosomaldominantconditionswithlowpenetrance.Thisresultedinanincrementalcost-effectivenessratioof$77,300per
QALYwhencomparedwithpanelthree.TheauthorsconcludedthatutilizingaNGSpanelthatincludeshighlypenetrantCRCand
polyposissyndromesandLScancergenesasafirst-linetestwillmostlikelyprovideclinicallymeaningfulresultsinacost-effective
fashion.
Anotherstudyaddressedcost-effectivenessofonlytestingforLS.[399]Theyevaluated21screeningstrategies.Themodelincluded
twosteps:1)measurementofthenumberofLSdiagnosesand2)measurementofthelife-yearsgainedasaresultofconfirming
LSinahealthycarrier.Amongallofthestrategiesmodeled,screeningtheprobandwithapredictivemodelsuchasPREMM1,2,6
followedbyIHCforMMRproteinexpressionandgermlinegenetictestingwasthebestapproach,withanincrementalcost-
effectivenessratioof$35,143perlife-yeargained.Germlinegenetictestingonallprobandswasthemosteffectiveapproachbutat
acostof$996,878perlife-yeargained.TheauthorsconcludedthattheinitialstepofLSscreeningshouldutilizeapredictivemodel
intheproband,andthatbothuniversaltestingandgeneralpopulationscreeningstrategieswerenotcost-effectivescreening
strategiesforLS.
Diagnostic strategies for all individuals diagnosed with endometrial cancer

BasedonaMarkovmathematicalmodel,astrategyofperformingIHCforMMRproteinexpressioninallpatientswithendometrial
cancer,irrespectiveoftheageatdiagnosis,whohaveafirst-degreerelativewithendometrialcancer,wasreportedtobecost-
effectiveinthedetectionofLSinpatientswithLS-relatedcancer.[400](RefertotheGenetictestingsectionofthissummaryfor
moreinformationaboutperformingIHCforMMRproteinexpression.)Inthisstudy,incrementalcost-effectivenessratiowas
definedastheadditionalcostofaspecificstrategydividedbyitshealthbenefitcomparedwithanalternativestrategy.Inthis
model,thestrategyofperformingIHConthetumorfromallpatientsdiagnosedwithLS-relatedcancerwhohaveafirst-degree
relativewithendometrialcancerhadanincrementalcostratioof$9,126peryearoflifegainedrelativetotheleast-costlystrategy,
whichwasgenetictestingonallwomendiagnosedwithendometrialcanceryoungerthan50yearswithatleastonefirst-degree
relativewithLS-relatedcancer.
ThemodelpredictedthatifallendometrialcancersintheUnitedStates(estimatedtobe45,000newcasesin2010)underwentIHC
screening,827women(1.84%)wouldbediagnosedasLSpatients.[400]However,applyingthestrategyoftestingonlythose
endometrialtumorsofpatientswithatleastafirst-degreerelativewithLS-relatedcancer,755affectedindividuals(1.68%)wouldbe
identified.IftheAmsterdamIIcriteriawereapplied,539carriers(1.2%)wouldbeidentified.Theauthorsstatedthatthe
incrementalbenefitofthemostcost-effectivestrategywasassociatedwithanaveragelifeexpectancygainofonly1daycompared
withtestingbyAmsterdamIIcriteria.However,theyarguethatthismaybesignificant,asitiscomparabletothelifeexpectancy
gainfromtriennialcervicalcancerscreening,whichisacurrentrecommendationfromtheAmericanCollegeofObstetriciansand
Gynecologistsforwomenolderthan30yearsinthegeneralpopulation.
Interventions for LS
SeveralaspectsofthebiologicbehaviorofadenomasandcoloncancersinpatientswithLSsuggesthowtheapproachto
surveillanceinthispopulationshoulddifferfromthatforaverage-riskpeople:
CRCpresentsatayoungerage.
CRCsinLSoccurearlierinlifethandosporadiccancers.ForcarriersofMLH1andMSH2pathogenicvariants,theestimatedrisk
ofCRCatage40yearsis31%forwomenand32%formen;atage50years,theestimatedrisksare52%and57%,respectively.
[3]Theauthorsofameta-analysisoffourstudiesinwhichtheestimatedCRCriskwaselevatedincarriersstratifiedbyageand
sexconcludedthatscreeningmaystartbetweentheagesof30and39years,ratherthanbetweentheagesof20and29
years,basedonthenumberofcolonoscopiesrequiredtopreventonedeathfromCRCinindividualsyoungerthan30years
(seeTable10).[401]
Table 10. Estimated Number Needed to Screen by Annual Colonoscopy Over 5 Years to
Prevent One Colorectal Cancer Deatha
AgeGroup(y) NumberNeededtoScreen
Men Women
2029 155 217
3039 45 66
4049 29 35
5059 16 25
6069 24 35
7079 29 40
a
AdaptedfromJenkinsetal.[401]
Thereisaright-sidedpredominanceofcoloncancer.
AlargerproportionofLSCRCs(60%70%)occurintherightcolon,suggestingthatsigmoidoscopyaloneisnotanappropriate
screeningstrategyandthatacolonoscopyprovidesamorecompletestructuralexaminationofthecolon.Evidence-based
reviewsofsurveillancecolonoscopyinLShavebeenreported.[141,402,403]TheincidenceofCRCthroughoutlifeis
substantiallyhigherinpatientswithLS,suggestingthatthemost-sensitivetestavailableshouldbeused.(RefertoTable11for
availablecolonsurveillancerecommendations.)
Theadenoma-carcinomasequenceisaccelerated.
Theprogressionfromnormalmucosatoadenomatocancerisaccelerated,[404,405]suggestingthatscreeningshouldbe
performedatshorterintervals(every12years)andwithcolonoscopy.[405-408]Ithasbeendemonstratedthatcarriersof
MMRgenepathogenicvariantsdevelopadenomasatanearlieragethandononcarriers.[252]
Thereisanincreasedriskofextracolonicmalignancies.
PatientswithLSareatanincreasedriskofothercancers,especiallythoseoftheendometrium.Thecumulativeriskof
extracoloniccancerhasbeenestimatedtobe20%byage70yearsin1,018womenin86families,comparedwith3%inthe
generalpopulation.[261]Thereissomeevidencethattherateofindividualcancersvariesfromkindredtokindred.
[260,409,410](RefertoTable12foravailableextracolonicscreeningrecommendationsfromprofessionalsocieties.)
Table11andTable12summarizetheclinicalpracticeguidelinesfromdifferentprofessionalsocietiesregardingdiagnosisand
surveillanceforLS.
Table 11. Practice Guidelines for Diagnosis and Colon Surveillance of Lynch Syndromea
Organization Tumor MMR/ Age Freq. Method Comments

MSI/IHC EPCAM Screening
Genetic Initiated
Testing
ESMO(2013)b MSI:Yes MMR:Yes 2025yOR 12y C

[413] 5ybefore
youngest
caseofCRC
infamily;no
IHC:Yes EPCAM:Yes upperlimit
established
U.S.Multi- MSI:Yes MMR:Yes 2025yOR 12y C ForMSH6and

SocietyTask 25ybefore (annualfor PMS2carriers,
Forceon youngest carriersof considerstarting
Colorectal caseofCRC MMR screeningatages
Cancer infamilyif pathogenic 30yand35y,
(2014)c[414] beforeage variants) respectively,
IHC:Yes EPCAM:NA 25y unlessanearly-
onsetcancer
occursinthe
family.
NCCN(2015) MSI:Yes MMR:Yes MLH1, MSH2, 12y C Additional

[93] EPCAM recommendations
carriers:20 forfamiliesin
25yOR25 whomatumor
ybefore hasshown
youngest informativeIHC
caseofCRC andMSI,butno
infamilyif germline
beforeage pathogenic
25y variantfound.
(RefertopageLS-
A-3oftheNCCN
guidelinesfor
more
information.)[93]
Organization Tumor MMR/ Age Freq. Method Comments

MSI/IHC EPCAM Screening
Genetic Initiated
Testing
IHC:Yes EPCAM:Yes MSH6, PMS2

carriers:25
30yOR25
ybeforethe
youngest
caseofCRC
infamilyif
beforeage
30y
C=colonoscopy;ESMO=EuropeanSocietyforMedicalOncology;IHC=immunohistochemistry;MMR=mismatchrepair;MSI=microsatellite
instability;NA=notaddressed;NCCN=NationalComprehensiveCancerNetwork.
a
Thistablesummarizesavailableguidelinesfrom2010andlater.Otherorganizations,includingtheAmericanCancerSociety,havepublished
guidelinesbefore2010.[411]
b
TheAmericanSocietyofClinicalOncologyandtheJapaneseSocietyofMedicalOncologyhaveendorsedtheESMOguidelinesaspresentedin
thetable.[412,413]
c
U.S.Multi-SocietyTaskForceonColorectalCancerincludesthefollowingorganizations:AmericanAcademyofFamilyPractice,AmericanCollege
ofGastroenterology,AmericanCollegeofPhysicians-AmericanSocietyofInternalMedicine,AmericanCollegeofRadiology,American
GastroenterologicalAssociation,AmericanSocietyofColorectalSurgeons,andAmericanSocietyforGastrointestinalEndoscopy.
Table 12. Potential Surveillance for Extracolonic Sites in Lynch Syndromea
Site ESMO(2013)b,c[413] U.S.Multi-SocietyTask NCCN(2015)[93]

ForceonColorectalCancer
(2014)d[414]
Uterus/ovaries Yes Yes Yes
Stomach/smallintestine Yes Yes Onlyinselect

individuals/families
Urinarytract Noc Yes Yes
Breast Noc No No
Prostate Noc No No
Site ESMO(2013) [413] U.S.Multi-SocietyTask NCCN(2015)[93]

ForceonColorectalCancer
(2014) [414]
Pancreas Noc No No
Centralnervoussystem Noc NA Physical/neurologicexam
ESMO=EuropeanSocietyforMedicalOncology;NA=notaddressed;NCCN=NationalComprehensiveCancerNetwork.
a
Thistablesummarizesavailableguidelinesfrom2010andlater.Otherorganizations,includingtheAmericanCancerSociety,havepublished
guidelinesbefore2010.[411]
b
TheJapaneseSocietyofMedicalOncologyhasendorsedtheESMOGuidelinesaspresentedinthetable.[413]
c
TheAmericanSocietyofClinicalOncologyhasendorsedtheESMOrecommendationsregardingsurveillanceoftheuterus/ovariesand
stomach/smallintestinebutrecommendsconsideringscreeningforotherLynchsyndromeassociatedcancerinthecontextoffamilyhistory.
[412]
d
U.S.Multi-SocietyTaskForceonColorectalCancerincludesthefollowingorganizations:AmericanAcademyofFamilyPractice,AmericanCollege
ofGastroenterology,AmericanCollegeofPhysicians-AmericanSocietyofInternalMedicine,AmericanCollegeofRadiology,American
GastroenterologicalAssociation,AmericanSocietyofColorectalSurgeons,andAmericanSocietyforGastrointestinalEndoscopy.
Levelofevidence(colonsurveillance):2ai
Levelofevidence(extracolonicsurveillance):5
Chemoprevention in LS
TheColorectalAdenoma/CarcinomaPreventionProgramme(CAPP2)wasadouble-blind,placebo-controlled,randomizedtrialto
determinetheroleofaspirininpreventingCRCinpatientswithLSwhowereinsurveillanceprogramsatanumberofinternational
centers.[415]Thestudyrandomlyassigned861participantstoaspirin(600mg/day),aspirinplacebo,resistantstarch(30g/day),or
starchplaceboforupto4years.Atameanfollow-upof55.7months(range:1128mo),53primaryCRCsdevelopedin48
participants(18of427intheaspiringroupand30of434intheaspirinplacebogroup).Seventy-sixpatientswhorefused
randomizationtotheaspiringroups(becauseofanaspirinsensitivityorahistoryofpepticulcerdisease)wererandomlyassigned
toreceiveresistantstarchorresistantstarchplacebo.Theintention-to-treatanalysisyieldedanHRforCRCof0.63(95%CI,0.35
1.13;P=.12).However,fiveofthepatientswhodevelopedCRCdevelopedtwoprimarycoloncancers.APoissonregressionwas
performedtoaccountfortheeffectofthemultipleprimaryCRCsandyieldedaprotectiveeffectforaspirin(incidencerateratio
[IRR],0.56;95%CI,0.320.99;P=.05).Forparticipantswhocompletedatleast2yearsoftreatment,theper-protocolanalysis
yieldedanHRof0.41(95%CI,0.190.86;P=.02)andanIRRof0.37(0.180.78;P=.008).AnanalysisofallLScancers(endometrial,
ovarian,pancreatic,smallbowel,gallbladder,ureter,stomach,kidney,andbrain)revealedaprotectiveeffectofaspirinversus
placebo(HR,0.65;95%CI,0.421.00; P=.05).Therewerenosignificantdifferencesinadverseeventsbetweentheaspirinand
placebogroups,andnoseriousadverseeffectswerenotedwithanytreatment.Theauthorsconcludedthat600mgofaspirinper
dayforameanof25monthssubstantiallyreducedcancerincidenceinLSpatients.CAPP2failedtoshowanyeffectfromdaily
resistantstarchintake.Alimitationofthetrialisthatthefrequencyofsurveillancestudiesatthevariouscenterswasnotreported
asbeingstandardized.EarlierCAPP2trialresultsfor746LSpatientsenrolledinthestudywerepublishedin2008[416]andfailedto
showasignificantpreventiveeffectonincidentcolonicadenomasorcarcinomas(RR,1.0;95%CI,0.71.4)withashortermean
follow-upof29months(range,774mo).A2015surveyof1,858participantsintheColonCancerFamilyRegistrysuggestedthat
aspirinandibuprofenmightbechemopreventiveforcarriersofMMRgenepathogenicvariants.[417]TheCAPP3trial,whichis
evaluatingtheeffectoflowerdosesofaspirin(blinded100mg,300mg,and600mgenteric-coatedaspirin),beganin2013is
expectedtoenrollapproximately3,000carriersofpathogenicvariantsbyabout2021.[418]
Screening for endometrial cancer in LS families

Note:AseparatePDQsummaryonEndometrialCancerScreeninginthegeneralpopulationisalsoavailable.
CanceroftheendometriumisthesecondmostcommoncancerobservedinLSfamilieswithinitialestimatesofcumulativeriskin
LScarriersof30%to39%byage70years.[260,262]InalargeFinnishstudyof293putativeLSgenecarriers,thecumulativelifetime
riskofendometrialcancerwas43%.Endometrialcancerriskwasdirectlyrelatedtoage,rangingfrom3.7%atage40yearsto42.6%
byage80years,comparedwitha3%endometrialcancerriskinthegeneralpopulation.[244]Themaximalriskofendometrial
cancerinLSfamiliesoccurs15yearsearlierthaninthegeneralpopulation,withthehighestriskoccurringbetweenages55and65
years.InacommunitystudyofunselectedendometrialcancerpatientsincentralOhio,atleast1.8%(95%CI,0.9%3.5%)ofnewly
diagnosedpatientshadLS.[419]AdenocarcinomasoftheloweruterinesegmentmaycarryagreaterriskofmanifestingLS.[420]
Inthegeneralpopulation,thediagnosisofendometrialcancerisgenerallymadewhenwomenpresentwithsymptomsincluding
abnormalorpostmenopausalbleeding.Anofficeendometrialsampling,oradilatationandcurettage(D&C),isthenperformed,
providingahistologicspecimenfordiagnosis.EightypercentofwomenwithendometrialcancerpresentwithsymptomsofstageI
disease.TherearenodatasuggestingtheclinicalpresentationinwomenwithLSdiffersfromthegeneralpopulation.
Giventheirsubstantialincreasedriskofendometrialcancer,endometrialscreeningforwomenwithLShasbeensuggested.
Proposedmodalitiesforscreeningincludetransvaginalultrasound(TVUS)and/orendometrialbiopsy.AlthoughthePaptest
occasionallyleadstoadiagnosisofendometrialcancer,thesensitivityistoolowforittobeausefulscreeningtest.Thepresenceof
endometrialcellsinaPapsmearobtainedfromapostmenopausalwomannottakinghormonereplacementtherapyisabnormal
andwarrantsfurtherinvestigation.[421,422]TwostudieshaveexaminedtheuseofTVUSinendometrialscreeningforwomenwith
LS.[423,424]Inonestudyof292womenfromLSorLS-likefamilies,nocasesofendometrialcancerweredetectedbyTVUS.In
addition,twointervalcancersdevelopedinsymptomaticwomen.[423]Inasecondstudy,41womenwithLSwereenrolledina
TVUSscreeningprogram.Of179TVUSproceduresperformed,therewere17abnormalscans.Threeofthe17womenhadcomplex
atypicalhyperplasiaonendometrialsampling,while14hadnormalendometrialsampling.However,TVUSfailedtoidentifyone
patientwhopresented8monthsafteranormalTVUSwithabnormalvaginalbleeding,andwasfoundtohavestageIBendometrial
cancer.[424]BothofthesestudiesconcludedthatTVUSisneithersensitiveorspecific.Astudyof175womenwithLS,which
includedbothendometrialsamplingandTVUS,showedthatendometrialsamplingimprovedsensitivityoverTVUS.Endometrial
samplingfound11ofthe14casesofendometrialcancer.Twoofthethreeothercaseswereintervalcancersthatdevelopedin
symptomaticwomenandonecasewasanoccultendometrialcancerfoundatthetimeofhysterectomy.Endometrialsampling
alsoidentified14additionalcasesofendometrialhyperplasia.Amongthegroupof14womenwithendometrialcancer,tenalso
hadTVUSscreeningwithendometrialsampling.FourofthetenhadabnormalTVUS,butsixhadnormalTVUS.[425]Whilethis
cohortstudydemonstratesthatendometrialsamplingmayhavebenefitsoverTVUSforendometrialscreening,therearenodata
thatpredictscreeningwithanyothermodalityhasbenefitsforendometrialcancersurvivalinwomenwithLS.Giventhefavorable
survivalforendometrialcancerdiagnosedbysymptoms,itisunlikelythatasufficientlypoweredscreeningstudywillbeableto
demonstrateasurvivaladvantage.Certainly,womenwithLSshouldbecounseledthatabnormalorpostmenopausalvaginal
bleedingwarrantsanendometrialsamplingorD&C.
Routinescreeningforendometrialcancerhasnotbeenshowntobebeneficialinthegeneralpopulation,butexpertconsensus
suggeststhatitbeconsideredinwomenwhoaremembersofhigh-riskLSfamilies.Somestudiessuggestthatwomenwitha
clinicalorgeneticdiagnosisofLSdonotuniversallyadoptintensivegynecologicscreening.[426,427](RefertotheGynecologic
cancerscreeninginLSsectionofthissummaryformoreinformation.)Despiteabsenceofasurvivaladvantage,ataskforce
organizedbyNIHhassuggestedannualendometrialsamplingbeginningatage30to35years.TVUScanalsobeconsidered
annuallytoevaluatetheovaries.[403,428]
ThepublishedliteratureonTVUSforendometrialcancerscreeninghasshownittobeinsensitiveandnonspecific,butbecause
theremaystillbearoleforTVUSinovariancancerscreening,clinicalpracticeguidelineshavebeenreluctanttodateto
recommendagainstTVUS.
Levelofevidence:5
Surgical management in LS
OneofthehallmarksofLSisthepresenceofsynchronousandmetachronousCRCs.TheincidenceofmetachronousCRCshasbeen
reportedtobe16%at10years,41%at20years,and63%at30yearsaftersegmentalcolectomy.[429]Becauseoftheincreased
incidenceofsynchronousandmetachronousneoplasms,thetreatmentofchoiceforapatientwithLSwithneoplasticlesionsinthe
colonisgenerallyanextendedcolectomy(totalorsubtotal).Nevertheless,treatmenthastobeindividualized.Mathematical
modelssuggestthatthereareminimalbenefitsofextendedproceduresinindividualsolderthan67years,comparedwiththe
benefitsseeninyoungerindividualswithearly-onsetcancer.InoneMarkovdecisionanalysismodel,thesurvivaladvantagefora
youngindividualwithearly-onsetCRCundergoinganextendedprocedurecouldbeupto4yearslongerthanthatseeninthesame
individualundergoingasegmentalresection.[430]Therecommendationforanextendedproceduremustbebalancedwiththe
comorbiditiesofthepatient,theclinicalstageofthedisease,thewishesofthepatient,andsurgicalexpertise.Noprospectiveor
retrospectivestudyhasshownasurvivaladvantageforpatientswithLSwhounderwentanextendedresectionversusasegmental
procedure.TwostudieshaveshownthatpatientswhoundergoextendedprocedureshavefewermetachronousCRCsand
additionalsurgicalproceduresrelatedtoCRCthandopatientswhoundergosegmentalresections.[429,431]Balancingfunctional
resultsofanextendedprocedureversusasegmentalprocedureisofparamountimportance.Althoughthemajorityofpatients
adaptwellafteranabdominalcolectomy,somepatientswillrequireantidiarrhealmedication.AdecisionmodelcomparedQALYs)
fora30-year-oldpatientundergoinganabdominalcolectomyversusasegmentalcolectomy.[432]Inthismodel,therewasnot
muchdifferencebetweentheextendedandsegmentalprocedure,withQALYsbeing0.3yearsmoreinpatientsundergoinga
segmentalprocedurethaninthoseundergoinganextendedprocedure.[432]
Whenconsideringsurgicaloptions,itisimportanttorecognizethatasubtotalortotalcolectomywillnoteliminatetherectal
cancerrisk.Thelifetimeriskofdevelopingcancerintherectalremnantafteranabdominalcolectomyhasbeenreportedtobe12%
at12yearspost-colectomy.[433]Inadditiontothegeneralcomplicationsofsurgery,therearethepotentialrisksofurinaryand
sexualdysfunctionanddiarrheaafteranextendedcolectomy,withtheserisksbeinggreaterthemoredistaltheanastomosis.
Therefore,thechoiceofsurgerymustbemadeonanindividualbasisbythesurgeonandthepatient.
InpatientswithLSandrectalcancer,similarsurgicaloptions(extendedvs.segmentalresection)andconsiderationsmustbegiven.
ExtendedproceduresincluderestorativeproctocolectomyandIPAAifthesphinctercanbesavedorproctocolectomywithloop
ileostomyifthesphinctercannotbesaved.Tworetrospectivesstudiesreporteda15%and18%incidenceofmetachronouscolon
canceraftersegmentalrectalcancerresectioninpatientswithLS.[434,435]Inoneofthestudies,thecombinedriskof
metachronoushigh-riskadenomasandcancerswas51%atamedianfollow-upof101.7monthsafterproctectomy.[435]
TherearenodataaboutfertilityinLSpatientsbasedontypeofsurgery.InFAPpatients,nodifferenceinfecundityafterabdominal
colectomyandIRAhasbeenreported,whereasthereisa54%decreaseinfecundityinpatientswhoundergorestorative
proctocolectomywithilealpouchanastomosiscomparedwiththegeneralpopulation.[436]
MostclinicianswhotreatpatientswithLSwillfavoranextendedprocedureatthetimeofCRCdiagnosis.However,asstatedabove,
thechoiceofsurgerymustbemadeonanindividualbasisbythesurgeonandthepatient.ThetopicofsurgicalmanagementinLS
hasbeensummarizedinthefollowingreviews.[437-439]
LevelofEvidence:4
Immunotherapy in LS
TumorsthatdevelopviatheMSIpathwayhavemoresomaticvariantsthantumorsthatdevelopviaotherpathways.Thiscould
implythatMMR-deficient(dMMR)tumorsmayhavemorepotentialantigensandmaybemoreresponsivetoimmunesystem
manipulationbyprogrammedcelldeath(PD-1)blockadethanproficientMMR(pMMR)tumors.Thiswasthehypothesisputforthin
astudyinwhichpatientswithmetastaticdiseasethathadfailedvariouschemotherapyregimensweretreatedwith
pembrolizumab,ananti-PD-1immunecheckpointinhibitor.[440]InthissmallphaseIIstudy,32patientswithCRC(11weredMMR,
21werepMMR,and9othershadnoncolorectaldMMRtumors)weretreatedwithintravenouspembrolizumabevery14days.The
immune-relatedresponseamongevaluablepatientswas40%(4of10)fordMMRCRCtumors,0%(0of18)forpMMRCRCtumors,
and71%(5of7)fornon-CRCdMMRtumors.Theimmune-relatedprogression-freesurvival(PFS)was78%(7of9)inpatientswith
dMMRCRCtumors,11%(2of18)inpatientswithpMMRCRCtumors,and67%(4of6)inpatientswithnon-CRCdMMRtumors.
dMMRtumorshadameanof24-foldmoresomaticvariantsthanpMMRtumors.Additionally,inthisstudysomaticvariantloadwas
associatedwithprolongedPFS.TheauthorsconcludedthatMMRstatuspredictedclinicalbenefittoimmunecheckpointblockade
withpembrolizumab.
Advances in Endoscopic Imaging in Hereditary CRC
PerformanceofendoscopictherapiesforadenomasinFAPandLS,anddecision-makingregardingsurgicalreferralandplanning,
requireaccurateestimatesofthepresenceofadenomas.InbothAFAPandLSthepresenceofverysubtleadenomasposesspecial
challengesmicroadenomasinthecaseofAFAPandflat,thoughsometimeslarge,adenomasinLS.
Chromoendoscopy
Theneedforsensitivemeanstoendoscopicallydetectsubtlepolypshasincreasedwiththerecognitionofflatadenomasand
sessileserratedpolypsinotherwiseaverage-risksubjects,veryattenuatedadenomaphenotypesinAFAP,andsubtleflatadenomas
inLS.Modernhigh-resolutionendoscopesimproveadenomadetectionyield,buttheuseofvariousvitaldyes,especiallyindigo
carminedye-spray,hasfurtherimproveddetection.Severalstudieshaveshownthattheimprovedmucosalcontrastachievedwith
theuseofindigocarminecanimprovetheadenomadetectionrate.Whetherfamilyhistoryissignificantornot,carefulclinical
evaluationconsistingofdye-spraycolonoscopy(indigocarmineormethyleneblue),[441-447]withorwithoutmagnification,or
possiblynewerimagingtechniquessuchasnarrow-bandimaging,[448]mayrevealthecharacteristicright-sidedclusteringofmore
numerousmicroadenomas.Uppergastrointestinalendoscopymaybeinformativeifduodenaladenomasorfundicglandpolyps
withsurfacedysplasiaarefound.SuchfindingswillincreasethelikelihoodofvariantdetectionifAPCorMYHtestingispursued.
Invariouslargeseriesofaverage-riskpopulations,subtleflatlesionsweredetectedinabout5%to10%ofcases,including
adenomaswithhigh-gradedysplasiaandinvasiveadenocarcinoma.[449]Someofthesestudiesinvolvedtandemprocedures
white-lightexamfollowedbyrandomizationtointensive(>20-minutepull-backfromcecum)inspectionversus
chromoendoscopywithsignificantlymoreadenomasdetectedinthechromoendoscopygroup.[450]However,inseveral
randomizedtrials,nosignificantdifferenceinyieldwasseen.[451,452]
InarandomizedtrialofsubjectswithLS,[453]standardcolonoscopy,withpolypectomyasindicated,wasfollowedbyeitherindigo
carminechromoendoscopyorrepeatintensivewhite-lightcolonoscopy(adesignverynearlyidenticaltotheaverage-risk
screeninggroupnotedabove).Inthisseries,nosignificantdifferenceinadenomayieldbetweenthechromoendoscopyand
intensivewhite-lightgroupswasdetected.However,thesepatientswereyoungerandinmanycaseshadundergoneseveral
previousexamsthatmighthaveresultedinpolypclearing.
InaGermanstudy,[454]oneseriesofLSpatientsunderwentwhite-lightexamfollowedbychromoendoscopy,whileasecond
seriesunderwentcolonoscopywithnarrow-bandimagingfollowedbychromoendoscopy.Significantdifferencesinflatpolyp
detectionfavoredchromoendoscopyinbothseries,althoughsomeofthedetectedlesionswerehyperplastic.InaFrenchseriesof
LSsubjectsthatalsoemployedwhite-lightexamfollowedbychromoendoscopy,significantlymoreadenomasweredetectedwith
chromoendoscopy.[455]
FewerevaluationsofchromoendoscopyhavebeenperformedinattenuatedFAPthaninLS.Onestudyexaminedfourpatientswith
presumedAFAPandfewerthan20adenomasuponwhite-lightexamination.[456]Allhadmorethan1,000diminutiveadenomas
foundonchromoendoscopy,inagreementwithpathologyevaluationaftercolectomy.
AsimilarroleforchromoendoscopyhasbeensuggestedtoevaluatetheduodenuminFAP.OnestudyfromHollandthatused
indigocarminedye-spraytodetectduodenaladenomasshowedanincreaseinthenumberandsizeofadenomas,includingsome
largeones.OverallSpigelmanscorewasnotsignificantlyaffected.[457]
Small bowel imaging

PatientswithPJSandjuvenilepolyposissyndromeareatgreaterriskofdisease-relatedcomplicationsinthesmallbowel(e.g.,
bleeding,obstruction,intussusception,orcancer).FAPpatients,althoughatgreatriskofduodenalneoplasia,havearelativelylow
riskofjejunoilealinvolvement.TheRRofsmallbowelmalignancyisveryhighinLS,butabsoluteriskislessthan10%.Althoughthe
risksofsmallbowelneoplasiaarehighenoughtowarrantconsiderationofsurveillanceineachdisease,thetechnicalchallengesof
doingsohavebeendaunting.Becauseofthetechnicalchallengesandrelativelylowprevalences,thereisvirtuallynoevidence
baseforsmall-bowelscreeninginLS.
Historically,therelativeendoscopicinaccessibilityofthemidanddistalsmallbowelrequiredradiographicmeasuresforits
evaluation,includingthebariumsmallbowelseriesoravariantcalledtubeenteroclysis,inwhichanasogastroduodenaltubeis
placedsothatallofthecontrastgoesintothesmallintestineformorepreciseimaging.Noneofthesemeasuresweresensitivefor
smalllesions.Anytherapeuticundertakingrequiredlaparotomy.Thisentailedresectioninmostcases,althoughintraoperative
endoscopy,withorwithoutenterotomyforscopeaccess,hasbeenavailableformanyyears.Peroralenteroscopy(aidedby
stiffeningovertubeswithtwoballoons,oneballoon,orspiralribs)hasbeenemployedtoovercomethetechnicalproblemof
excessivelooping,enablingdeepjejunalaccesswiththerapeutic(polypectomy)potential.
MostdatarelatethatPJSwithdouble-balloonenteroscopyisthepreferredmethodforendoscopyofthesmallbowel.[458]This
mayinvolveonlyperoralenteroscopy,althoughsubsequentretrogradeenteroscopyhasbeendescribedformorecomplete
evaluationofthetotalsmallbowel.Becausetheseproceduresaretime-consumingandinvolvesomeriskofcomplication,deep
enteroscopyisusuallyprecededbymorenoninvasiveimaging,includingtraditionalbariumexams,capsuleendoscopy,andCTor
magneticresonanceenterography.[81]
InFAP,datafromcapsuleendoscopy[81]showa50%to100%prevalenceofjejunaland/orilealpolypsinpatientswithSpigelman
stageIIIorstageIVduodenalinvolvementbutvirtuallynosuchpolypsinSpigelmanstageIorstageIIdisease.Allpolypswere
smallerthan10mmandwerenotbiopsiedorremoved.Consequently,theirclinicalsignificanceremainsuncertainbutislikely
limited,giventheinfrequencyofjejunoilealcancerreportsinFAP.
CapsuleendoscopyinthesmallseriesofPJSpatientsdescribedabove[81]showedthepresenceofasimilarfrequency(50%100%)
ofpolyps,buttheprevalentpolypsweremuchlargerthaninFAP,weremorelikelytobecomesymptomatic,andwarranted
endoscopicorsurgicalexcision.Capsulestudiesweresuggestedasanappropriatereplacementforradiographicstudiesbecause
ofthesensitivityofcapsule.
Familial CRC
Anestimated7%to10%ofpeoplehaveafirst-degreerelativewithCRC,[459,460]andapproximatelytwicethatmanyhaveeithera
first-degreeorasecond-degreerelativewithCRC.[460,461]AsimplefamilyhistoryofCRC(definedasoneormorecloserelatives
withCRCintheabsenceofaknownhereditarycoloncancer)confersatwofoldtosixfoldincreaseinrisk.Theriskassociatedwith
familyhistoryvariesgreatlyaccordingtotheageofonsetofCRCinthefamilymembers,thenumberofaffectedrelatives,the
closenessofthegeneticrelationship(e.g.,first-degreerelatives),andwhethercancershaveoccurredacrossgenerations.[459,462]
ApositivefamilyhistoryofCRCappearstoincreasetheriskofCRCearlierinlifesuchthatatage45years,theannualincidenceis
morethanthreetimeshigherthanthatinaverage-riskpeople;atage70years,theriskissimilartothatinaverage-riskindividuals.
[459]Theincidenceina35-to40-year-oldisaboutthesameasthatofanaverage-riskpersonatage50years.Thereisnoevidence
tosuggestthatCRCinpeoplewithoneaffectedfirst-degreerelativeismorelikelytobeproximalorismorerapidlyprogressive.
Apersonalhistoryofadenomatouspolypsconfersa15%to20%riskofsubsequentlydevelopingpolyps[463]andincreasesthe
riskofCRCinrelatives.[464]TheRRofCRC,adjustedfortheyearofbirthandsex,was1.78(95%CI,1.182.67)fortheparentsand
siblingsofthepatientswithadenomasascomparedwiththespousecontrols.TheRRforsiblingsofpatientsinwhomadenomas
werediagnosedbeforeage60yearswas2.59(95%CI,1.464.58),comparedwiththesiblingsofpatientswhowere60yearsor
olderatthetimeofdiagnosisandafteradjustmentforthesibling'syearofbirthandsex,withaparentalhistoryofCRC.
Whilefamilialclustersaccountforapproximately20%ofallCRCcasesindevelopedcountries,[465]therareandhighlypenetrant
MendelianCRCdiseasescontributetoonlyafractionoffamilialcases,whichsuggeststhatothergenesand/orshared
environmentalfactorsmaycontributetotheremainderofthecancers.Twostudiesattemptedtodeterminethedegreetowhich
hereditaryfactorscontributetofamilialCRCs.
ThefirststudyutilizedtheSwedish,Danish,andFinnishtwinregistriesthatcumulativelyprovided44,788pairsofsame-sextwins
(formen:7,231monozygotic[MZ]and13,769dizygotic[DZ]pairs;forwomen:8,437MZand15,351DZpairs)tostudythe
contributionofheritableandenvironmentalfactorsinvolvedin11differentcancers.[466]Thetwinsincludedinthestudyall
residedintheirrespectivecountriesoforiginintoadulthood(>50years).Cancerswereidentifiedthroughtheirrespectivenational
cancerregistriesin10,803individualsfrom9,512pairsoftwins.ThepremiseofthestudywasbasedonthefactthatMZtwinsshare
100%andDZtwinsshare50%oftheirgenesonaverageforanyindividualtwinpair.Thisstudycalculatedthatheritablefactors
accountedfor35%,sharedenvironmentalfactorsfor5%,andnonsharedenvironmentalfactorsfor60%oftheriskofCRC.ForCRC,
theestimatedheritabilitywasonlyslightlygreaterinyoungergroupsthaninoldergroups.Thisstudyrevealedthatalthough
nonsharedenvironmentalfactorsconstitutethemajorriskoffamilialCRC,heredityplaysalarger-than-expectedrole.
ThesecondstudyutilizedtheSwedishFamily-CancerDatabase,whichcontained6,773and31,100CRCsinoffspringandtheir
parents,respectively,from1991to2000.[467]Thedatabaseincluded253,467pairsofspouses,whoweremarriedandlived
togetherforatleast30years,andwhowereusedtocontrolforcommonenvironmentaleffectsoncancerrisk.TheoverallSIRfor
cancersofthecolon,rectum,andcolonandrectumcombinedintheoffspringofanaffectedparentwas1.81(95%CI,1.622.02),
1.74(95%CI,1.531.96),and1.78(95%CI,1.531.96),respectively.Theriskconferredbyaffectedsiblingswasalsosignificantly
elevated.BecausetherewasnosignificantlyincreasedriskofCRCconferredbetweenspouses,theauthorsconcludedthatheredity
playsasignificantroleinfamilialCRCs;however,controlsforsharedenvironmentaleffectsamongsiblingswereabsentinthis
study.
Tenpercentto15%ofpersonswithCRCand/orcolorectaladenomashaveotheraffectedfamilymembers,[459,460,462-464,468-
473]buttheirfindingsdonotfitthecriteriaforFAP,andtheirfamilyhistoriesmayormaynotmeetclinicalcriteriaforLS.Such
familiesarecategorizedashavingfamilialCRC,whichiscurrentlyadiagnosisofexclusion(ofknownhereditaryCRCdisorders).The
presenceofCRCinmorethanonefamilymembermaybecausedbyhereditaryfactors,sharedenvironmentalriskfactors,oreven
chance.Becauseofthisetiologicheterogeneity,understandingthebasisoffamilialCRCremainsaresearchchallenge.
Geneticstudieshavedemonstratedacommonautosomaldominantinheritancepatternforcolontumors,adenomas,andcancers
infamilialCRCfamilies,[474]withagenefrequencyof0.19foradenomasandcolorectaladenocarcinomas.[473]Asubsetof
familieswithMSI-negativefamilialcolorectalneoplasiawasfoundtolinktochromosome9q22.2-31.2.[475]Amorerecentstudy
haslinkedthreepotentiallociinfamilialCRCfamiliesonchromosomes11,14,and22.[476]
Familial colorectal cancer type X (FCCX)

FamiliesmeetingAmsterdam-IcriteriaforLSwhodonotshowevidenceofdefectiveMMRbyMSItestingdonotappeartohavethe
sameriskofcolorectalorothercancersasthosefamilieswithclassicLSandclearevidenceofdefectiveMMR.TheseAmsterdam-I
criteriafamilieswithintactMMRsystemshavebeendescribedasFCCX,[237,477-481]andithasbeensuggestedthatthesefamilies
beclassifiedasadistinctgroup.
ThegeneticetiologyofFCCXremainsunclear.Utilizingwhole-genomelinkageanalysisandexomesequencing,atruncatingvariant
inribosomal protein S20(RPS20),aribosomalproteingene,wasidentifiedinfourindividualswithCRCfromanFCCXfamily.[481]
ThevariantcosegregatedwithCRCinthefamily,withalogarithmoftheoddsscoreof3.Additionally,thevariantwasnotidentified
in292controls.NoLOHwasobservedintumorsamples,andin vitroanalysesofmatureRNAformationconfirmedamodelof
haploinsufficiencyforRPS20.NogermlinevariantsinRPS20werefoundin25additionalFCCXfamiliesstudied,suggestingRPS20
variantsareaninfrequentcauseofFCCX.Thesamegrouphadpreviouslyidentifiedvariantsinthebone morphogenetic protein
receptor type 1A(BMPR1A)geneinaffectedindividualsfrom2of18familieswithFCCX.[482]Additionalstudiesarenecessaryto
definitivelyconfirmorrefutearoleforRPS20orBMPR1AinFCCX.
AgeofCRConsetinLSrangesfrom44years(registryseries)toameanof52years(population-basedseries).[241-243]Thereare
nocorrespondingpopulation-baseddataforFCCXbecauseFCCXbydefinitionrequiresatleastoneearly-onsetcaseandisnot
likelytolenditselftoanypopulation-basedfiguresintheforeseeablefuture.Studiesthathavedirectlycomparedageofonset
betweenFCCXandLShavesuggestedthattheageofonsetisslightlyolderinFCCX,[237,477,479]butthelifetimeriskofcanceris
substantiallylower.TheSIRforCRCamongfamilieswithintactMMR(FCCXfamilies)was2.3(95%CI,1.73.0)inonelargestudy,
comparedwith6.1(95%CI,5.77.2)infamilieswithdefectiveMMR(LSfamilies).[237]Theriskofextracolonictumorswasalsonot
foundtobeelevatedfortheFCCXfamilies,suggestingthatenhancedsurveillanceforCRCwassufficient.Althoughfurtherstudies
arerequired,tumorsarisingwithinFCCXfamiliesalsoappeartohaveadifferentpathologicphenotype,withfewertumor-
infiltratinglymphocytesthanthosefromfamilieswithLS.[478]
Interventions for family history of CRC

TherearenocontrolledcomparisonsofscreeninginpeoplewithamildormodestfamilyhistoryofCRC.Mostexperts,ifthey
acceptthataverage-riskpeopleshouldbescreenedstartingatage50years,suggestthatscreeningshouldbeginearlierinlife
(e.g.,atage3540years)whenthemagnitudeofriskiscomparabletothatofa50-year-old.Becausetheriskincreaseswiththe
extentoffamilyhistory,thereisroomforclinicaljudgmentinfavorofevenearlierscreening,dependingonthedetailsofthe
familyhistory.Someexpertssuggestshorteningthefrequencyofthescreeningintervaltoevery5years,ratherthanevery10
years.[142]
AcommonbutunprovenclinicalpracticeistoinitiateCRCscreening10yearsbeforetheageoftheyoungestCRCcaseinthe
family.Thereisneitherdirectevidencenorastrongrationalargumentforusingaggressivescreeningmethodssimplybecauseofa
modestfamilyhistoryofCRC.
TheseissueswereweighedbyapanelofexpertsconvenedbytheAmericanGastroenterologicalAssociationbeforepublishing
clinicalguidelinesforCRCscreening,includingthoseforpersonswithapositivefamilyhistoryofCRC.[483]Theseguidelineshave
beenendorsedbyanumberofotherorganizations.
TheAmericanCancerSocietyandtheUnitedStatesMulti-SocietyTaskForceonColorectalCancerhavepublishedguidelinesfor
average-riskindividuals.[142,484-487]TheseguidelinesaddressscreeningissuesrelatedtomodestfamilyhistoryofCRCor
adenomas.Giventheheterogeneityofthisgrouping,itisbeyondthescopeofthismoretargeteddiscussionofmajorgene
conditions.
Rare Colon Cancer Syndromes
PTEN hamartoma tumor syndromes (including Cowden syndrome)
CowdensyndromeandBannayan-Riley-RuvalcabaSyndrome(BRRS)arepartofaspectrumofconditionsknowncollectivelyas
PTENhamartomatumorsyndromes.Approximately85%ofpatientsdiagnosedwithCowdensyndrome,andapproximately60%of
patientswithBRRShaveanidentifiablePTENpathogenicvariant.[488]Inaddition,PTENpathogenicvariantshavebeenidentifiedin
patientswithverydiverseclinicalphenotypes.[489]ThetermPTENhamartomatumorsyndromesreferstoanypatientwithaPTEN
pathogenicvariant,irrespectiveofclinicalpresentation.
PTENfunctionsasadual-specificityphosphatasethatremovesphosphategroupsfromtyrosine,serine,andthreonine.Pathogenic
variantsofPTENarediverse,includingnonsense,missense,frameshift,andsplice-sitevariants.Approximately40%ofvariantsare
foundinexon5,whichencodesthephosphatasecoremotif,andseveralrecurrentpathogenicvariantshavebeenobserved.[490]
Individualswithvariantsinthe5endorwithinthephosphatasecoreofPTENtendtohavemoreorgansystemsinvolved.[491]
OperationalcriteriaforthediagnosisofCowdensyndromehavebeenpublishedandsubsequentlyupdated.[492,493]These
includedmajor,minor,andpathognomoniccriteriaconsistingofcertainmucocutaneousmanifestationsandadult-onsetdysplastic
gangliocytomaofthecerebellum(Lhermitte-Duclosdisease).Anupdatedsetofcriteriabasedonasystematicliteraturereviewhas
beensuggested[494]andiscurrentlyutilizedintheNationalComprehensiveCancerNetwork(NCCN)guidelines.[93]Contraryto
previouscriteria,theauthorsconcludedthattherewasinsufficientevidenceforanyfeaturestobeclassifiedaspathognomonic.
Withincreasedutilizationofgenetictesting,especiallytheuseofmulti-genepanels,clinicalcriteriaforCowdensyndromewillneed
tobereconciledwiththephenotypeofindividualswithdocumentedgermlinePTENpathogenicvariantswhodonotmeetthese
criteria.Untilthen,whetherCowdensyndromeandtheotherPTENhamartomatumorsyndromeswillbedefinedclinicallyorbased
ontheresultsofgenetictestingremainsambiguous.TheAmericanCollegeofMedicalGeneticsandGenomics(ACMG)suggests
thatreferralforgeneticsconsultationbeconsideredforindividualswithapersonalhistoryoforafirst-degreerelativewith1)
adult-onsetLhermitte-Duclosdiseaseor2)anythreeofthemajororminorcriteriathathavebeenestablishedforthediagnosisof
Cowdensyndrome.[495]Detailedrecommendations,includingdiagnosticcriteriaforCowdensyndrome,canbefoundintheNCCN
andACMGguidelines.[93,495]Additionally,apredictivemodelthatusesclinicalcriteriatoestimatetheprobabilityofaPTEN
pathogenicvariantisavailable;acost-effectivenessanalysissuggeststhatgermlinePTENtestingiscosteffectiveiftheprobability
ofavariantisgreaterthan10%.[496]
Overa10-yearperiod,theInternationalCowdenConsortium(ICC)prospectivelyrecruitedaconsecutiveseriesofadultand
pediatricpatientsmeetingrelaxedICCcriteriaforPTENtestingintheUnitedStates,Europe,andAsia.[497]Thevastmajorityof
individualsdidnotmeettheclinicalcriteriaforadiagnosisofCowdensyndromeorBRRS.Ofthe3,399individualsrecruitedand
tested,295probands(8.8%)andanadditional73familymemberswerefoundtoharborgermlinePTENpathogenicvariants.In
additiontobreast,thyroid,andendometrialcancers,theauthorsconcludedthatonthebasisofcancerrisk,melanoma,kidney
cancer,andcolorectalcancersshouldbeconsideredpartofthecancerspectraarisingfromgermlinePTENpathogenicvariants.A
secondstudyofapproximately100patientswithagermlinePTENpathogenicvariantconfirmedthesefindingsandsuggesteda
cumulativecancerriskof85%byage70years.[498]
Theage-adjustedriskofCRCwasincreasedincarriersofpathogenicvariantsinbothstudies(SIR,5.710.3).[497,498]Inaddition,
onestudyfoundthat93%ofindividualswithPTENpathogenicvariantswhohadundergoneatleastonecolonoscopyhadpolyps.
Themostcommonhistologywashyperplastic,althoughadenomasandsessileserratedpolypswerealsoobserved.Theincreased
riskofCRCamongcarriersofPTENpathogenicvariantshasledtotherecommendationofsurveillancecolonoscopyinthese
patients.[498,499]However,boththeageatwhichtobegin(3040years)andthesubsequentfrequencyofcolonoscopies(biennial
toevery35years)varyconsiderablyandarebasedonexpertopinion.
Table 13. Cancer Risk in Individuals with Germline PTEN Pathogenic Variantsa
Cancer Age-AdjustedSIR(95%CI) Age-RelatedPenetranceEstimates
Breast 25.4(19.832.0) 85%startingaroundage30yb
Colorectal 10.3(5.6-17.4) 9%startingaroundage40y
Endometrial 42.9(28.162.8) 28%startingaroundage25y
Kidney 30.6(17.849.4) 34%startingaroundage40y
Melanoma 8.5(4.115.6) 6%withearliestageofonset3y
Thyroid 51.1(38.167.1) 35%atbirthandthroughoutlife
CI=confidenceinterval;SIR=standardizedincidenceratio.
a
AdaptedfromTanetal.[497]
b
Otherhistoricalstudieshavesuggestedalowerlifetimeriskofbreastcancer,intherangeof25%50%.[494](RefertothePTENhamartoma
tumorsyndromes[includingCowdensyndrome]sectioninthePDQsummaryonGeneticsofBreastandGynecologicCancersformore
information.)
Peutz-Jeghers syndrome (PJS)
PJSisanearly-onsetautosomaldominantdisordercharacterizedbymelanocyticmaculesonthelips,theperioralregion,and
buccalregion;andmultiplegastrointestinalpolyps,bothhamartomatousandadenomatous.[500-502]Germlinepathogenic
variantsintheSTK11geneatchromosome19p13.3havebeenidentifiedinthevastmajorityofPJSfamilies.[503-507]Themost
commoncancersinPJSaregastrointestinal.However,otherorgansareatincreasedriskofdevelopingmalignancies.Forexample,
thecumulativeriskshavebeenestimatedtobe32%to54%forbreastcancer[6,508,509]and21%forovariancancer.[508]A
systematicreviewfoundalifetimecumulativecancerrisk,allsitescombined,ofupto93%inpatientswithPJS.[510]Table14shows
thecumulativeriskofthesetumors.ThehighcumulativeriskofcancersinPJShasledtothevariousscreeningrecommendations
summarizedinthetableofPublishedRecommendationsforDiagnosisandSurveillanceofPeutz-JeghersSyndrome(PJS)inthe
PDQsummaryonGeneticsofColorectalCancer.
FemaleswithPJSarealsopredisposedtothedevelopmentofcervicaladenomamalignum,arareandveryaggressive
adenocarcinomaofthecervix.[511]Inaddition,femaleswithPJScommonlydevelopbenignovariansex-cordtumorswithannular
tubules,whereasmaleswithPJSarepredisposedtodevelopmentofSertoli-celltesticulartumors;[512]althoughneitherofthese
twotumortypesismalignant,theycancausesymptomsrelatedtoincreasedestrogenproduction.
AlthoughtheriskofmalignancyappearstobeexceedinglyhighinindividualswithPJSbasedonthepublishedliterature,the
possibilitythatselectionandreferralbiaseshaveresultedinoverestimatesoftheserisksshouldbeconsidered.
Table 14. Cumulative Cancer Risks in Peutz-Jeghers Syndrome Up To Specified Agea
Site Age(y) CumulativeRisk(%)b Reference(s)
Anycancer 6070 3793 [6,507-509,513,514]
GIcancerc,d 6070 3866 [6,509,513,514]
Gynecologicalcancer 6070 1318 [6,509]
Per origin
Stomach 65 29 [508]
Smallbowel 65 13 [508]
Colorectum 65 39 [6,508]
Pancreas 6570 1136 [6,508]
Lung 6570 717 [6,508,509]
Breast 6070 3254 [6,508,509]
Uterus 65 9 [508]
Ovary 65 21 [508]
Cervixe 65 10 [508]
Testese 65 9 [508]
GI=gastrointestinal.
a
ReprintedwithpermissionfromMacmillanPublishersLtd:Gastroenterology[510],copyright2010.
Site Age(y) CumulativeRisk(%) Reference(s)
b
Allcumulativeriskswereincreasedcomparedwiththegeneralpopulation(P<.05),withtheexceptionofcervixandtestes.
c
GIcancersincludecolorectal,smallintestinal,gastric,esophageal,andpancreatic.
d
Westermanetal.:GIcancerdoesnotincludepancreaticcancer.[513]
e
DidnotincludeadenomamalignumofthecervixorSertolicelltumorsofthetestes.
Peutz-Jeghers gene(s)
PJSiscausedbypathogenicvariantsintheSTK11(alsocalledLKB1)tumorsuppressorgenelocatedonchromosome19p13.
[504,505]Unliketheadenomasseeninfamilialadenomatouspolyposis,thepolypsarisinginPJSarehamartomas.Studiesofthe
hamartomatouspolypsandcancersofPJSshowallelicimbalance(lossofheterozygosity[LOH])consistentwiththetwo-hit
hypothesis,demonstratingthatSTK11isatumorsuppressorgene.[515,516]However,heterozygousSTK11knockoutmicedevelop
hamartomaswithoutinactivationoftheremainingwild-typeallele,suggestingthathaploinsufficiencyissufficientforinitialtumor
developmentinPJS.[517]Subsequently,thecancersthatdevelopinSTK11+/-micedoshowLOH;[518]indeed,compoundmutant
miceheterozygousforpathogenicvariantsinSTK11+/-andhomozygousforpathogenicvariantsinTP53-/-haveaccelerated
developmentofbothhamartomasandcancers.[519]
GermlinevariantsoftheSTK11generepresentaspectrumofnonsense,frameshift,andmissensevariants,andsplice-sitevariants
andlargedeletions.[6,503]Approximately85%ofvariantsarelocalizedtoregionsofthekinasedomainoftheexpressedprotein,
andnogermlinevariantshavebeenreportedinexon9.Nostronggenotype-phenotypecorrelationshavebeenidentified.[6]
STK11hasbeenunequivocallydemonstratedtocausePJS.AlthoughearlierestimatesusingdirectDNAsequencingshoweda50%
pathogenicvariantdetectionrateinSTK11,studiesaddingtechniquestodetectlargedeletionshavefoundpathogenicvariantsin
upto94%ofindividualsmeetingclinicalcriteriaforPJS.[503,510,520]Giventheresultsofthesestudies,itisunlikelythatother
majorgenescausePJS.
Juvenile polyposis syndrome (JPS)

JPSisageneticallyheterogeneous,rare,childhood-toearlyadult-onset,autosomaldominantdiseasethatpresents
characteristicallyashamartomatouspolyposisthroughouttheGItract,althoughcolorectalpolypspredominate.[521]JPScan
presentwithdiarrhea,GItracthemorrhage,protein-losingenteropathy,andprolapsingpolyps.[521-523]JPSisdefinedbythe
presenceofaspecifictypeofhamartomatouspolypcalledajuvenilepolyp,ofteninthesettingofafamilyhistoryofJPS.The
diagnosisofajuvenilepolypisbasedonitshistologicappearance,ratherthanageatonset.Solitaryjuvenilepolypsofthecolonor
rectumareseensporadicallyininfantsandyoungchildrenanddonotimplyadiagnosisofJPS.AclinicaldiagnosisofJPSismetby
individualsfulfillingoneormoreofthefollowingcriteria:[524]
1.Morethanfivejuvenilepolypsofthecolonorrectum.
2.JuvenilepolypsinotherpartsoftheGItract.
3.AnynumberofjuvenilepolypsandapositivefamilyhistoryofJPS.
JPSiscausedbygermlinepathogenicvariantsintheSMAD4gene,alsoknownasMADH4/DPC4,atchromosome18q21[525]in
approximately15%to60%ofcases,[521]andbypathogenicvariantsinthegeneencodingthebone morphogenic protein receptor 1A
(BMPR1A)residingonchromosomeband10q22inapproximately25%to40%ofcases.[526,527]Genotype/phenotypecorrelations
suggestSMAD4variantsmaybeassociatedwithagreaterriskofseveregastricpolyposis[528]andfeaturesofhereditary
hemorrhagictelangiectasia(HHT)(seebelow).[521]ThelifetimeCRCriskinJPShasbeenreportedtobe39%.[529]Thereappearsto
beanincreasedriskofgastriccancer,albeitmuchlowerthantheriskofCRC.[521]Cardiacvalvularabnormalitieswerepresentin
12%ofindividualswithJPSwhowerefollowedthroughasingle-institutionbasedpolyposisregistry,[521]andallthosewith
identifiablepathogenicvariantshadSMAD4variants.
JPSpatientsmayalsohavesignsandsymptomsofHHT,suchasarteriovenousmalformations,mucocutaneoustelangiectasias,
digitalclubbing,osteoarthropathy,hepaticarteriovenousmalformations,andcerebellarcavernoushemangioma,suggestingthat
thetwosyndromesoverlap.[530]MostHHTpatientswillhaveapathogenicvariantintheactivin receptor-like kinase 1(ALK1)geneor
intheendoglin(ENG)gene,butSMAD4pathogenicvariantshavealsobeenreported,althoughtheyarequiterare(approximately
1%2%ofpatientswithHHT).[531]Inoneseries,3of30patients(10%)withHHTwithoutaclinicaldiagnosisofJPSwerefoundto
havegermlinevariantsinSMAD4.[532]Conversely,featuresofHHTwerenotedin21%to22%ofcarriersofSMAD4pathogenic
variantsintwostudiesofindividualswithaclinicaldiagnosisofJPS.[521,533]Inastudyof21carriersofSMAD4pathogenicvariants
fromnineJPSfamilies,81%(17of21)ofpatientshadHHTmanifestations.[534]Thehighprevalenceinthisstudymayhavebeena
resultoftheinclusionofseveralrelativesfromasinglefamilyandtheinclusionofseveralfamilieswiththesamepathogenic
variant.[534]
SurveillanceforHHThasbeensuggestedinJPSpatientswithgermlineSMAD4pathogenicvariants.[521,534]Ontheotherhand,
patientswithHHTwithoutgermlinevariantsinALK1orENGmaybeconsideredforSMAD4germlinegenetictesting;theGItract
shouldbeevaluatedifaSMAD4germlinepathogenicvariantisconfirmed.[535](RefertoTable16,PublishedRecommendationsfor
DiagnosisandSurveillanceofJPS,formoreinformation.)
AsevereformofJPS,inwhichpolyposisdevelopsinthefirstfewyearsoflife,isreferredtoasJPSofinfancy.JPSofinfancyisoften
causedbymicrodeletionsofchromosome10q22-23,aregionthatincludesBMPR1AandPTEN.(RefertothePTENhamartoma
tumorsyndromes(includingCowdensyndrome)sectionofthissummaryformoreinformationaboutPTEN.)Thephenotypeoften
includesfeaturessuchasmacrocephalyanddevelopmentaldelay,possiblyasaresultoflossofPTENfunction.[536]RecurrentGI
bleeding,diarrhea,exudativeenteropathy,inadditiontoassociateddevelopmentaldelay,areassociatedwithaveryhighrateof
morbidityandmortalityintheseinfants,therebylimitingtheheritabilityofsuchcases.[536]
Juvenile polyposis gene(s)

JPSiscausedbygermlinepathogenicvariantsintheSMAD4geneinapproximately15%to60%ofcases,andtopathogenicvariants
inBMPR1Ainapproximately25%to40%ofcases.[521,526,527]Thelargevariabilityinvariantfrequencylikelyreflectstherelatively
smallnumberofpatientsreportedinindividualstudies.AsubsetofindividualsmeetingclinicalcriteriaforJPSwillnothavean
identifiedpathogenicvariantineitherSMAD4 orBMPR1A.
SMAD4encodesaproteinthatisamediatorofthetransforminggrowthfactor(TGF)-betasignalingpathway,whichmediates
growthinhibitorysignalsfromthecellsurfacetothenucleus.GermlinepathogenicvariantsinSMAD4predisposeindividualsto
formingjuvenilepolypsandcancer,[525]andgermlinevariantshavebeenfoundin6of11exons.Mostvariantsareunique,but
severalrecurrentpathogenicvariantshavebeenidentifiedinmultipleindependentfamilies.[533,537]
BMPR1Aisaserine-threoninekinasetypeIreceptoroftheTGF-betasuperfamilythat,whenactivated,leadstophosphorylationof
SMAD4.TheBMPR1AgenewasfirstidentifiedbylinkageanalysisinfamilieswithJPSwhodidnothaveidentifiablepathogenic
variantsinSMAD4.VariantsinBMPR1Aincludenonsense,frameshift,missense,andsplice-sitevariants.[526]Largegenomic
deletionsdetectedbyMLPAhavebeenreportedinbothBMPR1AandSMAD4inpatientswithJPS.[533,537]RareJPSfamilieshave
demonstratedvariantsintheENGandPTENgenes,butthesehavenotbeenconfirmedinotherstudies.[538,539]
JPSofinfancyisoftencausedbymicrodeletionsofchromosome10q22-23,aregionthatincludesBMPR1AandPTEN.[536]
CHEK2
Severalstudiesinitiallysuggestedthatasubsetoffamilieswithhereditarybreastandcoloncancersmayhaveacancerfamily
syndromecausedbyapathogenicvariantintheCHEK2gene.[540-542]However,subsequentstudieshavesuggestedthatCHEK2
variantsareassociatedwithonlyamodestincreaseinCRCrisk(i.e.,lowpenetrance).Onelargestudyshowedthattruncating
variantsinCHEK2werenotsignificantlyassociatedwithCRC;however,aspecificmissensepathogenicvariant(I157T)was
associatedwithmodestincreasedrisk(OR,1.5;95%CI,1.23.0)ofCRC.[543]
SimilarresultswereobtainedinanotherstudyconductedinPoland.[544]Inthisstudy,463probandsfromLSandLS-related
familiesand5,496controlsweregenotypedforfourCHEK2pathogenicvariants,includingI157T.ThemissenseI157Tallelewas
associatedwithLS-relatedcanceronlyforMMRvariant-negativecases(OR,2.1;95%CI,1.43.1).Therewasnoassociationfound
withthetruncatingvariants.FurtherstudiesareneededtoconfirmthisfindingandtodeterminewhethertheyarerelatedtoFCCX.
Onthebasisofavailabledatathusfar,clinicaltestingforCHEK2variantsisnotroutinelyrecommendedinclinicalpractice.There
arenoestablishedguidelinesforCRCscreeninginindividualswithCHEK2variants.
(RefertotheCHEK2sectioninthePDQsummaryonGeneticsofBreastandGynecologicCancersformoreinformation.)
Hereditary mixed polyposis syndrome (HMPS)

HMPSisararecancerfamilysyndromecharacterizedbythedevelopmentofavarietyofcolonpolyptypes,includingserrated
adenomas,atypicaljuvenilepolypsandadenomas,andcolonadenocarcinoma.Althoughinitiallymappedtoalocusbetween6q16-
q21,theHMPSlocusisnowbelievedtomapto15q13-q14.[545,546]WhilethereisconsiderablephenotypicoverlapbetweenJPS
andHMPS,onelargefamilyhasbeenlinkedtoalocusonchromosome15,raisingthepossibilitythatthismaybeadistinct
disorder.LinkageanalysisofAshkenaziJewishfamilieswithHMPSrevealedsharedhaplotypesonchromosome15q13.3.[547]An
unusualheterozygous40kbsingle-copyduplicationwasdiscoveredupstreamofgremlin 1(GREM1)thatsegregatedperfectlywith
individualsandfamilymemberswithHMPSandnotwithunaffectedcontrols.[547]ThepresenceofthisduplicationinHMPS
individualswasassociatedwithincreasedexpressionofGREM1transcriptlevelsinthenormalintestinalepithelium.[547]GREM1isa
bonemorphogeneticprotein(BMP)antagonistandthustheoreticallywouldpromotethestemcellphenotypeintheintestine.
GermlinevariantsleadingtodefectiveBMPsignalingalsounderlieJPS,thusdrawingapotentiallinkbetweenHMPSandJPS.
Serrated polyposis syndrome (SPS)/Hyperplastic polyposis syndrome (HPPS)

Isolatedandmultiplehyperplasticpolyps(HPs)(typicallywhite,flat,andsmall)arecommoninthegeneralpopulation,andtheir
presencedoesnotsuggestanunderlyinggeneticdisorder.Historically,theclinicaldiagnosisofSPS,asdefinedbyWHO,must
satisfyoneofthefollowingcriteria:
AtleastfivehistologicallydiagnosedHPoccurringproximaltothesigmoidcolon(ofwhichatleasttwoare>10mmin
diameter).
OneHPoccurringproximaltothesigmoidcoloninanindividualwhohasatleastonefirst-degreerelativewithhyperplastic
polyposis.
Morethan30HPsdistributedthroughoutthecolon.[548]
[Note: Other groups have included serrated adenomas as part of the revised clinical criteria for SPS.[549]]
AlthoughthevastmajorityofcasesofSPSlackafamilyhistoryofHPs,approximatelyhalfoftheSPScaseshaveapositivefamily
historyofCRC.[550,551]Severalstudiesshowthattheprevalenceofcolorectaladenocarcinomainpatientswithformallydefined
criteriaforSPSis50%ormore.[552-559]Onestudy,usingavariationoftheWHOcriteriaforSPS(SPSwasdefinedasatleastfive
histologicallydiagnosedHPsand/orsessileserratedadenomas(SSAs)proximaltothesigmoidcolon,ofwhichtwoaregreaterthan
10mmindiameter,ormorethan20HPsand/orSSAsdistributedthroughoutthecolon),foundarelativeriskforCRCin347first-
degreerelatives(41%male)from57pedigreesof5.4(95%CI,3.77.8).[549]
TheWHOcriteriaarebasedonexpertopinion;and,thereisnoknownsusceptibilitygeneorgenomicregionthathasbeen
reproduciblylinkedtothisdisorder,sogeneticdiagnosisisnotpossible.Twostudieshavereportedpotentiallycausativegermline
variantsinSPSindividuals.[550,560]
Inastudyof38patientswithmorethan20HPs,alarge(>1cm)HP,orHPsintheproximalcolon,molecularalterationswere
soughtinthebase-excisionrepairgenesMBD4andMYH.[550]OnepatientwasfoundtohavebiallelicMYHpathogenicvariants,and
thuswasdiagnosedwithMYH-associatedpolyposis.NopathogenicvariantsweredetectedinMBD4among27patientstested.
However,sixpatientshadSNPsofuncertainsignificance.OnlytwopatientshadaknownfamilyhistoryofSPS,andtenofthe38
patientsdevelopedCRC.ThisseriespresumablyincludedpatientswithsporadicHPsmixedinwithotherpatientswhomayhave
SPS.
Inacohortof40SPSpatients,definedashavingmorethanfiveHPsormorethanthreeHPs,twoofwhichwerelargerthan1cmin
diameter,onepatientwasfoundtohaveagermlinevariantintheEPHB2gene(D861N).[560]Thepatienthadserratedadenomas
andmorethan100HPsinhercolonatage58years,andhermotherdiedofcoloncanceratage36years.EPHB2germlinevariants
werenotfoundin100additionalpatientswithapersonalhistoryofCRCorin200population-matchedhealthycontrolpatients.
FarmoreisknownaboutthesomaticmoleculargeneticalterationsfoundinthecolonictumorsoccurringinSPSpatients.Ina
studyofpatientswitheithermorethan20HPspercolon,morethanfourHPslargerthan1cmindiameter,ormultiple(510)HPs
percolon,aspecificsomaticBRAFvariant(V600E)wasfoundinpolyptissue.[561]FiftypercentofHPs(20of40)fromthesepatients
demonstratedtheV600EBRAFpathogenicvariant.TheHPsfromthesepatientsalsodemonstratedsignificantlyhigherCpGisland
methylationphenotypes(CIMP-high),andfewerKRASvariantsthanleft-sidedsporadicHPs.Inapreviousstudyfromthisgroup,
HPsfrompatientswithSPSshowedalossofchromosome1pin21%(16of76)versus0%inHPsfrompatientswithlargeHPs(>1
cm),oronlyfivetotenHPs.[553]
ManyofthegeneticandhistologicalalterationsfoundinHPsofpatientswithSPSarecommonwiththerecentlydefinedCIMP
pathwayofcolorectaladenocarcinoma.
Interventions for rare colon cancer syndromes

IndividualswithPJSandJPSareatincreasedriskofCRCandextracoloniccancers.Becausethesesyndromesarerare,therehave
beennoevidence-basedsurveillancerecommendations.Becauseofthemarkedlyincreasedriskofcolorectalandothercancersin
thesesyndromes,anumberofguidelineshavebeenpublishedbasedonretrospectiveandcaseseries(i.e.,basedexclusivelyon
expertopinion).[143,562-565]Clinicaljudgmentmustbeusedinmakingscreeningrecommendationsbasedonpublished
guidelines.
Table 15. Published Recommendations for Diagnosis and Surveillance of Peutz-

Jeghers Syndrome (PJS)
Organization STK11Gene Age Frequency Method Extracolonic Comment

Testing Colon Screening
Recommendeda Screening Recommendations
Initiated
Johns Yes,atage8y 18y 23y C Breast,gynecologic

Hopkins (cervix,ovaries,
(2006)[564] uterus),pancreas,
smallintestine,
stomach,testes
Johns Yes,agenot Lateteens 3y C Breast,gynecologic Genetictesting

Hopkins specified orat (cervix,ovaries, inthelateteens
(2007)[565] onsetof uterus),pancreas, oratonsetof
symptoms smallintestine, symptoms.
stomach,testes
ACPGBI 18y 3y CorFS Nomentionof No

(2007) +BE extracolonic recommendation
screening forgenetic
testing;needto
consider
STK11/LKB1
testing.
Cleveland 18y 3y C Breast,gynecologic

Clinic(2007) (cervix,ovaries),
[566] pancreas,small
intestine,stomach,
testes
Organization STK11Gene Age Frequency Method Extracolonic Comment

Testing Colon Screening
Recommended Screening Recommendations
Initiated
Erasmus 2530y C Breast,gynecologic

University (cervix,ovaries,
Medical uterus),pancreas,
Center(2010) smallintestine,
[510] stomach
NCCN(2015) Nospecific Lateteens 23y C Breast,gynecologic Referto

[93] recommendation (cervix,ovaries, specializedteam.
uterus),lungb,
pancreas,small
intestine,stomach,
testes
ACPGBI=AssociationofColoproctologyofGreatBritainandIreland;BE=bariumenema;C=colonoscopy;FS=flexiblesigmoidoscopy;NCCN=National
ComprehensiveCancerNetwork.
a
STK11testingincludessequencingfollowedbyanalysisfordeletions(e.g.,multiplexligation-dependentprobeamplification),ifnovariantfoundby
sequencing.
b
Lungcancerriskisincreased,buttherearenorecommendationsbeyondsmokingcessationandheightenedawarenessofsymptoms.
(RefertotheOtherHigh-PenetranceSyndromesAssociatedWithBreastand/orGynecologicCancersectioninthePDQsummaryontheGeneticsof
BreastandGynecologicCancersformoreinformationaboutPJSandtheriskofbreastandovariancancer.)
Levelofevidence:5
Table 16. Published Recommendations for Diagnosis and Surveillance of Juvenile Polyposis
Syndrome (JPS)
Organization/ SMAD4 / AgeScreening Frequency Method Comment

Author BMPR1ATesting Initiated
Recommendeda
ACPGBI(2007) 1518yb 12y CorFS+BE Surveillancefor

genecarriers
andaffected
untilage70y
anddiscussion
ofprophylactic
surgery.
Organization/ SMAD4 / AgeScreening Frequency Method Comment

Author BMPR1ATesting Initiated
Recommended
ClevelandClinic 15y 3y C,EGD Somefamilies

(2007)[566] withSMAD4
pathogenic
variantalsohave
HHT;these
individualsmay
needtobe
screenedfor
HHT.
JohnsHopkins Yes,genetic 15yoratonset Yearlyuntil C Prophylactic

(2007)[565] testingpreferred ofsymptoms polypfreethen surgeryif>50
over every23y 100polyps,
colonoscopy unableto
manage
endoscopically,
severeGI
bleeding,JPS
with
adenomatous
changes,strong
familyhistoryof
CRC.
St.Mark's Yes,genetic 12y 13ybasedon C,EGD ConsiderHHT

(2012)[521] testingatage4 severity workup.
y
NCCN(2015) Yes ~15y 23yor1yif C Referto

[93] polypsare specializedteam.
found
ACPGBI=AssociationofColoproctologyofGreatBritainandIreland;BE=bariumenema;C=colonoscopy;CRC=colorectalcancer;EGD=
esophagogastroduodenoscopy;FS=flexiblesigmoidoscopy;GI=gastrointestinal;HHT=hereditaryhemorrhagictelangiectasia;NCCN=National
ComprehensiveCancerNetwork.
a
SMAD4/BMPR1Atestingincludessequencingfollowedbyanalysisfordeletions(e.g.,multiplexligation-dependentprobeamplification),ifno
variantfoundbysequencing.[537]
b
Younger,ifpatienthaspresentedwithsymptoms.
Levelofevidence:5
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Abstract]
Psychosocial Issues in Hereditary Colon Cancer Syndromes

Introduction
Psychosocialresearchincancergeneticcounselingandtestingfocusesontheinterestintestingamongpopulationsatvarying
levelsofdiseaserisk,psychologicaloutcomes,interpersonalandfamilialeffects,andculturalandcommunityreactions.The
researchalsoidentifiesbehavioralfactorsthatencourageorimpedesurveillanceandotherhealthbehaviors.Dataresultingfrom
psychosocialresearchcanguideclinicianinteractionswithpatientsandmayincludethefollowing:
Decision-makingaboutrisk-reductioninterventions,riskassessment,andgenetictesting.
Evaluationofpsychosocialinterventionstoreducedistressand/orothernegativesequelaerelatedtorisknotificationof
genetictesting.
Resolutionofethicalconcerns.
ThissectionofthesummarywillfocusonpsychosocialaspectsofgeneticcounselingandtestingforLynchsyndrome(LS),familial
adenomatouspolyposis(FAP),andPeutz-Jegherssyndrome(PJS),includingissuessurroundingmedicalscreening,risk-reducing
surgery,andchemopreventionforthesesyndromes.
Participation in Genetic Counseling and Testing for Hereditary CRC

LS
ThereareanincreasingnumberofstudiesexaminingtheactualuptakeofgeneticcounselingandtestingforLS(seeTable17).
Studieshaveincludedcolorectalcancer(CRC)patientsandunaffected,high-riskfamilymembers,recruitedmainlyfromclinical
settingsandfamilialcoloncancerregistries.Moststudiesactivelyrecruitedparticipantsforfreegeneticcounselingandtestingas
partofresearchprotocols.[1-8]Participationoruptakewasdefinedatvariouspointsintheprocess,includinggeneticcounseling
beforetesting;provisionofabloodsamplefortesting;andgeneticcounselingfordisclosureoftestresults.
Table 17. Summary of Prospective Studies Evaluating Participation in Genetic Counseling and
Testing for Hereditary Colorectal Cancer (CRC)a,b,c
Syndrome StudyPopulation Nd GCandGTParticipatione
LS Affectedfandunaffectedf 219 59%pretestGC;posttestGC,

membersoffourextended GT
familiesfromHCCRwitha
knownLSpathogenicvariant
inkindred[3]
LS UnaffectedFDRsofCRC 505 21%pretestGC;26%

patientsfromHCCR[1] pendingpretestGC;15%GT
(blood);4%pendingGT
(blood)
LS Affectedandunaffected 208 47%pretestGC;43%

membersoffourextended posttestGC,GT
familiesfromHCCRwitha
inkindred[2]
LS CRCpatientsfroman 510 89%GT(blood)

oncologyclinicandHCCR[4]
LS Unaffectedmembersof36 446 78%pretestGC;75%

Finnishfamilieswitha posttestGC,GT
inkindred[5]
LSandfamilialCRC Affectedandunaffected 57(LS);91(familialCRC) LS:14%posttestGC,GT

personswhounderwentGC
inahigh-riskcoloncancer
clinic[9]
APCI130K:85%posttestGC,
GT
LS CRCpatientsdiagnosedage 101 47%pretestGC;36%

<60ywithaffectedFDRor posttestGC,GT
second-degreerelative
recruitedthroughphysicians
[6]
LS UnaffectedFDRsofknown 111 51%pretestGC;50%

carriersofLSpathogenic posttestGC,GT
variants[7]
LS CRCpatientsfromHCCR, 140 26%pretestGC

relatives,andspouses[8]
FAP Unaffectedpersonsfrom 57adults;38minors 87%pretestGC;posttestGC,

HCCRage>5ywithFAP- GT(82%adults;95%minors)
affectedparentandknown
APCpathogenicvariantin
family[10]
FAP=familialadenomatouspolyposis;FDR=first-degreerelative;GC=geneticcounseling;GT=genetictesting;HCCR=hereditarycoloncancer
registry;LS=Lynchsyndrome.
a
Allstudiesusedaprospective,observationaldesignwiththeexceptionofonerandomizedtrialevaluatingtworecruitmentmethods.[6]
b
AllstudiesofferedfreeGCandGT,withtheexceptionofonestudy.[9]
c
AllstudieswereconductedintheUnitedStates,withtheexceptionofoneFinnishstudyandoneGermanstudy.[5,8]
d
Indicatesnumberofparticipantsolderthan18years,unlessotherwisespecified.
e
GC=participatedinpretestorposttestgeneticcounseling;GT=participatedingenetictestingandreceivedresults;GT(blood)=onlyprovided
bloodsampleforgenetictesting.
f
Affected=currentorpreviousCRCdiagnosis;Unaffected=nopreviousdiagnosisofCRC.
Participationinbothpretestgeneticcounselingandposttestcounselingfordisclosureofresultsrangedfrom14%to59%across
studies(seeTable17).Thewiderangeofuptakeratessuggeststhatfactorssuchascost,testcharacteristics,andthecontextin
whichcounselingandtestingwereofferedmayhaveinfluencedparticipantsdecisions.Forexample,amongstudiesthatoffered
freegeneticcounselingandtestinginthecontextofaresearchprotocol,counselinguptakerangedfrom21%to59%,andtesting
uptakerangedfrom36%to59%.[1-3,5-8]Mostofthosewhohadparticipatedinafreepretestcounselingoreducationsession
followedthroughwithgenetictesting.FurtherresearchisneededtoevaluateLSgeneticcounselingandtestingparticipationinthe
clinicalsetting.
Althoughlimitedinnumber,thesestudiesofferinsightintowhyindividualsfromfamiliesatriskofLSdecidetoundergoordecline
geneticcounselingandtesting.ParticipationinLSgeneticcounselingwasassociatedwithhavingchildren,havingagreater
numberofrelativesaffectedbyCRC,andgreatersocialsupport.[6]AstudyofCRCpatientswhohaddonatedabloodsamplefor
genetictestingalsoshowedthatthosewhointendedtofollowthroughwithreceivingresultsweremoreworriedthattheycarried
aLS-predisposingpathogenicvariant,believedthattestingwouldhelpfamilymembers,andmorestronglyendorsedthebenefits
andimportanceofhavingtesting.[4]Factorsassociatedwithbothcounselingandtestinguptakeincludedhaving:children,a
greaternumberofaffectedrelatives,agreaterperceivedriskofdevelopingCRC,andmorefrequentthoughtsaboutCRC.[1-3,5-
7,11]
LessisknownaboutthecharacteristicsofpersonswhodecidetonotundergoLSgeneticcounselingandtesting.Studieshave
foundthatpersonswhodeclinedcounselingandtestingreportedtohavealowerperceivedriskofCRC,[1]tohavefewerfirst-
degreerelativesaffectedwithcancer,[7]tobelesslikelytohavehadapreviouscolonoscopy,[1]tohaveacollegeeducation,[2]to
havepreviouslyparticipatedincancergeneticsresearch,[2]ortobeemployed.[5]Psychologicalfactorsalsomaylimittheuptakeof
geneticcounselingandtesting.Thosewhodeclinedcounselingandtesting,especiallywomen,reportedalowerperceivedabilityto
copewithpathogenicvariantpositivetestresults,[1]andweremorelikelytoreporthavingdepressivesymptoms.[2]Reasonscited
fornotseekinggeneticcounselingortestinghaveincludedconcernsaboutpotentialinsurancediscrimination,howgenetictesting
wouldaffectone'sfamily,andhowonewouldemotionallyhandlegenetictestresults.[7]
IncontrasttotheLSgeneticcounselingandtestinguptakestudiesthathavebeenconductedintheUnitedStates,findingsfrom
similarstudiesconductedinothercountriesmaydiffer.AFinnishstudyfoundthat75%ofindividualsatriskofdevelopingLS
underwentgenetictestingandcounselingfordisclosureoftestresults.[5]Beingemployedwastheonlyfactorthatindependently
predictedtestuptake.FundamentaldifferencesbetweenU.S.andFinnishhealthcaresystemsmayhaveaccountedforthe
substantialdifferencesintestinguptakeinthisstudycomparedwithsimilaronesconductedintheUnitedStates.Inparticular,the
lowerlikelihoodofhealthorlifeinsurancediscriminationinaEuropeanstatesuchasFinlandmayhaveeliminatedanimportant
barriertotestinginthatsetting.[5]
ThemajorityofthesestudiesthatevaluatedtheuptakeofgenetictestingforLShavefocusedongenetictestingformismatch
repair(MMR)pathogenicvariantsassociatedwiththissyndrome.Fewstudieshaveexamineduptakeofmicrosatelliteinstability
(MSI)andimmunohistochemical(IHC)testing.OnestudyreportedlowlevelsofknowledgeandawarenessofMSItestingamonga
sampleofCRCpatientswhomettherevisedBethesdaguidelinesforLSandwereofferedMSItesting.[12]Patientsinthisstudy
generallyreportedpositiveattitudesaboutthebenefitsofMSItesting;however,patientswithhigherlevelsofcancer-specific
distressalsoperceivedagreaternumberofbarrierstohavingMSItesting.
Inastudyof145patientswithCRCintheKaiserPermanenteNorthwesthealthcaresystemwhoweresurveyedbeforereceiving
theirMSIresults,mostpatientshadapositiveattitudetowardtumorscreening.[13]Themajority(84.8%)endorsedsixormore
benefitsoftumortesting;however,89.4%alsoendorsedfewerthanfourpotentialbarriers,primarilythecostofadditionaltesting
andsurveillance.Patientswithstrongerfamilyhistoriesofcancerweremorelikelytocitefewerbarriersoftumortesting.Patients
alsoexperiencedminimaldistressassociatedwithtumortesting,with77.2%oftheparticipantshavingascoreofzero(indicating
nodistress).
ResearchisemergingontheusefulnessofdecisionaidsforLSgenetictesting.Onestudythatincludedindividualswhocompleted
aninitialgeneticcounselingsessionshowedthatadecisionaid,inbookletformat,waseffectiveinreducinguncertaintyaboutthe
decisiontopursuegermlinetesting,assistingindividualstomakeaninformeddecisionabouttesting,andimprovingtesting
knowledgeamongmen.However,thedecisionaiddidnotappeartoinfluenceactualtestingdecisions.[14]Anotherstudy
evaluatedtheimpactofaneducationalinterventioninhigh-riskCRCpatientsbeforeMSIandIHCtumortestingbutnotgermline
varianttesting.PatientswhoreceivedabriefeducationalsessiondeliveredbyahealtheducatorplusaCD-ROMdecisionaidabout
MSIandIHCtestingwerefoundtohavegreaterincreasesinknowledgeaboutsuchtesting,highersatisfactionwithpreparation
fordecision-makingabouttumortesting,lowerdecisionalconflict,andgreaterdecisionalself-efficacycomparedwithpatientswho
receivedonlyabriefeducationalsession.[15]
FAP
TheuptakeforgenetictestingforFAPmaybehigherthantestingforLS.AstudyofasymptomaticindividualsintheUnitedStates
atriskofFAPwhowereenrolledinaCRCregistryandwereofferedgeneticcounselingfoundthat82%ofadultsand95%ofminors
underwentgenetictesting.[10]Uptakeratescloseto100%havebeenreportedintheUnitedKingdom.[16]Apossibleexplanation
forthegreateruptakeofAPCgenetictestingisthatitmaybemorecost-effectivethanannualendoscopicscreening[17]andcan
eliminatetheburdenofannualscreening,whichmustoftenbeinitiatedbeforepuberty.Theopportunitytoeliminateworryabout
potentialrisk-reducingsurgeryisanotherpossiblebenefitofgenetictestingforFAP.ThedecisiontohaveAPCgenetictestingmay
beviewedasamedicalmanagementdecision;[18]thepotentialpsychosocialfactorsthatmayinfluencethetestingdecisionare
notaswellstudiedforFAPasforotherhereditarycancersyndromes.ThehigherpenetranceofAPCpathogenicvariantsandearlier
onsetofdiseasealsomayinfluencethedecisiontoundergogenetictestingforthiscondition,possiblybecauseofagreater
awarenessofthediseaseandmoreexperiencewithmultiplefamilymembersbeingaffected.
GenetictestingforFAPispresentlyofferedtochildrenwithaffectedparents,oftenattheageof10to12years,whenendoscopic
screeningisrecommended.BecauseitisoptimaltodiagnoseFAPbeforeage18yearstopreventCRCandbecausescreeningand
possiblysurgeryarewarrantedatthetimeanindividualisidentifiedasacarrierofanAPCpathogenicvariant,genetictestingof
minorsisjustifiedinthisinstance.(RefertotheTestinginchildrensectioninthePDQsummaryonCancerGeneticsRisk
AssessmentandCounselingforamoredetaileddiscussionregardingtheethical,psychosocial,andgeneticcounselingissues
relatedtogenetictestinginchildren.)
InasurveyconductedintheNetherlandsofmembersoffamilieswithFAP,one-third(34%)believedthatitwasmostsuitableto
offerAPCgenetestingtochildrenbeforeage12years,whereas38%preferredtooffertestingtochildrenbetweentheagesof12
and16years,whenchildrenwouldbebetterabletounderstandtheDNAtestingprocess.Only4%feltthatchildrenshouldnot
undergoDNAtestingatall.[19]
Resultsofqualitativeinterviewdatafrom28U.S.parentsdiagnosedwithFAPshowedthat61%favoredgenetictestingofAPC
variantsintheirat-riskchildren(aged1017years);71%believedthattheirchildrenshouldreceivetheirtestresults.Theprimary
reasonswhyparentschosetotesttheirchildrenincludedearlydetectionandmanagement,reductioninparentalanxietyand
uncertainty,andhelpwithdecisionmakingregardingsurveillance.Reasonsprovidedfornottestingfocusedondiscrimination
concernsandcost.[20]
ClinicalobservationssuggestthatchildrenwhohavefamilymembersaffectedwithFAPareveryawareofthepossibilityofrisk-
reducingsurgery,andfocusonthetestresultasthefactorthatdeterminestheneedforsuchsurgery.[10]Itisimportantto
considerthetimingofdisclosureofgenetictestresultstochildreninregardtotheirage,developmentalissues,andpsychological
concernsaboutFAP.ChildrenwhocarryanAPCpathogenicvarianthaveexpressedconcernregardinghowtheywillbeperceived
bypeersandmightbenefitfromassistanceinformulatinganexplanationforothersthatpreservesself-esteem.[10]
Interest in the Use of Assisted Reproductive Technology (ART)

ThepossibilityoftransmittingapathogenicvarianttoachildmayposeaconcerntofamiliesaffectedbyhereditaryCRCsyndromes
totheextentthatsomecarriersmayavoidchildbearing.Theseconcernsalsomaypromptindividualstoconsiderusingprenatal
diagnosis(PND)methodstohelpreducetheriskoftransmission.PNDisanencompassingtermusedtorefertoanymedical
procedureconductedtoassessthepresenceofageneticdisorderinafetus.Methodsincludeamniocentesisandchorionicvillous
sampling.[21,22]Bothprocedurescarryasmallriskofmiscarriage.[21,23]Moreover,discoveringthefetusisacarrierofacancer
susceptibilityvariantmayimposeadifficultdecisionforcouplesregardingpregnancycontinuationorterminationandmayrequire
additionalprofessionalconsultationandsupport.
Analternativetothesetestsispreimplantationgeneticdiagnosis(PGD),aprocedureusedtotestfertilizedembryosforgenetic
disordersbeforeuterineimplantation.[24,25]Usingtheinformationobtainedfromthegenetictesting,potentialparentscan
decidewhetherornottoimplant.PGDcanbeusedtodetectpathogenicvariantsinhereditarycancerpredisposinggenes,
includingAPC.[19,26,27]
Fromthelimitedstudiespublishedtodate,thereappearstobeinterestintheuseofARTforFAP,LS,andPJS.[19,26,28-30]
However,actualuptakerateshavenotbeenreported.
Table 18. Summary of Studies Evaluating Attitudes Toward, Interest in, or Intention to Use
a b a
Assisted Reproductive Technology (ART) for FAP , LS , and PJS
c
StudyPopulation N InterestorIntentionin Comments
ART
FAP-affectedindividuals 20 95%(19/20)would
[26] considerprenatalGTfor
FAP;90%(18/20)would
considerPGD;75%
(15/20)wouldconsider
amniocentesisor
chorionicvilloussampling
FAP-affectedindividuals 341 33%(16/64)would 24%and25%ofpatientsdidnot

[19] considerPNDforFAP; respondtoquestionsaboutattitudes
30%(76/256)would towardPNDandPGD,respectively.
considerPGD;15%
(52/341)feltterminating
pregnancyforFAPwas
acceptable
StudyPopulation N InterestorIntentionin Comments

ART
d
IndividualswithanAPC 65 25%(16/64)wereaware
pathogenicvariant ofPGD;78%(50/64)
associatedwithFAP[30] thoughtPGDshouldbe
offered;55%(31/56)
wouldconsiderPGD
e
Individualsundergoing 48 21%10/48)would At1yearafterdisclosureofGT
genetictestingforLS[28] considerPNDand/or results,twoofninecarriersreported
PGD;19%(9/48)would thattheywereconsideringPGDfor
consideronlyPND;2% futurepregnancy.
(1/48)wouldconsider
onlyPGD
f
Individualswithan 43 19%(8/42)wereawareof
identifiedLSpathogenic PGD;69%(29/42)thought
variant[30] PGDshouldbeoffered;
41%(16/39)would
considerPGD
a
PJS-affectedindividuals 52 15%(8/52)indicatedthat Ten(19%)individuals,nineofwhom
[29] pregnancytermination werefemale,reportedthattheyhad
wasacceptableifPND decidednottoconceiveachild
identifiedafetuswithPJS; becauseofPJS.
52%(27/52)indicated
PGDwasacceptablefor
personswithPJS
FAP=familialadenomatouspolyposis;GT=genetictesting;LS=Lynchsyndrome;PGD=preimplantationgeneticdiagnosis;PJS=Peutz-Jeghers
syndrome;PND=prenataldiagnosis.
a
Studiesusedacross-sectionaldesignandwereconductedintheUnitedStates,[26]andintheNetherlands.[19,29].
b
ParticipantswereinvitedtocompletequestionnairesbeforeclinicalgenetictestingforLSandat3monthsand1yearafterdisclosureofgenetic
testresults.
c
Indicatesnumberofparticipantsolderthan18y,unlessotherwisespecified.
d
TotalnumberofindividualswithanAPCpathogenicvariant.Notallindividualsansweredorwereeligibletoanswereachquestion.
e
Representsthenumberwhoindicatedthattheywereconsideringhavingchildreninthefuture,outofatotalof130individualswhoanswereda
questionnairebeforegenetictesting.[28]
f
TotalnumberofindividualswithaLSpathogenicvariant.Notallindividualsansweredorwereeligibletoanswereachquestion.
Psychological Impact of Participating in Hereditary CRC Genetic Counseling and Testing
LS
Studieshaveexaminedthepsychologicalstatusofindividualsbefore,during,andaftergeneticcounselingandtestingforLS.Some
studieshaveincludedonlypersonswithnopersonalhistoryofanyLS-associatedcancers,[31-34]andothershaveincludedboth
CRCpatientsandcancer-unaffectedpersonswhoareatriskofhavingaLSpathogenicvariant.[35-39]Cross-sectionalevaluations
ofthepsychosocialcharacteristicsofindividualsundergoingLSgeneticcounselingandtestinghaveindicatedthatmeanpretest
scoresofpsychologicalfunctioningformostparticipantsarewithinnormallimits,[35-37]althoughonestudycomparingaffected
andunaffectedindividualsshowedthataffectedindividualshadgreaterdistressandworryassociatedwithLS.[40]
SeverallongitudinalstudieshaveevaluatedpsychologicaloutcomesbeforegeneticcounselingandtestingforLSandatmultiple
timeperiodsintheyearafterdisclosureoftestresults.Onestudyexaminedchangesinanxietybasedonpersonalcancerhistory,
gender,andage(youngerthan50yearsvs.olderthan50years)beforeand2weeksafterapretestgenetic-counselingsession.
Affectedandunaffectedfemaleparticipantsinbothagegroupsandaffectedmenolderthan50yearsshowedsignificant
decreasesinanxietyovertime.Unaffectedmenyoungerthan50yearsmaintainedlowlevelsofanxiety;however,affectedmen
youngerthan50yearsshowednoreductionsintheanxietylevelsreportedatthetimeofpretestcounseling.[41]Astudythat
evaluatedpsychologicaldistress8weekspostcounseling(beforedisclosureoftestresults)amongbothaffectedandunaffected
individualsfoundasignificantreductioningeneralanxiety,cancerworry,anddistress.[40]Ingeneral,findingsfromstudieswithin
thetimeperiodimmediatelyafterdisclosureofpathogenicvariantstatus(e.g.,2weeksto1month)suggestedthatcarriersof
MMRpathogenicvariantsmayexperienceincreasedgeneraldistress,[33,38]cancer-specificdistress,[31,32]orcancerworries[38]
relativetotheirpretestmeasurements.Carriersoftenexperiencedsignificantlyhigherdistressafterdisclosureoftestresultsthan
doindividualswhodonotcarryapathogenicvariantpreviouslyidentifiedinthefamily(noncarrier).[31-33,38]However,inmost
cases,carriersdistresslevelssubsidedduringthecourseoftheyearafterdisclosure[33,38]anddidnotdifferfrompretest
distresslevelsat1yearpostdisclosure.[31,32]Findingsfromthesestudiesalsoindicatedthatnoncarriersexperiencedareduction
ornochangeindistressupto1yearafterresultsdisclosure.[31-33,38]AstudythatincludedunaffectedindividualsandCRC
patientsfoundthatdistresslevelsamongpatientsdidnotdifferbetweencarriersandindividualswhoreceivedresultsthatwere
uninformativeorshowedavariantofunknownsignificanceatanypointupto1yearposttestandweresimilarcomparedwith
pretestdistresslevels.[39]
Alimitednumberofstudieshaveexaminedlonger-termpsychosocialoutcomesafterLSgeneticcounselingandtesting.[31,42,43]
Longitudinalstudiesthatevaluatedpsychologicaldistressbeforeandaftergenetictestingfoundthatlong-termdistresslevels
(measuredat3or7yearsposttesting)amongcarriersandnoncarriersofpathogenicvariantsweresimilartodistresslevelsat
baseline.[31,43]withoneexception:noncarrierscancer-specificdistressscoresinonestudy[31]showedasustaineddecrease
posttestingandweresignificantlylowerthantheirbaselinescoresandwithcarriersscoresat1yearposttesting,withasimilar
trendobservedat3yearsposttesting.Inonestudy,carriersweremorelikelytobeworriedaboutCRCriskat7yearsposttesting;
however,noncarrierswhoreportedworryaboutCRC(i.e.,worriedtosomeextentorveryworried)weremorelikelytodoubt
thevalidityoftheirtestresultthanwerenoncarrierswhoreportednoworry.[43]Whenaskedabouttheirsatisfactionwiththe
decisiontohavetesting,themajorityofcarriersandnoncarrierswereextremelysatisfiedupto7yearsposttestingandindicated
theywouldbewillingtoundergotestingagain.[43]
Findingsfromsomestudiessuggestedthattheremaybesubgroupsofindividualsathigherriskofpsychologicaldistressafter
disclosureoftestresults,includingthosewhopresentwithrelativelyhigherscoresonmeasuresofgeneralorcancer-specific
distressbeforeundergoingtesting.[35-39,44]AstudyofCRCpatientswhohaddonatedbloodforLStestingfoundthathigher
levelsofdepressivesymptomsand/oranxietywerefoundamongwomen,youngerpersons,nonwhites,andthosewithlessformal
educationandfewerandlesssatisfactorysourcesofsocialsupport.[35]Asubgroupofindividualswhoshowedhigherlevelsof
psychologicaldistressandlowerqualityoflifeandsocialsupportwereidentifiedfromthesamepopulation;inaddition,this
subgroupwasmorelikelytoworryaboutfindingoutthattheywerecarriersofLSpathogenicvariantsandbeingabletocopewith
learningtheirtestresults.[36]Inafollow-upreportthatevaluatedpsychologicaloutcomesafterthedisclosureoftestresults
amongCRCpatientsandrelativesatriskofhavingaLSpathogenicvariant,asubgroupwiththesamepsychosocialcharacteristics
experiencedhigherlevelsofgeneraldistressanddistressspecifictotheexperienceofhavinggenetictestingwithintheyearafter
disclosure,regardlessofvariantstatus.Nonwhitesandthosewithlowereducationhadhigherlevelsofdepressionandanxiety
scoresatalltimescomparedwithwhitesandthosewithhighereducation,respectively.[38]Otherstudieshavealsofoundthata
priorhistoryofmajororminordepression,higherpretestlevelsofcancer-specificdistress,havingagreaternumberofcancer-
affectedfirst-degreerelatives,greatergriefreactions,andgreateremotionalillnessrelatedrepresentationspredictedhigher
levelsofdistressfrom1to6monthsafterdisclosureoftestresults.[39,44]Whilefurtherresearchisneededinthisarea,case
studiesindicatethatitisimportanttoidentifypersonswhomaybeatriskofexperiencingpsychiatricdistressandtoprovide
psychologicalsupportandfollow-upthroughoutthegeneticcounselingandgenetictestingprocess.[45]
StudiesalsohaveexaminedtheeffectofLSgeneticcounselingandtestingoncancerriskcomprehension.Onestudyreportedthat
nearlyallcarriersandnoncarriersofpathogenicvariantscouldaccuratelyrecallthetestresult1yearafterdisclosure.More
noncarriersthancarrierscorrectlyidentifiedtheirriskofdevelopingCRCatboth1monthand1yearafterresultdisclosure.
CarriersofpathogenicvariantswhoincorrectlyidentifiedtheirCRCriskweremorelikelytohavehadlowerlevelsofpretest
subjectiveriskperceptioncomparedwiththosewhocorrectlyidentifiedtheirlevelofrisk.[33]Anotherstudyreportedthataccuracy
ofestimatingcolorectalandendometrialcancerriskimprovedafterdisclosureofvariantstatusincarriersandnoncarriers.[34]
FAP
StudiesevaluatingpsychologicaloutcomesaftergenetictestingforFAPsuggestthatsomeindividuals,particularlycarriersof
pathogenicvariants,maybeatriskofexperiencingincreaseddistress.Inacross-sectionalstudyofadultswhohadpreviously
undergoneAPCgenetictesting,thosewhowerecarriersofpathogenicvariantsexhibitedhigherlevelsofstateanxietythan
noncarriersandweremorelikelytoexhibitclinicallysignificantanxietylevels.[46]Loweroptimismandlowerself-esteemwere
associatedwithhigheranxietyinthisstudy,[46]andFAP-relateddistress,perceivedseriousnessofFAP,andbeliefintheaccuracy
ofgenetictestingwereassociatedwithmorestateanxietyamongcarriers.[47]However,inanearlierstudythatcomparedadults
whohadundergonegenetictestingforFAP,Huntingtondisease,andhereditarybreast/ovariancancersyndrome,FAP-specific
distresswassomewhatelevatedwithin1weekafterdisclosureofeitherpositiveornegativetestresultsandwasloweroverallthan
theothersyndromes.[18]
Inacross-sectionalAustralianstudyfocusingonyoungeradultsaged18to35yearsdiagnosedwithFAP(N=88),participantsmost
frequentlyreportedthefollowingFAP-relatedissuesforwhichtheyperceivedtheneedformoderate-to-highlevelsofsupportor
assistance:anxietyregardingtheirchildrensriskofdevelopingFAP,fearaboutdevelopingcancer,anduncertaintyaboutthe
impactofFAP.[48]Seventy-fivepercentindicatedthattheywouldconsiderprenataltestingforFAP;61%wouldconsiderPGD,and
61%wouldpreferthattheirchildrenundergogenetictestingatbirthorbeforeage10years.Asmallproportionofrespondents
(16%)reportedexperiencingsomeFAP-relateddiscrimination,primarilyindicatingthatattendingtotheirmedicalorself-care
needs(e.g.,timeoffworkforscreening,needforfrequenttoiletbreaks,andphysicallimitations)mayengendernegativeattitudes
incolleaguesandmanagers.
Anotherlargecross-sectionalstudyofFAPfamiliesconductedintheNetherlandsincludedpersonsaged16to84yearswhoeither
hadanFAPdiagnosis,wereat50%riskofhavinganAPCpathogenicvariant,orwereprovenAPCnoncarriers.[49]Ofthosewhohad
APCtesting,48%haddonesoatleast5yearsorlongerbeforethisstudy.OfpersonswithanFAPdiagnosis,76%hadundergone
preventivecolectomy,and78%ofthosewereatleast5yearspostsurgery.Thestudyevaluatedtheprevalenceofgeneralized
psychologicaldistress,distressrelatedspecificallytoFAP,andcancer-relatedworries.MeanscoresontheMentalHealthIndex-5,a
subscaleoftheSF-36thatassessedgeneralizeddistress,werecomparabletothegeneralDutchpopulation.Twentypercentof
respondentswereclassifiedashavingmoderatetohighlevelsofFAP-specificdistressasmeasuredbytheImpactofEventscale
(IES),with23%ofthosewithanFAPdiagnosis,11%ofthoseatriskofFAP,and17%ofnoncarriersreportingscoresinthisrange.
FivepercentreportedscoresontheIESthatindicatedsevereandclinicallyrelevantdistress;ofthose,themajority(78%)hadan
FAPdiagnosis.Overall,meanscoresontheCancerWorryScalewerecomparabletothosefoundinanotherstudyoffamilieswith
LS.PersonswithanFAPdiagnosisweremorelikelytoreportmorefrequentcancerworries,andthemostcommonlyreported
worrieswerethepotentialneedforadditionalsurgery(26%)andthelikelihoodthatthey(17%)orafamilymember(14%)will
developcancer.Inmultivariateanalysis,factorsassociatedwithhigherlevelsofFAP-specificdistressincludedgreaterperceived
riskofdevelopingcancer,morefrequentdiscussionaboutFAPwithfamilyorfriends,andhavingnochildren.Factorsassociated
withhigherlevelsofcancer-specificworriesincludedbeingfemale,poorerfamilyfunctioning,greateractualanddesired
discussionaboutFAPwithfamilyorfriends,greaterperceivedcancerrisk,poorergeneralhealthperceptions,andhavingbeena
caregiverforafamilymemberwithcancer.Theauthorsnotedthatmostfactorsthatwereassociatedwithhigherlevelsofcancer-
andFAP-specificdistressorworrywerepsychosocialfactors,ratherthanclinicalordemographicfactors.
Anothercross-sectionalstudyconductedintheNetherlandsfoundthatamongFAPpatients,37%indicatedthatthediseasehad
influencedtheirdesiretohavechildren(i.e.,wantingfewerornochildren).Thirty-threepercentindicatedthattheywouldconsider
PNDforFAP;30%wouldconsiderPGD.Higherlevelsofguiltandmorepositiveattitudestowardsterminatingpregnancywere
associatedwithgreaterinterestforbothPNDandPGD.[19]InaseparateU.S.study,predictorsofwillingnesstoconsiderprenatal
testingincludedhavinganaffectedchildandexperiencingafirst-degreerelativesdeathsecondarytoFAP.[26]
ThepsychologicalvulnerabilityofchildrenundergoingtestingisofparticularconcerningenetictestingforFAP.Researchfindings
suggestthatmostchildrendonotexperienceclinicallysignificantpsychologicaldistressafterAPCtesting.Asinstudiesinvolving
adults,however,subgroupsmaybevulnerabletoincreaseddistressandwouldbenefitfromcontinuedpsychologicalsupport.A
studyofchildrenwhohadundergonegenetictestingforFAPfoundthattheirmoodandbehaviorremainedinthenormalrange
aftergeneticcounselinganddisclosureoftestresults.Aspectsofthefamilysituation,includingillnessinthemotherorasibling
wereassociatedwithsubclinicalincreasesindepressivesymptoms.[50]Inalong-termfollow-upstudyof48childrenundergoing
testingforFAP,mostchildrendidnotsufferpsychologicaldistress;however,asmallproportionofchildrentesteddemonstrated
clinicallysignificantposttestdistress.[51]AnotherstudyfoundthatalthoughAPCpathogenicvariantpositivechildrensperceived
riskofdevelopingthediseaseincreasedafterdisclosureofresults,anxietyanddepressionlevelsremainunchangedintheyear
afterdisclosure.[46]Pathogenicvariantnegativechildreninthisstudyexperiencedlessanxietyandimprovedself-esteemoverthis
sametimeperiod.
Psychosocial Aspects of Screening and Risk Reduction Interventions for LS and FAP
Colorectal screening for LS

BenefitsofgeneticcounselingandtestingforLSincludetheopportunityforindividualstolearnaboutoptionsfortheearly
detectionandpreventionofcancer,includingscreeningandrisk-reducingsurgery.StudiessuggestthatmanypersonsatriskofLS
mayhavehadsomeCRCscreeningbeforegeneticcounselingandtesting,butmostarenotlikelytoadheretoLSscreening
recommendations.Amongpersonsaged18yearsorolderwhodidnothaveapersonalhistoryofCRCandwhoparticipatedinU.S.-
basedresearchprotocolsofferinggeneticcounselingandtestingforLS,between52%and62%reportedeverhavinghada
colonoscopybeforegenetictesting.[1,3,52,53]Amongcancer-unaffectedpersonswhoparticipatedinsimilarresearchinBelgium
andAustralia,51%and68%,respectively,hadeverhadacolonoscopybeforestudyentry.[34,54]Factorsassociatedwithever
havingacolonoscopybeforegenetictestingincludedhigherincomeandolderage,[52]higherperceivedriskofdevelopingCRC,
[54]highereducationlevel,andbeinginformedofincreasedriskofCRC.[53]
Inastudyofcancer-affectedandcancer-unaffectedpersonswhofulfilledclinicalcriteriaforLS,92%reportedhavinghada
colonoscopyand/orflexiblesigmoidoscopyatleastoncebeforegenetictesting.[55]Anotherstudyofunaffectedindividuals
presentingforgeneticriskassessmentandpossibleconsiderationofLS,FAP,orAPCI1307Kgenetictestingreportedthat77%had
undergoneatleastonescreeningexam(eithercolonoscopy,flexiblesigmoidoscopy,orbariumenema).
Threestudiesdeterminedwhethercancer-unaffectedpersonsadheredtoLScolonoscopyscreeningrecommendationsbefore
genetictesting,andreportedadherenceratesof10%,[34]28%,[53]and47%.[55]
Severallongitudinalstudiesexaminedtheuseofscreeningcolonoscopybycancer-unaffectedpersonsafterundergoingtestingfor
aknownLSpathogenicvariant.[34,52-54]ThesestudiescomparedcolonoscopyusebeforeLSgenetictestingwithcolonoscopyuse
within1yearafterdisclosureoftestresults.OnestudyreportedthatcarriersofLSpathogenicvariantsweremorelikelytohavea
colonoscopythanwerenoncarriersandthosewhodeclinedtesting(73%vs.16%vs.22%)andthatcolonoscopyuseincreased
amongcarriers(36%vs.73%)intheyearafterdisclosureofresults.[53]Twootherstudiesreportedthatcarrierscolonoscopyrates
at1yearafterdisclosureofresults(71%and53%)werenotsignificantlydifferentfromratesbeforetesting,[52,54]although
noncarrierscolonoscopyratesdecreasedinthesametimeperiod.Factorsassociatedwithcolonoscopyuseat1yearafter
disclosureofresultsincludedcarryingaLS-predisposingpathogenicvariant,[52-54]olderage,[52]andgreaterperceivedcontrol
overCRC.Thesefindingssuggestthatcolonoscopyratesincreaseoraremaintainedamongcarriersofpathogenicvariantswithin
theyearafterdisclosureofresultsandthatratesdecreaseamongnoncarriers.Datafromalongitudinalstudyincluding134
carriersofMMRpathogenicvariantswithandwithoutapriorLS-relatedcancerdiagnosisfoundthatthosewhodidnotundergo
colonoscopyforsurveillancewithin6monthsafterreceivinggenetictestresultsweresixtimesmorelikelytoreportclinically
significantdepressivesymptomsasmeasuredbytheCenterforEpidemiologicalStudies-Depression(CES-D)scale(oddsratio[OR],
6.06;95%confidenceinterval[CI],2.0917.59).HigherlevelsofCRCworrymeasuredbeforegenetictestingalsowereassociated
withclinicallysignificantdepressivesymptoms(OR,1.53;95%CI,1.191.97).[56]
TwostudiesexaminedthelevelofadherencetopublishedscreeningguidelinesafterLSgenetictesting,basedonvariantstatus.
Onestudyreportedacolonoscopyadherencerateof100%amongcarriersofpathogenicvariants.[34]Anotherstudyfoundthat
35%ofcarriersand13%ofnoncarriersdidnotadheretopublishedguidelinesforappropriateCRCscreening;[52]inbothgroups,
aboutone-halfscreenedmorefrequentlythanpublishedguidelinesrecommend,andone-halfscreenedlessfrequently.
Thelongitudinalstudiesdescribedaboveexaminedcolorectalscreeningbehaviorwithinarelativelyshortperiodoftime(1year)
afterreceivinggenetictestresults,andlessisknownaboutlonger-termuseofscreeningbehaviors.Alongitudinalstudy(N=73)
thatexaminedpsychologicalandbehavioraloutcomesamongcancer-unaffectedpersonsat3yearsafterdisclosureofgenetictest
resultsfoundthatallcarriers(n=19)hadundergoneatleastonecolonoscopybetween1and3yearspostdisclosure.[31]A
longitudinalstudyofsimilaroutcomesupto7yearsposttestingalsofoundthatallcarriershadundergonecolonoscopy;most
(83%)underwenttheprocedureevery3yearsormorefrequentlyasrecommended,and11%reportedlongerscreeningintervals.
[43]Inthisstudy,thosewhoreportedlongerscreeningintervalsthanrecommendedalsoweremorelikelytoreportafearofdying
soon.Also,16%ofnoncarriersreportedundergoingcolonoscopywithinthe7yearsposttesting;thosewhoindicateddoubtsabout
thevalidityoftheirtestresultweremorelikelytohavehadacolonoscopy.[43]Ninety-fourpercentofcarriersinonestudystated
anintentiontohaveannualorbiannualcolonoscopyinthefuture;amongnoncarriers,64%didnotintendtohavecolonoscopyin
thefutureorwereunsure,and33%intendedtohavecolonoscopyat5-to6-yearintervalsorlessfrequently.[34]Across-sectional
studyconductedintheNetherlandsexaminedtheuseofflexiblesigmoidoscopyorcolonoscopyamongpersonswithCRC,
endometrialcancer,oraclinicalorgeneticdiagnosisofLSduringatimethatrangedfrom2yearsto18yearsafterriskassessment
andcounseling.[57]Eighty-sixpercentofcarriersofLSpathogenicvariants,68%ofthosewhodidnottestorwhohadan
uninformativeLSgenetictestresult,and73%ofthosewithaclinicalLSdiagnosiswereconsideredadherentwithscreening
recommendations,basedondataobtainedfrommedicalrecords.Participantsalsoansweredquestionsregardingscreening
adherence,and16%oftheoverallsamplereportedthattheyhadundergonescreeninglessfrequentlythanrecommended.Forthe
overallsample,greaterperceivedbarrierstoscreeningwereassociatedwithscreeningnonadherenceasdeterminedthrough
medicalrecordreview,andembarrassmentwithscreeningprocedureswasassociatedwithself-reportednonadherence.Asecond
cross-sectionalstudy,alsoconductedintheNetherlands,surveyedcancer-unaffectedcarriersofLSvariants(n=42)regardingtheir
colorectalscreeningbehaviorsafterlearningtheirpathogenicvariantstatus(range,6months8.5years).Thirty-onepercentof
respondentsreportedthattheyhadundergoneannualcolonoscopybeforeLSgenetictesting,and88%reportedthattheyhad
undergonecolonoscopysincetheirgeneticdiagnosis(P<.001).[42]
Gynecologic cancer screening in LS

SeveralsmallstudieshaveexaminedtheuseofscreeningforendometrialandovariancancersassociatedwithLS(seeTable19).
Thereareseverallimitationstothesestudies,includingsmallsamplesizes,shortfollow-up,retrospectivedesign,relianceonself-
reportasthedatasource,andsomenotincludingpatientswhohadundergoneLSgenetictesting.Severalstudieshaveincluded
individualsinthescreeninguptakeanalysiswhodonotmeettheminimumagecriteriaforundergoingscreening.Ofthestudies
thatassessedscreeninguseafteranegativetestresultforaknownpathogenicvariantinthefamily,onlyafewassessed
indicationsforthatscreening,suchasfollow-upofapreviouslyidentifiedabnormality.Last,somestudieshaveincludedpatientsin
theuptakeanalysiswhowereactivelyundergoingtreatmentforanothercancer,whichcouldinfluenceproviderscreening
recommendations.Therefore,Table19islimitedtostudieswithpatientswhohadundergoneLSgenetictesting,largersample
sizes,longerfollow-up,andanalysisthatincludedindividualsofanappropriatescreeningage.
Table 19. Uptake of Gynecologic Screening Among Women Who Have Undergone Lynch
Syndrome (LS) Genetic Testing
StudyCitation Study Uptakeof Uptakeof Lengthof Comments

Population Gynecologic Gynecologic Follow-up
Screening ScreeningAfter
BeforeGenetic Receiptof
Counselingand GeneticTest
Testing Results
Claesetal. Carriers(n=7) Notreported TVUS 1y Onenoncarrier

(2005)1,a[34] reported
undergoing
TVUSfora
Carriers86%
previous
(6/7)
endometrial
problem,while
three
noncarriers
reported
undergoingthe
StudyCitation Study Uptakeof Uptakeof Lengthof procedurefor
Comments
Population Gynecologic Gynecologic Follow-up preventive
Screening ScreeningAfter reasons.
Testing Results
Noncarriers(n=
16)
Noncarriers
27%(4/15)
Collinsetal. Carriers(n=13) Notreported TVUS 3y Twooffour

(2007)1,a[31] carriershadan
RRH/RRSOby
the3-year
Carriers69%
follow-up
(9/13)
assessment.
Noncarriers
6%(2/32)
Noncarriers(n= ES
32)
Carriers54%
(7/13)
Noncarriers
3%(1/32)
Yurgelunetal. 77atriskofLS- 75%(58/77) Notreported N/A

(2012):Cohort associatedEC; engagedinEC
12,a[58] 45carriers;19 screeningorEC
nogenetic risk-reduction
testingbutLS- intervention;42
associated underwent
familyhistory annualTVUS
and/orES;16
underwentRRH
StudyCitation Study Uptakeof Uptakeof Lengthof Comments

Population Gynecologic Gynecologic Follow-up
Screening ScreeningAfter
Testing Results
Yurgelunetal. 40womenat 65%(26/40) Carriers:100% 1y

(2012):Cohort clinicalriskofLS adheredtoEC (n=16)adhered
21,a[58] screeningor toECscreening
riskreduction;6 orrisk-reducing
underwentRRH; strategies;4
13underwent underwent
annualES pretestRRH;5
and/orTVUS;6 underwentRRH;
hadnotreached 5underwentEC
Carriers(n=16) recommended screening(TVUS
screeningage and/orES);2
hadnotreached
recommended
screeningage
Noncarriers(n= Noncarriers:
9);14 11%(1/9)
indeterminate underwentEC
results;1variant screening;11%
ofuncertain (1/9)underwent
significance RRH
EC=endometrialcancer;ES=endometrialsampling;RRH=risk-reducingtotalabdominalhysterectomy;RRSO=risk-reducingsalpingo-
oophorectomy;TVUS=transvaginalultrasound.
Noncarrier(s)=negativeforknownpathogenicvariantinfamily.
1
Prospectivestudydesign.
2
Retrospectivestudydesign.
a
Self-reportasdatasource.
Overall,thesestudieshaveincludedrelativelysmallnumbersofwomenandsuggestthatscreeningratesforLS-associated
gynecologiccancersarelowbeforegeneticcounselingandtesting.However,afterparticipationingeneticeducationand
counselingandthereceiptofLSpathogenicvarianttestresults,uptakeofgynecologiccancerscreeningincarriersgenerally
increases,whilenoncarriersdecreaseuse.
Risk-reducing surgery for LS

Thereisnoconsensusregardingtheuseofrisk-reducingcolectomyforLS,andlittleisknownaboutdecision-makingand
psychologicalsequelaesurroundingrisk-reducingcolectomyforLS.
Amongpersonswhoreceivedpositivetestresults,agreaterproportionindicatedinterestinhavingrisk-reducingcolectomyafter
disclosureofresultsthanatbaseline.[3]Thisstudyalsoindicatedthatconsiderationofrisk-reducingsurgeryforLSmaymotivate
participationingenetictesting.Beforereceivingresults,46%indicatedthattheywereconsideringrisk-reducingcolectomy,and
69%ofwomenwereconsideringrisk-reducingtotalabdominalhysterectomy(RRH)andriskreducingbilateralsalpingo-
oophorectomy(RRSO);however,thisstudydidnotassesswhetherpersonsactuallyfollowedthroughwithrisk-reducingsurgery
aftertheyreceivedtheirtestresults.BeforeundergoingLSgeneticcounselingandtesting,5%ofcancer-unaffectedindividualsat
riskofaMMRvariantinalongitudinalstudyreportedthattheywouldconsidercolectomy,and5%ofwomenindicatedthatthey
wouldhaveanRRHandanRRSO,iftheywerefoundtobepathogenicvariantpositive.At3yearsafterdisclosureofresults,no
participantshadundergonerisk-reducingcolectomy.[31,54]TwowomenwhohadundergoneanRRHbeforegenetictesting
underwentRRSOwithin1yearaftertesting,[54]however,nootherfemalecarriersofpathogenicvariantsinthestudyreported
havingeitherprocedureat3yearsaftertestresultdisclosure.[31]
Inacross-sectionalquality-of-lifeandfunctionaloutcomesurveyofLSpatientswithmoreextensive(subtotalcolectomy)orless
extensive(segmentalresectionorhemicolectomy)resections,globalquality-of-lifeoutcomeswerecomparable,althoughpatients
withgreaterextentofresectiondescribedmorefrequentbowelmovementsandrelateddysfunction.[59]
Colorectal screening for FAP

LessisknownaboutpsychologicalaspectsofscreeningforFAP.Onestudyofasmallnumberofpersons(aged1753years)witha
familyhistoryofFAPwhowereofferedparticipationinageneticcounselingandtestingprotocolfoundthatamongthosewho
wereasymptomatic,allreportedundergoingatleastoneendoscopicsurveillancebeforeparticipationinthestudy.[55]Only33%
(twoofsixpatients)reportedcontinuingscreeningattherecommendedinterval.Oftheaffectedpersonswhohadundergone
colectomy,92%(11of12patients)wereadherenttorecommendedcolorectalsurveillance.Inacross-sectionalstudyof150
personswithaclinicalorgeneticdiagnosisofclassicFAPorattenuatedFAP(AFAP)andat-riskrelatives,52%ofthosewithFAPand
46%ofrelativesatriskofFAP,hadundergonerecommendedendoscopicscreening.[60]Amongpersonswhohadorwereatriskof
AFAP,58%and33%,respectively,hadundergonescreening.Comparedwithpersonswhohadundergonescreeningwithinthe
recommendedtimeinterval,thosewhohadnotscreenedwerelesslikelytorecallproviderrecommendationsforscreening,more
likelytolackhealthinsuranceorinsurancereimbursementforscreening,andmorelikelytobelievethattheyarenotatincreased
riskofCRC.Only42%ofthestudypopulationhadeverundergonegeneticcounseling.Asmallpercentageofparticipants(14%
19%)describedscreeningasanecessaryevil,indicatingadislikeforthebowelpreparation,orexperiencedpainanddiscomfort.
Nineteenpercentreportedthattheseissuesmightposebarrierstoundergoingfutureendoscopies.Nineteenpercentreported
thatimprovedtechniquesandtheuseofanesthesiahaveimprovedtoleranceforscreeningprocedures.
Risk-reducing surgery for FAP

WhenpersonsatriskofFAPdevelopmultiplepolyps,risk-reducingsurgeryintheformofsubtotalcolectomyorproctocolectomyis
theonlyeffectivewaytoreducetheriskofCRC.MostpersonswithFAPcanavoidapermanentostomyandpreservetheanus
and/orrectum,allowingsomedegreeofbowelcontinence.(RefertotheInterventionsforFAPsectionofthissummaryformore
informationaboutsurgicalmanagementproceduresinFAP.)Evidenceonthequality-of-lifeoutcomesfromtheseinterventions
continuestoaccumulateandissummarizedinTable20.
Table 20. Studies Measuring Quality-of-Life Variables in Familial Adenomatous

Polyposis (FAP)
Population Length Typeof Stool Stool Body Sexual Comments

of Procedure Frequency Continency Image Functioning
Follow-
up
b
279FAP- IRA IRA:n= Not Not EORTC QLQ- EORTC QLQ- SF-36 scores
a a
affected mean: 161 assessed assessed CR38 CR38 (Dutch
individuals 12y(SD, version)on
(135 7.5y) allsubscales
females were
and144 significantly
males) lowerthan
after thescoresin
colectomy; thegeneral
controls population
included
Population Length Typeof Stool Stool Body Sexual (IRA:P<
Comments
1,771 of Procedure Frequency Continency Image Functioning .001;IPAA:
individuals Follow- <.001).
fromthe up
general
Dutch
population
[61] IRA:87.5 IRA:38.9
(SD,21.9) (SD,26.6)
IPAA IPAA:n= IPAA:84.4 IPAA:42.2

mean: 118 (SD,22.7) (SD,26.3)
6.8y
(SD,4.9
y)
b b
88 Not IRA:n=33 Not Not SF-36 SF-36
Australian reported assessed assessed
individuals
(63females
IPAA:n= IRA:89.9 IRA:86.2
and25
21 (SD,16.1) (SD,21.6)
males)
aged1835
y,including
57after Ileostomy: IPAA:72.1 IPAA:77.5
colectomy n=1 (SD,23) (SD,26.2)
and14with
FAPbutno
surgery
[62] Unknown No Nosurgery:
surgery surgery: 91(SD,19)
type:n=2 94.1(SD,
9.4)
525 Range: IRA:n= Not Not EORTC QLQ- EORTC QLQ- 41%ofFAP
a a
individuals 01yto 136 assessed assessed CR38 CR38 patients
(283 >10y reported
females employment
and242 disruptions:
males)
including
296after
After After Partor
colectomy,
colectomy: colectomy: complete
45withFAP
85.4(SD, 42.2(SD, disability:n=
butno
20.5) 23.2) 73(59%)
surgery,50
atriskfor
FAPandno
surgery,
and134
noncarriers
[63]
Population Length Typeof Stool Stool Body Sexual Comments

Follow-
up
IPAA:n= FAPno After Workedless:

112 surgery: colectomy: n=30(24%)
91.9(SD, 42.2(SD,
16.1) 23.2)
Ileostomy: Atrisk:94.0 Atrisk:47.6 Worked

n=42 (SD,13.1) (SD,23.7) moren=5
(4%)
Other:n= Noncarrier: Noncarrier: Worked

6 92.3(SD, 45.7(SD, moreorless
13.1) 21.2) atdifferent
periods:n=
16(13%)
209 Mean IRA:n=71 Not Day:71%(n Not Not Themean

Swedish time assessed =149) assessed assessed numberof
FAP- since 21
affected last abdominal
individuals surgery: symptoms
(116 14y(SD, assessed
females 10; IPAA:n= was7(SD,
and93 range, 82 4.61;range,
males) 150y) 118).
after Women
colectomy reported
aged1875 more
y[64] symptoms
thanmen,
Ileostomy: Night:61%
butthere
n=39 (n=128)
wereno
differences
between
genders
regarding
thedegree
Continent the
ileostomy: symptoms
n=14 were
troublesome.
Higher
symptom
numberwas
an
independent
predictorof
poorer
physicaland
mental
Population Length Typeof Stool Stool Body Sexual health.
Comments
Follow-
up
Other:n=
3
28 12y(SD, IRA:n=7 Day: Day: Rosenberg Not 10/28

individuals 8.4; self-esteem assessed reported
(10females range, score : cancer-
c
and18 137y) 25.53/30 related
IRA:3.8 IRA:71.4%
males)who worrypost
(SD,1.5) (n=7)
underwent colectomy,
colectomy withatrend
atage14y thatyoung
oryounger IPAA:5.3 IPAA:85.7% age(<18y)
[65] (SD,2.4) (n=21) was
associated
withmore
cancer-
IPAA:n= Night: Night: related
21 worry.
IRA:1.3 IRA:50.0%
(SD,0.6) (n=7)
IPAA:1.3 IPAA:61.9%
(SD,0.5) (n=21)
EORTCQLQ=EuropeanOrganizationforResearchandTreatmentofCancerColorectalQualityofLifeQuestionnaire;IPAA=ilealpouch-analanastomosis;
IRA=ileorectalanastomosis;SD=standarddeviation;SF-36=ShortForm(36)HealthSurvey.
a
EORTCQLQ-C38scoresrangefrom0100.Functionalscales:0=lowestleveloffunctionand100=highest/healthyleveloffunction.Symptomscales:0=
lowestlevelofsymptomatologyand100=highestlevelofsymptomatology.
b
SF-36scoresrangefrom0100,with0=lowestpossiblehealthstatusand100=bestpossiblehealthstatus.
c
Withinnormalrangesforsameagegroup.
Studiesofrisk-reducingsurgeryforFAPhavefoundthatgeneralmeasuresofqualityoflifehavebeenwithinnormalrange,and
themajorityreportednonegativeimpactontheirbodyimage.However,thesestudiessuggestthatrisk-reducingsurgeryforFAP
mayhavenegativequality-of-lifeeffectsforatleastsomeproportionofthoseaffected.
Chemoprevention
ChemopreventiontrialsarecurrentlyunderwaytoevaluatetheeffectivenessofvarioustherapiesforpersonsatriskofLSandFAP.
[66,67]InasampleofpersonsdiagnosedwithFAPwhowereinvitedtotakepartina5-yeartrialtoevaluatetheeffectsofvitamins
andfiberonthedevelopmentofadenomatouspolyps,55%agreedtoparticipate.[68]Participantsweremorelikelytobeyounger,
tohavebeenmorerecentlydiagnosedwithFAP,andtolivefartherfromthetrialcenter,butdidnotdifferfromnonparticipantson
anyotherpsychosocialvariables.
Family communication
FamilycommunicationaboutgenetictestingforhereditaryCRCsusceptibility,andspecificallyabouttheresultsofsuchtesting,is
complex.Itisgenerallyacceptedthatcommunicationaboutgeneticriskinformationwithinfamiliesislargelytheresponsibilityof
familymembersthemselves.AfewstudieshaveexaminedcommunicationpatternsinfamilieswhohadbeenofferedLSgenetic
counselingandtesting.StudieshavefocusedonwhetherindividualsdisclosedinformationaboutLSgenetictestingtotheirfamily
members,towhomtheydisclosedthisinformation,andfamily-basedcharacteristicsorissuesthatmightfacilitateorinhibitsuch
communication.Thesestudiesexaminedcommunicationanddisclosureprocessesinfamiliesafternotificationbyhealthcare
professionalsaboutaLSpredispositionandhavecomprisedrelativelysmallsamples.
ResearchfindingsindicatethatpersonsgenerallyarewillingtoshareinformationaboutthepresenceofaLSpathogenicvariant
withintheirfamilies.[69-72]Motivationsforsharinggeneticriskinformationincludeadesiretoincreasefamilyawarenessabout
personalrisk,healthpromotionoptionsandpredictivegenetictesting,adesireforemotionalsupport,andaperceivedmoral
obligationandresponsibilitytohelpothersinthefamily.[70-72]Findingsacrossstudiessuggestthatmoststudyparticipants
believedthatLSgeneticriskinformationissharedopenlywithinfamilies;however,suchcommunicationismorelikelytooccurwith
first-degreerelatives(e.g.,siblings,children)thanwithmoredistantrelatives.[69-72]
OneFinnishstudyrecruitedparentsaged40yearsorolderandknowntocarryanMMRpathogenicvarianttocompletea
questionnairethatinvestigatedhowparentssharedknowledgeofgeneticriskwiththeiradultandminoroffspring.Thestudyalso
identifiedchallengesinthecommunicationprocess.[73]Of248parents,87%reportedthattheyhaddisclosedresultstotheir
children.Reasonsfornondisclosurewereconsistentwithpreviousstudies(youngageofoffspring,sociallydistantrelationships,or
feelingsofdifficultyindiscussingthetopic).[70,71,74]Nearlyallparentshadinformedtheiradultoffspringabouttheirgeneticrisk
andthepossibilityofgenetictesting,butnearlyone-thirdwereunsureofhowtheiroffspringhadusedtheinformation.Parents
identifieddiscussingtheirchildrenscancerriskasthemostdifficultaspectofthecommunicationprocess.Ofthe191firstborn
childreninformed,69%hadundergonegenetictesting.One-thirdoftheparentssuggestedthathealthprofessionalsshouldbe
involvedindisclosureoftheinformationandthatafamilyappointmentatthegeneticsclinicshouldbemadeatthetimeof
disclosure.
Inregardtoinformingsecond-andthird-degreerelatives,individualsmayfavoracascadeapproach;forexample,itisassumed
thatoncearelativeisgiveninformationaboutthefamilysriskofLS,heorshewouldthenberesponsibleforinforminghisorher
first-degreerelatives.[69-71]Thiscascadeapproachtocommunicationisdistinctlypreferredinregardtoinformingrelatives
offspring,particularlythoseofminorage,andtheconsensussuggeststhatitwouldbeinappropriatetodisclosesuchinformation
toasecond-degreeorthird-degreerelativewithoutfirstproceedingthroughthefamilyrelationalhierarchy.[69-71,74]Inonestudy,
personswhohadundergonetestingandwerefoundtocarryaLS-predisposingpathogenicvariantweremorelikelythanpersons
whohadreceivedtruenegativeoruninformativeresultstoinformatleastonesecond-degreeorthird-degreerelativeabouttheir
genetictestresults.[72]
Whilecommunicationaboutgeneticriskisgenerallyviewedasanopenprocess,somecommunicationbarrierswerereported
acrossstudies.Reasonsfornotinformingarelativeincludedlackofacloserelationshipandlackofcontactwiththeindividual;in
fact,emotional,ratherthanrelational,closenessseemedtobeamoreimportantdeterminantofthedegreeofriskcommunication.
Adesiretonotworryrelativeswithinformationabouttestresultsandtheperceptionthatrelativeswouldnotunderstandthe
meaningofthisinformationalsohavebeencitedascommunicationbarriers.[72]Disclosureseemedlesslikelyifat-riskindividuals
wereconsideredtooyoungtoreceivetheinformation(i.e.,children),ifinformationaboutthehereditarycancerriskhadpreviously
createdconflictinthefamily,[71]orifitwasassumedthatrelativeswouldbeuninterestedininformationabouttesting.[70]Prior
existenceofconflictseemedtoinhibitdiscussionsabouthereditarycancerrisk,particularlyifsuchdiscussionsinvolveddisclosure
ofbadnews.[71]
Formostparticipantsinthesestudies,thenewsthatthepatternofcancersintheirfamilieswasattributabletoaLS-predisposing
pathogenicvariantdidnotcomeasasurprise,[69,70]asindividualshadsuspectedahereditarycauseforthefamilialcancersor
hadpriorfamilydiscussionsaboutcancer.IdentificationofaLS-predisposingpathogenicvariantinthefamilywasconsidereda
privatematterbutnotnecessarilyasecret,[69]andmanyindividualshaddiscussedthefamilyspathogenicvariantstatuswith
someoneoutsideofthefamily.KnowledgeaboutthedetectionofaLS-predisposingpathogenicvariantinthefamilywasnot
viewedasstigmatizing,thoughindividualsexpressedconcernaboutthepotentialimpactofthisinformationoninsurance
discrimination.[69]Also,whiletheremaybeawillingnesstodiscloseinformationaboutthepresenceofapathogenicvariantinthe
family,onestudysuggestsatendencytoremainmoreprivateaboutthedisclosureofindividualresults,distinguishingpersonal
resultsfromfamilialriskinformation.[74]Inafewcases,individualsreportedthattheirrelativesexpressedanger,shock,orother
negativeemotionalreactionsafterreceivingnewsaboutthefamilysLSrisk;[71]however,mostindicatedlittletonodifficultyin
informingtheirrelatives.[70]Itwassuggestedthatfamilieswhoaremorecomfortableandopenwithcancer-relateddiscussions
maybemorereceptiveandacceptingofnewsaboutgeneticrisk.[71]
Insomecases,probandsreportedfeelingparticularlyobligedtoinformfamilymembersaboutahereditarycancerrisk[71]and
wereoftenthestrongestadvocatesforencouragingtheirfamilymemberstoundergogeneticcounselingandtestingforthefamily
pathogenicvariant.[69]Somegenderandfamilyroledifferencesalsoemergedinregardtothedisseminationofhereditarycancer
riskinformation.Onestudyreportedthatfemaleprobandsweremorecomfortablediscussinggeneticinformationthanweremale
probandsandthatmaleprobandsshowedagreaterneedforprofessionalsupportduringthefamilycommunicationprocess.[70]
Anotherstudysuggestedthatmothersmaybeparticularlyinfluentialmembersofthefamilynetworkinregardtocommunicating
healthriskinformation.[75]Pathogenicvariantnegativeindividuals,personswhochosenottobetested,andspousesofat-risk
personsreportednotfeelingaspersonallyinvolvedwiththeriskcommunicationprocesscomparedwithprobandsandotherat-
riskpersonswhohadundergonegenetictesting.[69]
Variousmodesofcommunication(e.g.,in-person,telephone,orwrittencontact)maytypicallybeusedtodisclosegeneticrisk
informationwithinfamilies.[69-71]Inonestudy,communicationaidssuchasageneticcounselingsummaryletterorLSbooklet
wereviewedashelpfuladjunctstothecommunicationprocessbutwerenotconsideredcentralornecessarytoitssuccess.[70]
Studieshavesuggestedthatrecommendationsbyhealthcareproviderstoinformrelativesabouthereditarycancerriskmay
encouragecommunicationaboutLS[71]andthatsupportbyhealthcareprofessionalsmaybehelpfulinovercomingbarriersto
communicatingsuchinformationtofamilymembers.[74]
Muchoftheliteraturetodateonfamilycommunicationhasfocusedondisclosureoftestresults;however,otherelementsof
familycommunicationarecurrentlybeingexplored.Onestudyevaluatedtheroleofolderfamilymembersinprovidingvarious
typesofsupport(e.g.,instrumental,emotional,crisishelp,anddependabilitywhenneeded)amongindividualswithLSandtheir
familymembers(206respondentsfrom33families).[7,76]Respondentscompletedinterviewsabouttheirfamilysocialnetwork
(biologicalandnon-biologicalrelativesandothersoutsidethefamily)andpatternsofcommunicationwithintheirfamily.The
averageageoftherespondentsandthemembersoftheirfamilysocialnetworkdidnotdiffer(age~43years).Thestudyfoundthat
23%ofthemembersofthefamilysocialnetworkencouragedCRCscreening(othertypesofsupport,suchassocialsupport,were
reportedmuchmorefrequently).Thosewhoencouragedscreeningwereolder,female,andsignificantothersorbiologicalfamily
members,ratherthannonfamilymembers.Giventhatmanyofthemembersofthefamilysocialnetworkdidnotliveinthesame
household,thestudypointsouttheimportanceofextendedfamilyinthecontextofscreeningencouragementandsupport.
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Changes to This Summary (10/07/2016)

ThePDQcancerinformationsummariesarereviewedregularlyandupdatedasnewinformationbecomesavailable.Thissection
describesthelatestchangesmadetothissummaryasofthedateabove.
ExecutiveSummary
Addedthisnewsection.
ColonCancerGenes
Addedtexttostatethatinone2016study,exomesequencingdataon1,006early-onsetfamilialcolorectalcancer(CRC)casesand
1,609healthycontrolswereanalyzed.Highlypenetrantrarepathogenicvariantswereidentifiedin16%offamilialCRCcases,of
whichthemajoritywereknowncoloncancergeneswhilePOT1,POLE2,andMRE11wereidentifiedascandidateCRCgenes.The
authorsconcludedthatthesefindingsprobablydiscounttheexistenceoffurthermajorhigh-penetrancesusceptibilityCRCgenes
(citedChubbetal.asreference12).
MajorGeneticSyndromes
Addedtexttostatethatpreclinicalstudiesofasmall-moleculeepidermalgrowthfactorreceptor(EGFR)inhibitorandlow-dose
sulindacintheApcmin/+mousediminishedintestinaladenomadevelopmentby87%suggestingthatEGFRinhibitorshadthe
potentialtoinhibitduodenalpolypsinfamilialadenomatouspolyposis(FAP)patients(citedRobertsetal.asreference184).A6-
monthdouble-blind,randomized,placebo-controlledtrialtestedtheefficacyofsulindacanderlotinibversusplaceboinFAPor
attenuatedFAP(AFAP)patientswithduodenalpolyps(citedSamadderetal.asreference185).Thetrialwasterminated
prematurelybecausetheprimaryendpointwasmet.Basedonthepreviouslymodesteffectsofsulindacandcelecoxibon
duodenalpolypsinFAPpatientsandthedramaticeffectofgeneticEGFRinhibitiononintestinaladenomadevelopmentinthe
Apcmin/+mouse(citedRinellaetal.asreference186),itislikelythaterlotinibwasresponsibleforthesuccessofthistrial.An
ongoingclinicaltrialisdeterminingwhetherlowerdosesoferlotinibalonearesufficientforsignificantlyreducingduodenalpolyp
burdeninFAPandAFAPpatients.
AddedtexttostatethataseriesfromtheUnitedKingdomcomposedofclinicallyreferredLynchsyndrome(LS)kindreds,with
effortstocorrectforascertainment,showedatwofoldincreasedriskofbreastcancerinMLH1familiesbutnotinfamilieswith
otherMMRvariants(citedHarknessetal.asreference273).
AddedImmunotherapyinLSasanewsubsection.
ThissummaryiswrittenandmaintainedbythePDQCancerGeneticsEditorialBoard,whichiseditoriallyindependentofNCI.The
summaryreflectsanindependentreviewoftheliteratureanddoesnotrepresentapolicystatementofNCIorNIH.More
informationaboutsummarypoliciesandtheroleofthePDQEditorialBoardsinmaintainingthePDQsummariescanbefoundon
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ThisPDQcancerinformationsummaryforhealthprofessionalsprovidescomprehensive,peer-reviewed,evidence-based
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FayKastrinos,MD,MPH
ScottKuwada,MD,AGAF,FACP(UniversityofHawaii)
PatrickM.Lynch,MD,JD(UniversityofTexas,M.D.AndersonCancerCenter)
SuzanneM.O'Neill,MS,PhD,CGC(NorthwesternUniversity)
BethN.Peshkin,MS,CGC(LombardiComprehensiveCancerCenteratGeorgetownUniversityMedicalCenter)
SusanK.Peterson,PhD,MPH(UniversityofTexas,M.D.AndersonCancerCenter)
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CatharineWang,PhD,MSc(BostonUniversitySchoolofPublicHealth)
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3/11/2016 GeneticsofColorectalCancer(PDQ)HealthProfessionalVersionNationalCancerInstitute

Genetics of Colorectal Cancer (PDQ)Health Professional Version

Natural History of CRC

Molecular Events Associated With Colon Carcinogenesis

Family History as a Risk Factor for CRC

FamilyHistory RelativeRiskofCRC[39] AbsoluteRisk(%)ofCRCbyAge79ya

Oneaffectedfirst-degreerelative 3.9(95%CI,2.46.2) 15b

FamilyHistory RelativeRiskofCRC[39] AbsoluteRisk(%)ofCRCbyAge79y

Inheritance of CRC Predisposition

Difficulties in Identifying a Family History of CRC Risk

Other risk factors for CRC

State of the evidence base

Rationale for screening

Identification of persons at high genetic risk of CRC

Primary Prevention of Familial CRC

Primary Prevention of Familial CRC

Modifying behavioral risk factors

Colon Cancer Genes

Table 2. Genes Associated with a High Susceptibility of Colorectal Cancer

Gene Syndrome HereditaryPattern PredominantCancer

APC(OMIM) FAP Dominant Colon,intestine,etc.

TP53(p53)(OMIM) Li-Fraumeni Dominant Multiple(includingcolon)

STK11(LKB1)(OMIM) PJS Dominant Multiple(includingintestine)

PTEN(OMIM) Cowden Dominant Multiple(includingintestine)

BMPR1A(OMIM) JPS Dominant Gastrointestinal

SMAD4(MADH/DPC4)(OMIM) JPS Dominant Gastrointestinal

MLH1(OMIM),MSH2(OMIM), LS Dominant Multiple(includingcolon,

Gene Syndrome HereditaryPattern PredominantCancer

EPCAM (TACSTD1)(OMIM) LS Dominant Multiple(includingcolon,

MYH(MUTYH)(OMIM) MYH-associatedpolyposis Recessive Colon

POLD1(OMIM),POLE(OMIM) Oligopolyposis Dominant Colon,endometrial

De Novo Pathogenic Variant Rate

Next-Generation Sequencing and Novel CRC Susceptibility Genes

Genetic Polymorphisms and CRC Risk

Polymorphism-modifying risk in average-risk populations

Low-penetrance candidate genes

Genetic variation in 8q24 and SMAD7

Variants of uncertain significance in major cancer susceptibility genes

Clinical implications of low-penetrance alleles

Major Genetic Syndromes

WiththedevelopmentoftheHumanGenomeProjectandtheidentificationin1990oftheadenomatous polyposis coli(APC)geneon

Familial Adenomatous Polyposis (FAP)

Table 4. Extracolonic Tumor Risks in Familial Adenomatous Polyposis

Malignancy RelativeRisk AbsoluteLifetimeRisk(%)

Desmoid 852.0 15.0

Duodenum 330.8 5.012.0

Thyroid 7.6 2.0

Brain 7.0 2.0

Ampullary 123.7 1.7

Pancreas 4.5 1.7

Hepatoblastoma 847.0 1.6

Malignancy RelativeRisk AbsoluteLifetimeRisk(%)

Adenomatous polyposis coli (APC)

Density of colonic polyposis

Duodenum/small bowel tumors

Table 5. Spigelman Classification

Points PolypNumber PolypSize(mm) Histology Dysplasia

2 520 410 Tubulovillous Moderate

3 >20 >10 Villous Severe

Table 6. Recommended Screening Intervals by Spigelman Stage

SpigelmanStage NCCN(2015)[93] Grovesetal.(2002)[80]

0(nopolyps) Endoscopyevery4y Endoscopyevery5y

III Endoscopyevery612mo Endoscopyevery12y