HereditaryColorectalCancerSyndromesKaterinaWellsMDMPHPaulEWiseIti - PDF document

HereditaryColorectalCancerSyndromesKaterinaWells,MD,MPH,PaulE.Wise,Itisestimatedthat20%to30%ofcolorectalcancers(CRCs)arefamilialwith5%to10%relatedtoaknowngeneticsyndrome.ThehereditaryCRCsarebroadlydividedintononpolyposisandpolyposissyndromes.Individualswithhereditary DisclosureStatement:Theauthorshavenothingtodisclose.DepartmentofSurgery,DivisionofColonandRectalSurgery,BaylorUniversityMedicalCen-ter,3409WorthStreet,Suite640,Dallas,TX75246,USA;DivisionofGeneralSurgery,SectionofColonandRectalSurgery,WashingtonUniversityInheritedColorectalCancerandPolyposisRegistry,WashingtonUniversityGeneralSurgeryResidency,WashingtonUniversityinStLouisSchoolofMedicine,660SouthEuclidAvenue,CampusBox8109,StLouis,MO63110,USA*Correspondingauthor. InheritedcoloncancerHereditarynonpolyposiscolorectalcancerLynchsyndromeFamilialadenomatouspolyposisMUTYH-associatedpolyposisSerratedpolyposissyndromeKEYPOINTS metachronouscancers,andextracolonicmanifestations.Assuch,identificationoftheseindividualsiscriticalforpreventionandearlydetectionandtreatmentofassoci-atedmalignanciestoreduceassociatedmorbidityandmortality.AlthoughthereareamultitudeofhereditarysyndromesassociatedwithincreasedriskofCRC,thisarticlefocusesonthemostcommonnonpolyposisandpolyposissyndromes.HEREDITARYNONPOLYPOSISCOLORECTALCANCER/LYNCHSYNDROMEHereditarynonpolyposisCRC(HNPCC),alsooftenusedsynonymouslywiththetermLynchsyndrome,isthemostcommonhereditaryCRCsyndrome,accountingforatleast2%to3%ofallCRCs.LynchsyndromeandHNPCCareassociatedwithapredis-positiontoCRCandothercancersfollowinganautosomal-dominantinheritancepattern,althoughraresporadicmutationsaredescribed.HNPCCdefinesapatientwhomeetsparticularclinicalcriteria(Box1),regardlessoftheresultsofgeneticassess-ment.Lynchsyndromeisreservedforpatientswithaknownmismatchrepair(MMR)genemutationregardlessofwhethertheyfulfilltheclinicalcriteriaforHNPCC(Fig.1BothsyndromesareassociatedwithonsetofCRCearlierthanthegeneralpopula-tionwithameanageatCRCdiagnosisof45years.Cancersaretypicallyproximaltothesplenicflexure;haveahighdegreeofmicrosatelliteinstability(MSI-high);andhavehistologicfeaturesincludingpoordifferentiation,Crohn’s-likehost-lymphocyticinfil-tration,lymphoidaggregationatthetumormargins,andmucinousfeatures.areassociatedwithsynchronouscancers,andmetachronouscancersarecommonwithanannualincidencerat

eof2.1%.Despitetheapparenthigh-riskhistologicfea-tures,HNPCC-relatedCRCdemonstrateslessnodalanddistantmetastaticspreadcomparedwithsporadicCRC.The“nonpolyposis”labelofHNPCCcanbemisleadingtolessexperiencedphysicians,becausecolorectaladenomatouspolypsaretheprecursorlesionsinthesesyndromes,withadenomastypicallydemonstratingavillousgrowthpatternandhavingahighdegreeofdysplasia.throughtheadenoma-carcinomasequenceisacceleratedwithCRCdevelopingwithina5-yearintervalcomparedwith10ormoreyearsinthecaseofsporadicCRC.12,13RiskofCancerRegardlessofthepatientpopulationsstudied,theriskofCRCextracolonicmalig-nancyisclearlyelevatedinHNPCC.Moststudiespresenttheserisksreportedin Box1RevisedHNPCCcriteria(AmsterdamcriteriaII)1.ThereshouldbeatleastthreerelativeswithanHNPCC-associatedcancer(CRC,canceroftheendometrium,smallbowel,ureter,orrenalpelvis)2.Oneshouldbeafirst-degreerelativeoftheothertwo3.Atleasttwosuccessivegenerationsshouldbeaffected4.Atleastoneshouldbediagnosedbeforeage505.FamilialadenomatouspolyposisshouldbeexcludedintheCRCcasesifany6.TumorsshouldbeverifiedbypathologicexaminationVasenHF,WatsonP,MecklinJP,etal.Newclinicalcriteriaforhereditarynonpolyposiscolorectalcancer(HNPCC,Lynchsyndrome)proposedbytheInternationalCollaborativegrouponHNPCC.Gastroenterology1999;116(6):1455;withpermission.Wells&Wise aggregateofallpotentiallyassociatedgenemutations;however,eachMMRmutationconfersauniquegenotype-phenotypecancer-riskprofile.PriorliteraturereportshigherlifetimeriskofCRC,upto69%inmenand52%inwomenbytheageof70years,emphasizingthevariablepenetranceamongindividuals.Dowtyandcol-leaguesreportsanaverageCRCcumulativeriskbyage70yearsforpatientswithmutationsof34%and47%formalecarriersand36%and37%forfemalecarriers,respectively;however,thereissignificantheterogeneitywithinthesegroupswithsomeproportionofcarriershavingCRCrisksimilartothatofthegeneralpopulationandsomehavingnearabsolutelikelihoodofdevelopingCRC.Patientsarealsoatincreasedriskofextracolonicmalignancies,inparticularendo-metrial,ovarian,gastricandsmallbowel,pancreatic,hepatobiliary,brain,andupperurothelialtract.Theaverageendometrialcancerriskis18%to60%withameanageofdiagnosisat50years.19–21isassociatedwithahigherriskofendometrialcancerandaone-thirdlowerriskofCRCcomparedwithTheestimatedriskforgastriccanceris6%to13%;however,thisvariesbytheendemicityofg

astriccancerinthepopulation.Forexample,inKoreathelife-timeriskofLynch-relatedgastriccancerapproaches30%andsurpassesendometrialcancerrisk.TherearealsosubtypesofHNPCC/LynchsyndromeincludingMuir-Torresyndrome,associatedwithsebaceouscarcinomasandkeratocanthomas,andTurcotsyndrome,whichisassociatedwithbrainmalignanciesandcolonicDiagnosisofHereditaryNonpolyposisColorectalCancerTheAmsterdamIclinicalcriteriaforHNPCCwerecreatedin1990tostandardizeinclu-sioncriteriaforclinicalresearchstudies.ForkindredoffamiliesmeetingAmsterdamcriteria,thechanceofidentifyingagermlinemutationis45%to50%.However,40%ofpatientswithanidentifiedgeneticmutationfailtomeetAmsterdamcriteria.ConcernoftheAmsterdamIcriteriamissingclearfamilialclusteringofextracolonicmalignanciesledtoestablishmentoftheAmsterdamIIcriteria(seeBox1),whichbroadenstheHNPCCdefinitiontoincludeassociatedcancers(eg,endometrial,small MSI-H CRC (Amsterdam I/II) - Germline mutaon HNPCC + Germline mutaon Lynch Syndrome - Clinical Criteria (Amsterdam I/II) - Germline mutaon Somac mutaon MSS CRC (Amsterdam I/II) - Germline mutaon Familial Colorectal Cancer X - Clinical Criteria (Amsterdam I/II) Sporadic CRC Fig.1.RelationshipbetweenHNPCCandLynchsyndrome.MSI-H,microsatelliteinstability,high;MSS,microsatellitestable.HereditaryColorectalCancerSyndromes TherevisedBethesdaguidelineswerethenpublishedin2004toidentifyCRCpatientswhoshouldundergopathologicexaminationforHNPCC/LynchsyndromeBox2Forpatientsmeetingthesecriteria,furtherpathologicanalysisoftheCRCspecimenincludesMSItestingorimmunohistochemistry(IHC)assessmentforthepresenceoftheMMRproteins.JerusalemguidelinesfurtherbroadentheindicationsforMSIorIHCtestingtoCRCinindividualsyoungerthan70years.Amsterdamcriteriafailtoidentifyapproximately50%ofcases,andBethesdaguide-linesfailtoidentifyatleast30%ofcases,whichhasledtoincreasedsupportfortheuniversalapplicationofpolymerasechainreaction(fordetectionofMSI-hightumors)and/orIHCtesting(forMMRproteindeficiency)toallCRCspecimens.Thisjustifica-tionalsosupportsuniversaltestingofendometrialcancer.Universaltestingfollowedbygermlinetestingoffersthehighestsensitivity(andsomewhatlowerspecificity)thanalternativescreeningstrategies,althoughtheincreaseinthediagnosticyieldismodestcomparedwithcriteria-basedscreeningtechniques(Table1effectivenessanalys

esdemonstratevaryingresults.33,34EtiologyofLynchSyndromeLynchsyndromeiscausedbyagermlinemutationinDNAMMRgenes(mostcom-monbeingMLH1MSH2MSH6,andPMS2).Ascellulardivisionoccurs,errorsinreplicatedDNAareidentifiedandcorrectedbytheMMRproteincomplexes.Loss-of-functionmutationsintheMMRgenesmayresultinDNAreplicationerrors,whichcanoccurintumorsuppressorgenesorproto-oncogenesleadingtocarcinogenesis.DNAreplicationerrorsarepropagatedthroughdaughtercells,leadingtorepetitiveDNAsequencescalledmicrosatellites,makingthemunstable(MSI-high).MSItestingviapolymerasechainreactionisaneffectiveandhighlyreproduciblemethodforiden-tifyingtumorswithanunderlyinggermlineMMRdefect(93%sensitivity).Usingapanelofmicrosatellitemarkers,tissueisclassifiedasbeingMSI-highiftwoormoreoffivecoremarkersshowinstability.Ifmoreexpansivepanelsareused,agreaterthan30%rateofinstabilityisconsideredMSI-high.SporadicCRCMSI Box2RevisedBethesdaguidelines1.CRCinapatientyearsofage2.SynchronousormetachronousCRCorthepresenceofotherHNPCC-associatedtumors,regardlessofage3.Pathologicfeaturesofamicrosatelliteinstability–highcancer(tumorinfiltratinglymphocytes,Crohn’s-likelymphocyticreaction,mucinous/signet-ringdifferentiation,ormedullarygrowthpattern)inapatientyears4.CRCinoneormorefirst-degreerelativeswithanHNPCC-relatedtumorwithoneofthecancersdiagnosedbytheageof50years(includingadenomabytheageof40years)5.CRCintwoormorefirst-orsecond-degreerelativeswithHNPCC-relatedtumors,regardlessofageEndometrial,stomach,ovarian,pancreas,smallbowel,biliarytract,ureterorrenalpelvis,brain,sebaceousglandadenoma,orkeratoacanthoma.UmarA,BolandCR,TerdimanJP,etal.RevisedBethesdaguidelinesforhereditarynon-polyposiscolorectalcancer(Lynchsyndrome)andmicrosatelliteinstability.JNatlCancerInst2004;96(4):266;withpermission.Wells&Wise testingtypicallyrevealsnoinstabilityandareconsideredmicrosatellitestable(MSS);however,15%ofsporadicCRCsareidentifiedasbeingMSI-highandlikelyoccurthroughtheepigeneticpathwayofhypermethylationoftheMLH1promoterre-gionandalsoharborBRAFmutations,distinguishingthemfromgermline-relatedpathways,whicharetypicallyBRAFwild-type.Ofnote,asmallpercentageofCRCsthatfulfillHNPCCclinicalcriteriaarefoundtobeMSS.Patientsmeetingthesecriteriahavebeendesignated“familialcolorectalcancertypeX”andhaveamoder-atelyincreasedriskofCRCbutnoincreasedriskforextracolon

iccancers(seeFig.138,39GeneticTestingforHereditaryNonpolyposisColorectalCancer/LynchSyndromeGenetictestingshouldalwaysbedoneinathoughtful,stepwisefashioninthesettingofeffectivecounselingtoensurethatthepatientandkindredunderstandtheimplica-tionsofanytestresults,whethertheyconfirmthepresenceofamutationornot.WhenanMSI-highCRCisidentifiedthroughtumortesting,IHCfortheMMRproteinsisper-formedtoidentifythelikelymutatedgene.Alternatively,IHCcanreplaceMSIastheinitialtumortestbecauseIHCistechnicallyeasytoperformandhasdemonstrated92%sensitivityinidentifyingmutations.AlthoughidentificationofaparticularMMRproteinlossonIHCguidesgermlinetesting,thefindingofthelossofinthetumorisnotsufficientforthediagnosisofLynchbecauseofthepotentialforsporadiclossfromhypermethylationasdescribedpreviouslyandre-quiresadditionaltestingforhypermethylationtestingtoidentifysomaticmutations.ThepresenceofamutationisthoughttoberareinLynchsyndromeandusuallyexcludesthediagnosis.WhengenetictestingisinitiatedafterMMRIHCtumortesting,theimplicatedgenesaretestedforfirstwithfurthergenetestingperformedonlyiftheresultisunrevealing.TherearetimeswhentheclinicalcriteriaforHNPCCaresoimpressiveinafamily(eg,significantphenotypeswithmultipleassociatedcancersinmultipleindividuals)thatitislogicaltoproceeddirectlytogermlinetestingofanaffectedindividualwithoutpriortumortesting.ThisisperformedusingamultigenepaneltotestfortheMMRgenesandanyotherCRC-relatedgenes.Costforthesetestshasdecreasedsignificantlyinrecentyearsbecauseofmoreaffordabletestingmethods;however,panelsmayvarygreatlybetweenlaboratories.Regardlessofmethodused,ifapathogenicmuta-tionisfound,thepatient’sat-riskkindredcanbetestedforthatparticularmutation. Table1Sensitivity,specificity,anddiagnosticyieldofscreeningtechniquesforHNPCCScreeningApproachSensitivity(%)Specificity(%)DiagnosticYield(%)Universalscreening100(95%CI,99.3–100)93(95%CI,2.2(95%CI,1.7–2.7)Bethesdaguidelines87.8(95%CI,78.9–93.2)97.5(95%CI,2.0(95%CI,1.5–2.4)Jerusalemrecommendations85.4(95%CI,77.1–93.6)96.7(95%CI,1.9(95%CI,1.4–2.3)SelectiveMMRtestingCRCinpatientsymeetingBethesdaguidelines95.1(95%CI,89.8–99)95.5(95%CI,2.1(95%CI,1.6–2.6)CI,confidenceinterval.MoreiraL,BalaguerF,LindorN,etal.IdentificationofLynchsyndromeamongpatientswithcolorectalcancer.JAMA2012;308(15):1555;withpermission.HereditaryColorectalCancerSyn

dromes SurveillanceofHereditaryNonpolyposisColorectalCancer/LynchSyndromeTherecommendationforCRCsurveillanceofat-riskandaffectedindividualsiscolo-noscopyevery1to2yearsinitiatedat20to25yearsofageor2to5yearsbeforetheageoftheearliestdiagnosedCRC,whichevercomesfirst(Table2withsurveillanceisparamounttoreducetheincidenceofCRCinaffectedindividuals.Inaprospectivecohortstudy,95%complianceratesofcolonoscopicandgyneco-logicscreeningovera10-yearperiodfoundnodifferenceinmortalityinaffectedindi-vidualscomparedwiththeirnonaffectedrelatives.AdditionalscreeningguidelinesforextracolonicmalignanciesareoutlinedinTable2SurgicalApproachtoHereditaryNonpolyposisColorectalCancer/LynchSyndromeSurgicaloptionsincludesegmentalorextendedresection,bothrequiringinformedconsentregardingimplicationsonfuturecancerdevelopmentbalancedwiththechangesinbowelfunctionandqualityoflifeassociatedwitheachprocedure.Extendedcolectomyistherecommendedtreatmentofyoungtomiddle-agedpatientswithcoloncancer,bothfortreatmentoftheprimarylesionandriskreductionformeta-chronousCRC.Subtotalcolectomyortotalabdominalcolectomywithileorectalanastomosis(TAC/IRA)decreasestheriskofmetachronouscancerby31%forevery10cmofbowelremoved.Intheelderly,incontinent,and/orcomorbidpatient,themorbidityofandquality-of-lifeimplicationsofanextendedresectionmustbeweighedheavilyagainstthebenefitofcancerriskreduction,andinsomecases,asegmentalcolectomymaybemoreappropriate.Inthecaseofrectalcancer,atotalproctocolec-tomywithendileostomyorrestorativeilealpouch-analanastomosis(IPAA)shouldbeconsidered;however,whenpatientshavealocallyadvancedrectalcancerwithhighriskformetastaticdisease,prophylacticsurgerybecomeslessofaconcern,andlowanteriorresectionorabdominoperinealresectionmaybemoreappropriate.Thede-cisiontoperformanextendedversussegmentalresectionforCRCisalsoinfluencedbythepatient’santicipatedcompliancewithsurveillance,whichisparamountforearlydetectionofrecurrenceandmetachronouslesions.ThereisnotanestablishedroleforprophylacticcolectomyintheasymptomaticLynchsyndromepatient.However,theroleofprophylactichysterectomywithbilateralsalpingoophorectomyiswellsupportedandrecommendedforwomenwhohavecompletedchildbearing.InthesettingofaplannedCRCresection,concomitantpro-phylactichysterectomywithbilateralsalpingoophorectomyshouldbeconsidered.FAMILIALADENOMATOUSPOLYPOSISFamilia

ladenomatouspolyposis(FAP)hasanincidenceof0.6to2.3permillionandaccountsforapproximately0.5%to1%ofallCRCs.FAPischaracterizedbythedevelopmentofnumerous�(100)colorectaladenomatouspolyps(Fig.2),oftenexceedingeffectiveendoscopicmanagement,andfollowsanautosomal-dominantin-heritancepattern,although20%to30%ofcasespresentasaresultofadenovoOnsetofpolyposisoccursinadolescencewithprogressiontoCRCbymiddle-age.ThepenetranceofFAPis100%,withanincidenceofCRCapproaching100%bytheageof50years.Enhancedawarenessofthisdiseaseandmoreaggres-sivestrategiesforscreeningandsurveillancehavesubstantiallydecreasedtheinci-denceofCRCandassociatedmortality.PatientswithFAPmaypresentwithextracolonicfindingsdependingonthespecificgenemutationinvolved.DuodenaladenomasareasignificantcontributortoFAP-relatedmortalitywiththeriskofmalignantprogressionguidedbytheSpigelmanclas-Desmoidtumorsoccurinapproximately15%to20%ofpatientsovertheWells&Wise Table2NationalComprehensiveCancerNetworksurveillancerecommendationsforhereditaryCRCsyndromesSyndromeSiteAgetoBeginSurveillance(y)Interval(y)ProceduresHNPCCColon20–25or2–5ybeforeearliestCRCdiagnosis1–2ColonoscopyandovarianNoevidencetosupport1ConsiderannualendometrialsamplingConsiderprophylactichysterectomy/BSOinwomenwhohavecompletedNoevidencetosupportroutineovarianscreening(transvaginalultrasoundorCA-125)Urinarytract30–351ConsiderannualurinalysisSmallbowelandgastricNoevidencetosupport3–5ConsiderEGDwithextendedduodenoscopyinat-riskindividualsColon10–151FlexiblesigmoidoscopyorcolonoscopyUpperGI20–25Earlierifcolectomyaty1–5EGDwithcompletevisualizationofthepapillaSurveillancebySpigelmanstagingConsiderCTorMRIforsmallbowelifduodenalpolyposisisadvancedThyroidLateteenageyears1AnnualthyroidexaminationConsiderannualthyroidultrasoundNoevidencetosupport1AnnualabdominalexaminationConsiderCTorMRI1–3yaftercolectomy,thenevery5–10yorsymptom-continuedonnextpageHereditaryColorectalCancerSyndromes Table2continuedSyndromeSiteAgetoBeginSurveillance(y)Interval(y)ProceduresColonLateteenageyears2–3ColonoscopyUpperGI20–25Earlierifcolectomyaty1–5EGDwithcompletevisualizationofthepapillaThyroid1AnnualthyroidexaminationandthyroidultrasoundColon25–302–3ColonoscopyUpperGI30–351–5EGDwithcompletevisualizationofthepapillaColon4010ybeforeearliestCRCdiagnosis1–3ColonoscopyBSO,bilateralsalpingoophorectomy;CT,

computedtomography;EGD,esophagogastroduodenoscopy;GI,gastrointestinal.AdaptedfromProvenzaleD,GuptaS,AhnenDJ,etal.Genetic/familialhigh-riskassessment:colorectalversion1.2016,NCCNClinicalPracticeGuidelinesinOncology.JNatlComprCancNetw2016;14(8):1010–30;withpermission.Wells&Wise secondandthirddecadesoflife(Fig.3)withriskfactorsbeingpriorabdominalsur-54,55positivefamilyhistory,andmutation3tocodon1399.Thyroidcancerriskisfivetimeshigherthanthatofthegeneralpopulationwithastrongfemalepre-Otherbenignfindingsincludeosteomas(20%);lipomas;epidermoidcysts;fibromas;dentalabnormalities;andcongenitalhypertrophyoftheretinalpigmentepithelium,whichispathognomonicforthediagnosis,albeitwithoutknownclinicalimport.Theseunusualextracolonicmanifestationsoftenprecedecolonicsymptomsandmayaidinearlydiagnosis. Fig.3.SectionsfromacontrastedabdominalcomputedtomographyscanofapatientwithFAPwithintra-abdominaldesmoidoriginatingfromthemesenteryandretroperitoneum,includingareaswithfistulizationwithoralcontrastwithinthedesmoid().(HawkinsAT,WisePE.Coloncancerinhereditarysyndromes.SeminColonRectalSurghttp://dx.doi.org/10.1053/j.scrs.2016.04.021;withpermission.) Fig.2.GrosspathologyofacolectomyspecimenfromapatientwithFAP.(HawkinsAT,WisePE.Coloncancerinhereditarysyndromes.SeminColonRectalSurg2016.http://dx.doi.org/10.1053/j.scrs.2016.04.021;withpermission.)HereditaryColorectalCancerSyndromes EtiologyofFamilialAdenomatousPolyposisFAPiscausedbyamutationintheadenomatouspolyposiscoli()gene.Thegeneencodesalargemultifunctionalscaffoldingproteinthatactsasatumorsuppres-sorwithinthe-signalingpathwaytodownregulatetheactivityof-catenin.WithlossofAPCfunction,accumulationof-cateninupregulatesseveralgenesthatmediatecellproliferation,differentiation,andapoptosis.APCalsomediatesmicrotu-bulestabilization,withdefectsresultinginaberrantmitosis.Morethan1100mutationsofthegeneareidentified,mostlyresultinginalossoffunction.Variationsinthelociofmutationsandothergeneticmodifiersresultingenotype-phenotypevariationinFAP.Threemajorphenotypesaredescribed.Thefirstisprofusepolyposisexhibitinganaggressivephenotypewithearlyonsetofpol-yposis,symptoms,andCRC-relateddeathatanaverageof10yearsearlierthantypi-callydescribed.Deletionsatcodon1309andtruncatingmutationsatcodons1250and1464areassociatedwiththisphenotype.Second,intermediatepolyposis,withmost

mutationslocatedbetweencodon157andcodon1595.Third,attenuatedpolyposis(AFAP)characterizedbyareducedpolypburden(10–100polyps)withlaterageofonsetandlowerriskofCRC.DiagnosisofAFAPischallengingbecausesomefeaturesofAFAParesimilartothoseof-associatedpolyposis(MAP),dis-cussedlater.Work-upofFamilialAdenomatousPolyposisItisimportanttoemphasizethatapproximately20%to30%ofpatientswithFAPpre-sentwithoutafamilyhistoryofCRCoftenviadenovoAPCupto40%to50%ofpatientswithFAPincludedinhereditarycancerregistriesarediagnosedbasedonsymptomaticpresentation(eg,rectalbleeding,changesinbowelhabits)inthethirdorfourthdecadeandaresignificantlymorelikelytohaveaninitialdiagnosisofCRCcomparedwiththosediagnosedbasedonfamilyhistoryorotherriskfactorsforFAP.51,63,64Atthetimeofclinicaldiagnosis,thepatientshouldbereferredtoageneticcounselorandtestingperformedtoconfirmthediagnosis.Ifageneticmu-tationisidentified,genetestingisextendedtoallat-riskkindred.Ifageneticmutationisnotidentifiedfortesting,surveillancemustbeextendedtoallat-riskkindred.InkindredbornintoanFAPfamily,geneticscreeningisrecommendedinmid-adolescence,beforetheinitiationofcancerscreening.Thegoldstandardandcurrentmethodforgenetictestingisdirectsequencingofthegene.Thismethodidentifiesgreaterthan85%ofmutationswithremainingmu-tationsresultingfromlargegenerearrangementsthatarediagnosedonmultiplexligation-dependentprobeamplificationtesting.Approximately20%ofclinicallydiagnosedpatientswithFAPdonothaveanidentifiedmutation.Ifthepatientex-pressesapolyposisphenotypedespitenegativetesting,genetictestingforMAPshouldbeconsidered.Occasionally,paneltestingidentifiesothergenotypesbeyondthosetypicallyassociatedwithFAPandMAP.SurveillanceforFamilialAdenomatousPolyposisInastudyof170patientsbyBussey,rectalinvolvementwithpolyposiswasidenti-fiedinallcases.Basedonthisfinding,itisreasonableforaffectedindividuals,at-riskkindred,andthosewhohavenothadgenetictestingorinwhomgenetictestingisun-informativetoundergoannualflexiblesigmoidoscopybeginningintheearlyteenageyears.Ifpolypsaredetected,fullcolonoscopyisindicated.Annualsurveillanceshouldbelife-longregardlessoffindingsbecauseof100%penetranceofthedisease.InthecaseofAFAP,onsetofCRCislaterandthereisapropensityforright-sidedWells&Wise adenomas,soscreeningcanbeinitiatedinlateteenageyears,butcolonoscopyshouldbeusedinsteadofflexiblesigm

oidoscopy.Furtherscreeningrecommenda-tionsareoutlinedinTable2ChemopreventionforFamilialAdenomatousPolyposisVariouschemopreventionstrategieshavebeenconsideredtodelayproctocolectomyinyoungpatientsandtomanageupperandlowergastrointestinalpolypswhensurgi-calinterventionisunfavorable.Sulindacandcelecoxibarethemostwidelystudiedagents.Themechanismofnonsteroidalanti-inflammatorydrug–mediatedchemopre-ventionisnotcompletelyunderstood;however,cyclooxygenase-2inhibitionisknowntoinhibitangiogenesisandneovascularization,andrestorenormalapoptosissignalinginCRCcells.Theseagentsdemonstratesignificantlyreducedcolonpolypburdeninplacebo-controlledtrialsandofferamoderateeffectinthereductioninduodenalepithelialproliferation;however,effectsareincompleteandtemporarywithrecur-rencefollowingcessationoftherapy.ItisalsonotclearthatareducedpolypburdentranslatesintoreducedCRCrisk.Currently,chemoprophylaxisisnotasuitablealternativetosurgicaltherapy.Chemopreventionisconsideredifcontraindicationsorunavoidabledelaytosurgeryexistandalsoservesasaneffectiveadjuncttoendo-scopicpolypectomyinthemanagementofilealpouchpolyposis.StudiesareunderwayexaminingothertherapeuticagentsandcombinationtherapiesforSurgeryforFamilialAdenomatousPolyposisSurgeryisthemainstayofCRCriskreductionforFAP.Timingisnotclearlydefinedbyguidelinesbecausemultiplefactorsmustplayintothedecision-makingprocesssharedbythesurgeonandthepatient.Ideally,surgicalinterventionisanelectivepro-cedurewiththeindicationofprophylaxisintheasymptomaticpatient.Thiscanbedelayeduntiladolescence,usually15to20yearsofage,consideringthepsycholog-icalimpacttotheyoungpatient,becausetheincidenceofCRCbeforethatageisPatientswithlargeordysplasticlesions,severediseaseeitherclinicallyorbygenotype,orwithsymptomsshouldproceedtocolectomyassoonaspossiblebecauseoftheriskofunderlyingCRC.Patientswithafamilyhistoryorgenotypepre-disposingtodesmoiddiseasemayopttodelaysurgeryprovidedCRCriskallowsforthis.ItisreasonableforpatientswithAFAPormilddiseasetodelayingsurgeryintoyoungadulthood(21–25yearsofage)orlater,especiallyifthediseasecanbeendo-scopicallycontrolled.ThreemainsurgicaloptionsforFAParedescribednextTable3TotalproctocolectomywithendileostomyTotalproctocolectomywithendileostomyisthegoldstandardtreatmentandofferscompleteextirpationofat-riskcolorectalmucosaattheexpenseofpermanentileos-t

omy.Althoughlesscommonlyperformed,thisprocedureshouldbeincludedinthediscussionofsurgicaloptionsforpatientswithlowrectalcancersthatprecludeIPAA,thosewithpoorsphincterfunction,anddesmoiddiseaseorotheranatomiccon-straintsthatpreventIPAAconstruction.Totalproctocolectomywithilealpouch–analanastomosisTotalproctocolectomywithIPAAisthemostwidelyusedprocedureandisconsid-eredstandardofcareforthetreatmentofFAPotherthanforthepreviouslynotedcontraindications.Thisisanear-completeextirpativeprocedurewiththebenefitofpreservedcontinence.Historically,mucosectomywithhandsewnIPAAwastherecommendedapproachtoremoveremainingat-riskmucosafromtheretainedHereditaryColorectalCancerSyndromes rectalcuff;however,theincidenceofdysplasiaisnotstatisticallydifferentincom-parisonsofeithermethod.TherelativeproceduraleaseandfunctionalbenefitaffordedbystapledIPAAmakesthisthepreferredmethodinmostclinicalscenarios.Theriskofcancerintheresidualrectalcufforanaltransitionzoneorpouchapproaches1.2%.Riskfactorsrelatedtopouchcancerincludepreopera-tivediagnosisofdysplasiaorcarpetingpolyposisoftherectum.Endoscopicsur-veillanceoftheanaltransitionzoneandpouchshouldbeperformedevery1to3yearsdependingonpolypburden.Surveillanceshouldbeincreasedtoevery6monthsinthecaseoflargepolyps,villousarchitecture,and/ordysplasiainthepouchorcuff.TotalabdominalcolectomywithileorectalanastomosisTAC/IRAistechnicallyeasiertoperformwiththebenefitofimprovedfecalandurinarycontinenceandsexualfunctioncomparedwithIPAA.Thisoptionisconsideredinpatientswhohavealimitedrectalpolypburden(polyps),alow-riskgenotype,andareabletocomplywithsurveillance.ThisisagoodoptionforpatientswithAFAPandrectalsparing.Endoscopicsurveillanceoftheresidualrectumshouldbeperformedevery6to12monthsdependingontheextentofpolypburden.PatientsconsideringIRAmustbecounseledregardingtheriskofmetachronouslesionswithintheretainedrectumandprogressiontopolyposisthatexceedsendoscopicmanagementbecausebothareindicationsforcompletionproctectomy.Inaregistry-basedreviewof427pa-tientsundergoingIRAforFAP,11%ofpatientsdevelopedrectalcancerwith50%ofpatientsundergoingproctectomybyage60.Riskfactorsforprogressionofrectaldis-easeincluderectalpolypburdengreaterthan20,colonicpolypburdengreaterthan Table3SurgicalmanagementoptionsforFAPSurgeryIndicationsContraindicationsTotalwithendileostomyLowrectalcancerpreclud

ingsphincterpreservationMesentericforeshorteningPoorsphincterfunctionRefusalofIPAANoncompliancetoRefusalofpermanentileostomyTotalabdominalcolectomywithAFAP/mildpolyposis0colonicadenomasrectaladenomasDesireforpreservedfertility/NoncompliancetoRectalpolyposis -3;.7;(20rectaladenomas)Rectaldysplasia/carcinomaRectalpolyp -3;.7;3cmPredispositiontodesmoiddiseaseAPCmutationpredisposingtorectalcancerTotalwithilealAcceptableanticipatedfunctionaloutcomePoorbaselinesphincterfunctionLowrectalcancerprecludingsphincterpreservationNoncompliancetoWells&Wise 500,andanmutationatcodon1250to1450suggestingthatIRAmaynotbeappropriateforthesepatients.MUTYH-ASSOCIATEDPOLYPOSISMAPwasfirstdescribedin2002withareportofabiallelicgermlinemutationinthegeneinafamilyexpressingarecessiveinheritancepatternofcolonade-nomasandCRC.Asthebodyofknowledgeregardinggenotypiccontributorstopol-yposishasgrown,MAPsharesclinicalfeatureswithFAP/AFAPsuchthat10%to20%ofpatientswithsuspectedFAP/AFAPwithoutanidentifiedmutationexhibitamu-tationinAffectedpatientshavea50-foldincreasedlifetimeriskofCRCwithameanageofdiagnosisat50years.Heterozygotecarriersexhibitathree-foldincreasedriskofCRC.MAPpolyposisincludesconventionaladenomas,serratedadenomas,andhyperplasticpolyps.Afamilyhistoryofpolyposisisrarelyevidentbecauseofanautosomal-recessiveinheritancepattern.Affectedindividualsarealsoatriskforextracolonicneoplasmwithduodenaladenomasfoundin17%toofpatientswitha4%lifetimeriskofduodenalcancer.MAPisalsoassociatedwithlate-onsetgynecologic,urothelial,andskincancers.EtiologyofMUTYH-AssociatedPolyposisgeneencodesaglycosylaseinvolvedinbaseexcisionrepair.deficiencyresultsingeneticinstabilityofthegeneandperhapsothers,including.ThepathogenesisofMAP-relatedtumorsisuniquebuthasoverlapwithFAP,perhapsaccountingforphenotypicsimilarities.DiagnosisofMUTYH-AssociatedPolyposisGenetictestingforMAPshouldbeconsideredinthecaseofclinicallydiagnosedpol-yposiswithoutanidentifiedmutation.Genetictestingisinitiallymutation-specific,because80%ofpatientsexhibitoneoftwomajormutations.Ifamutationisidentified,thensequencingoftheremainingalleleisperformedtoconfirmthepres-enceofbiallelicmutations.Ifaknownmutationisnotidentified,primarysequencingisSurveillanceandSurgicalApproachtoMUTYH-AssociatedPolyposisColonoscopicsurveillanceisrecommendedtostartat25year

sofagewithsurveil-lanceevery1to2yearsandextracolonicscreeningasoutlinedinTable2.Screeningforheterozygotecarriersissimilartopopulationscreeningguidelinesforhigh-riskin-dividuals.IndicationsforsurgicalinterventionandconsiderationsfortypeofresectionaresimilartothoseoutlinedforFAP/AFAP.SERRATEDPOLYPOSISSYNDROMESerratedpolyposissyndrome(SPS)hasanincidenceof1:100,00,0andischaracter-izedbythepresenceofmultipleorlargeserratedpolypsandapredispositiontoCRC.SPSisassociatedwithalifetimeriskofCRCapproaching70%.Thereisnoknownge-neticbasisforSPS,andidentifyingat-riskpatientsislimitedbecauseapositivefamilyhistoryisreportedin0%to59%ofpatientswithoutaconsistentmodeofinheri-Therefore,diagnosisisbasedonspecificclinicalcriteriaoutlinedbytheWorldHealthOrganization(Box3whichunderscoretheconsiderablephenotypicvaria-tionofthecondition(eg,patientsmayhavemultiplelesionsthroughouttheircolonsorfew,large,right-sidedlesionsoncumulativesurveillance).HereditaryColorectalCancerSyndromes Sessileserratedpolyps(SSPs)accountfor25%ofserratedlesionsandseemtobetheprecursorlesionsforSPS-associatedCRC.SSPsareflatwithanoverlyingmucuscapmakingidentificationandcompleteendoscopicclearingchallenging.SSPsaregenerallylocatedintheproximalcolonbutupto30%arefounddistally.associatedCRCscanpresentwithsynchronousand/ormetachronouslesions.Inter-valcancersmostoftenoccurintheproximalcolonandareoftenMSI-highviaanepigeneticallymediatedpathwayinvolvingCpGislandhypermethylation.Thispathwayisdescribedingreaterdetailnext.EtiologyofSerratedPolyposisSyndromeAlthoughnogenemutationhasclearlybeenlinkedtoSPS,theserratedadenoma–car-cinomapathwayiswelldescribed.ThisisanepigeneticallymediatedmechanismwherebyhypermethylationofCpGislandsoccursinthepromoterregionoftumorsup-pressorgenes.Hypermethylationresultsinsilencingofthetumorpromoterregionresult-inginMSI.TumorsarisingviathispathwayarecharacterizedbytheCpGislandmutationphenotype(CIMP-high).CIMP-highphenotypesarefoundin15%to20%ofsporadiccoloncarcinomas.Theserratedadenoma–carcinomapathwayisalsoassociatedwithmethylationofMLH1,whereingenedysfunctionpredisposestodysplasiaandrapidprogressiontocarcinoma,muchlikeMSI-highlesionsseeninHNPCC/Lynchsyn-drome.ThereissignificantheterogeneityinthemolecularprofilesofSSPssuggestingthatotherpathwaysforcarcinogenesisexist(Fig.4KRASmutationsareassociatedwithCIMP-low

,SPS-associatedCRC.GermlinemutationsingenesthatregulatecellularsenescencepathwayshavealsobeenidentifiedinSSPsofpatientswithSPS.ScreeningandSurveillanceforSerratedPolyposisSyndromeSurveillancerecommendationsforpatientswithSPSincludecolonoscopyevery1to3yearsdependingonpolypburden(seeTable2Inat-riskkindred,colonoscopyshouldbeginatage40or10yearsearlierthantheyoungestrelativediagnosedwithSPSifcomplicatedbyCRC,whicheverisearlier.Colonoscopyisrepeatedevery5yearsintheabsenceoffindingsorevery1to3yearsifpolypsareidentified.Althoughbasedonbestavailabledata,screeningguidelinesmayunderdiagnosepatientsresultinginprolongedscreeningintervalsbeforeadiagnosisisrealized,placingpatientsatincreasedriskforintervalcarcinomas.SomearguethatthefindingoftwoormoreserratedlesionsoncolonoscopyqualifiesasscreeningcriteriaforcloseintervalsurveillancedespitenotmeetingWorldHealthOrganizationcriteria.Inaretro-spectivereviewof500patientswithatleasttwoormoreserratedlesions,amedianof Box3WorldHealthOrganizationcriteriafordiagnosisofSPS1.Atleastfiveserratedclasspolypsproximaltothesigmoidofwhichatleasttwoaregreaterthan1cminsize2.Anyserratedclasspolypproximaltothesigmoidinafirst-degreerelativewithSPS20serratedclasspolypsdistributedthroughoutthecolon.SatisfactionofanyoneofthethreecriteriaestablishesthediagnosisofSPS.DatafromSnoverDC,AhnenDJ,BurtRW,etal.Serratedpolypsofthecolonandrectumandserratedpolyposis.In:BosmanFT,CarneiroF,HrubanRH,etal,editors.WHOClassificationofTumoursoftheDigestiveSystem.4thedition.Lyon:IARC;2010.p.160–65.Wells&Wise fourcolonoscopieswasperformedbeforethediagnosisofSPSwasmade.Ofthe40patients(8%)withSPS,onlyonewasdiagnosedatinitialcolonoscopyandall16pa-tientswithCRCwerediagnosedwithSPSatthetimeofcancerdiagnosis.Becauseofthesubtleappearanceofserratedpolyps,chromoendoscopyorvirtualchromoendoscopywithnarrowbandimagingisrecommendedtoaidindetectionoftheselesions.Increasedwithdrawaltimesofatleast9minutesareassociatedwithimprovedadenomadetectionrates.SSPshaveindistinctbordersandcompleteremovaloftheseflatlesionsischallenging.TherateofincompleteresectionforSSPsishigherthanconventionaladenomasat31%versus7.2%.Thismaycontributetothehigherrateofintervalcarcinomaspreviouslydiscussedandemphasizestheneedforshorterscreeningintervalsforlesionsgreaterthan1cm.Inthecaseofnumerous�(5),large�(2cm),ord

ysplasticlesions,someauthorssupporttheuseofserialendo-scopicmucosalresectionevery3to6monthsuntilendoscopicallycleared.SurgicalApproachtoSerratedPolyposisSyndromeSurgicalinterventioniswarrantedwhenthepolypburdenexceedsendoscopicman-agementorwhendysplasia/CRCisdiagnosed.ThereislimitedexperienceregardingthebenefitofsegmentalversusTAC/IRA;however,therateofsynchronousandmeta-chronousCRCapproaches26%,favoringextendedcolectomy.Inthecaseofsegmentalresection,annualcolonoscopyoftheremainingcolonisrecommended.Ifatleasttwosuccessivecolonoscopiesrevealnolesionsgreaterthan1cm,nodysplasticlesions,orthemeannumberandsizeofthelesionsisdeclining,thisintervalcanbeexpandedtoevery2years.SUMMARYInheritedCRCsyndromesareararecauseofCRCwithinthegeneralpopulation.Nevertheless,awarenessoftheseuniquesyndromesleadstoearlydiagnosisandpreventionofcancer-relatedmorbidityandmortalityinaffectedindividualsandfam-ilies.Moreover,screening,counseling,andtestingofat-riskkindredcantranslateintosignificantbenefitacrossmultiplegenerations,emphasizingthetremendousimportanceofunderstandingtheheritablerisksofeachsyndrome.Currently,surgeryisthemainstayofCRCpreventionandtreatmentofallofthesesyndromes.Operative Normal Mucosa Hyperplasc Polyp Sessile Serrated Polyp (SSP) SSP + dysplasia Carcinoma Rapid rate of tumor progression Normal Mucosa Tradional SSP + dysplasia Accumulaon of KRAS mutaons (CIMP-L/MSI-L) AB Fig.4.PathwaysforSPS-associatedcarcinogenesis.()Serratedadenoma-carcinomapathway:hypermethylationofCpGislandsresultsinMSI-H,CIMP-HcarcinomasimilartoLynch-associatedCRC.()KRASserratedpolyppathway:resultinginMSI-L,CIMP-Lcarci-noma.(DatafromSnoverDC,AhnenDJ,BurtRW,etal.Serratedpolypsofthecolonandrectumandserratedpolyposis.In:BosmanFT,CarneiroF,HrubanRH,etal,editors.WHOClassificationofTumoursoftheDigestiveSystem.4thedition.Lyon:IARC;2010.p.160–65.)HereditaryColorectalCancerSyndromes decision-makingmusttakeintoaccountthelife-longcancerriskofeachpatientandbalancethisagainstlong-termfunction.ThepathogenesisofmostheritableCRCsyn-dromesremainspoorlyunderstood.Theuseofcancerregistries,geneticcounselingandtesting,andongoingacademicpursuitsareinstrumentalindefiningthegeneticbasisofthisheterogeneousgroup,broadeningtheunderstandingofuniquegenotype-phenotypeprofiles,andcustomizingtreatmentstrategiesbasedonindivid-ua

lrisk.LichtensteinP,HolmNV,VerkasaloPK,etal.Environmentalandheritablefactorsinthecausationofcancer:analysesofcohortsoftwinsfromSweden,Denmark,andFinland.NEnglJMed2000;343(2):78–85JaspersonKW,TuohyTM,NeklasonDW,etal.Hereditaryandfamilialcoloncan-cer.Gastroenterology2010;138(6):2044–58KohlmannW,GruberSB.Lynchsyndrome[updated2014May22].In:PagonRA,AdamMP,ArdingerHH,etal,editors.GeneReviews[Internet].Seattle(WA):Uni-versityofWashington;2004.p.1993–2016VasenHF,WatsonP,MecklinJP,etal.Newclinicalcriteriaforhereditarynonpo-lyposiscolorectalcancer(HNPCC,Lynchsyndrome)proposedbytheInterna-tionalCollaborativegrouponHNPCC.Gastroenterology1999;116(6):1453–6GuillemJG,CalleJP-L,CelliniC,etal.Varyingfeaturesofearlyage-of-onset“sporadic”andhereditarynonpolyposiscolorectalcancerpatients.DisColonRectum1999;42(1):36–42ProvenzaleD,GuptaS,AhnenDJ,etal.Genetic/familialhigh-riskassessment:colorectalversion1.2016,NCCNclinicalpracticeguidelinesinoncology.JNatlComprCancNetw2016;14(8):1010–30LynchHT,laChapelledeA.Hereditarycolorectalcancer.NEnglJMed2003;SinhaA,TekkisPP,RashidS,etal.Riskfactorsforsecondaryproctectomyinpa-tientswithfamilialadenomatouspolyposis.BrJSurg2010;97(11):1710–5LinKM,ShashidharanM,TernentCA,etal.ColorectalandextracoloniccancervariationsinMLH1/MSH2hereditarynonpolyposiscolorectalcancerkindredsandthegeneralpopulation.DisColonRectum2016;41(4):428–33Al-TassanN,ChmielNH,MaynardJ,etal.InheritedvariantsofMYHassociatedwithsomaticG:CT:Amutationsincolorectaltumors.NatGenet2002;30(2):227–32BurtRW,LeppertMF,SlatteryML,etal.Genetictestingandphenotypeinalargekindredwithattenuatedfamilialadenomatouspolyposis.Gastroenterology2004;JenkinsMA.RiskofcolorectalcancerinmonoallelicandbialleliccarriersofMYHmutations:apopulation-basedcase-familystudy.CancerEpidemiolBiomarkersPrev2006;15(2):312–4EdelsteinDL,AxilbundJ,BaxterM,etal.RapiddevelopmentofcolorectalneoplasiainpatientswithLynchsyndrome.ClinGastroenterolHepatol2011;BoparaiKS,DekkerE,vanEedenS,etal.HyperplasticpolypsandsessileserratedadenomasasaphenotypicexpressionofMYH-associatedpolyposis.Gastroenterology2008;135(6):2014–8LindorNM,PetersenGM,HadleyDW,etal.Recommendationsforthecareofin-dividualswithaninheritedpredispositiontoLynchsyndrome:asystematicre-view.JAMA2006;296(12):1507–17Wells&Wise NielsenM,PoleyJW,VerhoefS,etal.DuodenalcarcinomainMUTYH-as

sociatedpolyposis.JClinPathol2006;59(11):1212–5HampelH,StephensJA,PukkalaE,etal.Cancerriskinhereditarynonpolyposiscolorectalcancersyndrome:laterageofonset.Gastroenterology2005;129(2):VogtS,JonesN,ChristianD,etal.Expandedextracolonictumorspectrum.Gastroenterology2009;137(6):1976–85.e1-e10DowtyJG,WinAK,BuchananDD,etal.CancerrisksforMLH1andMSH2muta-tioncarriers.HumMutat2013;34(3):490–7LiptonL,HalfordSE,JohnsonV,etal.CarcinogenesisinMYH-associatedpolyp-osisfollowsadistinctgeneticpathway.CancerRes2003;63(22):7595–9WinAK,LindorNM,YoungJP,etal.RisksofprimaryextracoloniccancersfollowingcolorectalcancerinLynchsyndrome.JNatlCancerInst2012;PlaschkeJ.Lowerincidenceofcolorectalcancerandlaterageofdiseaseonsetin27familieswithpathogenicMSH6germlinemutationscomparedwithfamilieswithMLH1orMSH2Mutations:theGermanHereditaryNonpolyposisColorectalCancerConsortium.JClinOncol2004;22(22):4486–94HendriksYMC,WagnerA,MorreauH,etal.Cancerriskinhereditarynonpolypo-siscolorectalcancerduetoMSH6mutations:impactoncounselingandsurveil-lance.Gastroenterology2004;127(1):17–25ParkYJ,ShinKH,ParkJG.Riskofgastriccancerinhereditarynonpolyposiscolo-rectalcancerinKorea.ClinCancerRes2000;6(8):2994–8FeltonK,GilchristDM,AndrewSE.ConstitutivedeficiencyinDNAmismatchrepair:isittimeforLynchIII?ClinGenet2007;71(6):499–500WijnenJ,KhanPM,VasenH,etal.HereditarynonpolyposiscolorectalcancerfamiliesnotcomplyingwiththeAmsterdamcriteriashowextremelylowfrequencyofmismatch-repair-genemutations.AmJHumGenet1997;61:329–35UmarA,BolandCR,TerdimanJP,etal.RevisedBethesdaguidelinesforhered-itarynonpolyposiscolorectalcancer(LynchSyndrome)andmicrosatelliteinsta-bility.JNatlCancerInst2004;96(4):261–8BolandCR,ShikeM.ReportfromtheJerusalemworkshoponLynchsyndrome-hereditarynonpolyposiscolorectalcancer.Gastroenterology2010;138(7):2197.e1–7SjursenW,HaukanesBI,GrindedalEM,etal.CurrentclinicalcriteriaforLynchsyndromearenotsensitiveenoughtoidentifyMSH6mutationcarriers.JMedGenet2010;47(9):579–85EvaluationofGenomicApplicationsinPracticeandPrevention(EGAPP)WorkingGroup.RecommendationsfromtheEGAPPWorkingGroup:genetictestingstra-tegiesinnewlydiagnosedindividualswithcolorectalcanceraimedatreducingmorbidityandmortalityfromLynchsyndromeinrelatives.GenetMed2009;MolineJ,MahdiH,YangB,etal.ImplementationoftumortestingforLynchsyn-dromeinendometrialcancersatalargeaca

demicmedicalcenter.GynecolOn-col2013;130(1):121–6MoreiraL,BalaguerF,LindorN,etal.IdentificationofLynchsyndromeamongpatientswithcolorectalcancer.JAMA2012;308(15):1555ChenY-E,KaoS-S,ChungR-H.Cost-effectivenessanalysisofdifferentgenetictestingstrategiesforLynchsyndromeinTaiwan.PLoSOne2016;11(8):e0160599SeverinF,StollenwerkB,Holinski-FederE,etal.EconomicevaluationofgeneticscreeningforLynchsyndromeinGermany.GenetMed2015;17(10):765–73HereditaryColorectalCancerSyndromes ShiaJ.Immunohistochemistryversusmicrosatelliteinstabilitytestingforscreeningcolorectalcancerpatientsatriskforhereditarynonpolyposiscolorectalcancersyndrome.PartI.Theutilityofimmunohistochemistry.JMolDiagn2008;BolandCR,ThibodeauSN,HamiltonSR,etal.ANationalCancerInstitutework-shoponmicrosatelliteinstabilityforcancerdetectionandfamilialpredisposition:developmentofinternationalcriteriaforthedeterminationofmicrosatelliteinsta-bilityincolorectalcancer.CancerRes1998;58(22):5248–57HegdeM,FerberM,MaoR,etal.ACMGtechnicalstandardsandguidelinesforgenetictestingforinheritedcolorectalcancer(Lynchsyndrome,familialadenoma-touspolyposis,andMYH-associatedpolyposis).GenetMed2014;16(1):101–16LindorNM,RabeK,PetersenGM,etal.LowercancerincidenceinAmsterdam-Icriteriafamilieswithoutmismatchrepairdeficiency:familialcolorectalcancertypeX.JAMA2005;293(16):1979–85StoffelEM,ChittendenA.Genetictestingforhereditarycolorectalcancer:chal-lengesinidentifying,counseling,andmanaginghigh-riskpatients.Gastroenter-ology2010;139(5):1436–41.e1NiessenRC,HofstraRMW,WestersH,etal.GermlinehypermethylationofMLH1andEPCAMdeletionsareafrequentcauseofLynchsyndrome.GenesChromo-somesCancer2009;48(8):737–44NagasakaT,RheesJ,KloorM,etal.SomatichypermethylationofMSH2isafrequenteventinLynchsyndromecolorectalcancers.CancerRes2010;70(8):BouzoureneH,HutterP,LosiL,etal.SelectionofpatientswithgermlineMLH1mutatedLynchsyndromebydeterminationofMLH1methylationandBRAFmu-tation.FamCancer2009;9(2):167–72SyngalS,BrandRE,ChurchJM,etal.ACGclinicalguideline:genetictestingandmanagementofhereditarygastrointestinalcancersyndromes.AmJGastroen-terol2015;110(2):223–62rvinenHJ,Renkonen-SinisaloL,Aktan-CollanK,etal.TenyearsaftermutationtestingforLynchsyndrome:cancerincidenceandoutcomeinmutation-positiveandmutation-negativefamilymembers.JClinOncol2009;27(28):4793–7NatarajanN,WatsonP,Silva-LopezE

,etal.ComparisonofextendedcolectomyandlimitedresectioninpatientswithLynchsyndrome.DisColonRectum2010;ParryS,WinAK,ParryB,etal.Metachronouscolorectalcancerriskformismatchrepairgenemutationcarriers:theadvantageofmoreextensivecolonsurgery.Gut2011;60(7):950–7MaedaT,CannomRR,BeartRW,etal.Decisionmodelofsegmentalcomparedwithtotalabdominalcolectomyforcoloncancerinhereditarynonpolyposiscolo-rectalcancer.JClinOncol2010;28(7):1175–80rvinenHJ.EpidemiologyoffamilialadenomatouspolyposisinFinland:impactoffamilyscreeningonthecolorectalcancerrateandsurvival.Gut1992;33(3):AretzS,UhlhaasS,CaspariR,etal.FrequencyandparentaloriginofdenovoAPCmutationsinfamilialadenomatouspolyposis.EurJHumGenet2004;BisgaardML,FengerK,BulowS,etal.Familialadenomatouspolyposis(FAP):frequency,penetrance,andmutationrate.HumMutat1994;3:121–3lowS.Resultsofnationalregistrationoffamilialadenomatouspolyposis.GutWells&Wise MallinsonEKL,NewtonKF,BowenJ,etal.Theimpactofscreeningandgeneticregistrationonmortalityandcolorectalcancerincidenceinfamilialadenomatouspolyposis.Gut2010;59(10):1378–82SpigelmanAD,WilliamsCB,TalbotIC,etal.Uppergastrointestinalcancerinpa-tientswithfamilialadenomatouspolyposis.Lancet1989;2(8666):783–5SinhaA,TekkisPP,GibbonsDC,etal.Riskfactorspredictingdesmoidoccur-renceinpatientswithfamilialadenomatouspolyposis:ameta-analysis.Colo-rectalDis2010;13(11):1222–9NieuwenhuisMH,LefevreJH,BulowS,etal.Familyhistory,surgery,andAPCmutationareriskfactorsfordesmoidtumorsinfamilialadenomatouspolyposis:aninternationalcohortstudy.DisColonRectum2011;54(10):1229–34ChurchJ,XhajaX,LaGuardiaL,etal.Desmoidsandgenotypeinfamilialadeno-matouspolyposis.DisColonRectum2015;58(4):444–8GroenEJ,RoosA,MuntingheFL,etal.Extra-intestinalmanifestationsoffamilialadenomatouspolyposis.AnnSurgOncol2008;15(9):2439–50KuboK,MiyataniH,TakenoshitaY,etal.Widespreadradiopacityofjawbonesinfamilialadenomatosiscoli.JCraniomaxillofacSurg1989;17(8):350–3BalaguerF,LeozM,CarballalS,etal.Thegeneticbasisoffamilialadenomatouspolyposisanditsimplicationsforclinicalpracticeandriskmanagement.ApplClinGenet2015;8:95–107CaspariR,FriedlW,MandlM,etal.Familialadenomatouspolyposis:mutationatcodon1309andearlyonsetofcoloncancer.Lancet1994;343(8898):629–32NieuwenhuisMH,VasenHFA.CorrelationsbetweenmutationsiteinAPCandphenotypeoffamilialadenomatouspolyposis(FAP):areviewoftheli

terature.CritRevOncolHematol2007;61(2):153–61RipaR,BisgaardML,BulowS,etal.Denovomutationsinfamilialadenomatouspolyposis(FAP).EurJHumGenet2002;10(10):631–7HoJW,ChuKM,TseCW.PhenotypeandmanagementofpatientswithfamilialadenomatouspolyposisinHongKong:perspectiveofthehereditarygastrointes-tinalcancerregistry.HongKongMedJ2002;8(5):342–7BjorkJ,AkerbrantH,IseliusL,etal.Epidemiologyoffamilialadenomatouspol-yposisinSweden:changesovertimeanddifferencesinphenotypebetweenmalesandfemales.ScandJGastroenterol1999;34(12):1230–5AretzS,UhlhaasS,GoergensH,etal.MUTYH-associatedpolyposis:70of71pa-tientswithbiallelicmutationspresentwithanattenuatedoratypicalphenotype.IntJCancer2006;119(4):807–14BusseyH.Familialpolyposiscoli:familystudies,histopathology,differentialdiag-nosis,andresultsoftreatment.Baltimore(MD):JohnsHopkinsUniversityPress;VasenHFA,MosleinG,AlonsoA,etal.Guidelinesfortheclinicalmanagementoffamilialadenomatouspolyposis(FAP).Gut2008;57(5):704–13HerendeenJM,LindleyC.UseofNSAIDsforthechemopreventionofcolorectalcancer.AnnPharmacother2003;37(11):1664GiardielloFM,HamiltonSR,KrushAJ.Treatmentofcolonicandrectaladenomaswithsulindacinfamilialadenomatouspolyposis.NEnglJMed1993;328(18):SteinbachG,LynchPM,PhillipsRK,etal.Theeffectofcelecoxib,acyclooxygenase-2inhibitor,infamilialadenomatouspolyposis.NEnglJMed2000;342(26):1946–52NugentKP,FarmerKC,SpigelmanAD,etal.Randomizedcontrolledtrialoftheeffectofsulindaconduodenalandrectalpolyposisandcellproliferationinpa-tientswithfamilialadenomatouspolyposis.BrJSurg1993;80(12):1618–9HereditaryColorectalCancerSyndromes O’BrienD.Polypsintheilealpouch.ClinColonRectalSurg2008;21(04):300–3SamadderNJ,NeklasonDW,BoucherKM,etal.Effectofsulindacanderlotinibvsplaceboonduodenalneoplasiainfamilialadenomatouspolyposis.JAMACamposFG.Surgicaltreatmentoffamilialadenomatouspolyposis:dilemmasandcurrentrecommendations.WorldJGastroenterol2014;20(44):16620LovegroveRE,ConstantinidesVA,HeriotAG,etal.Acomparisonofhand-sewnversusstapledilealpouchanalanastomosis(IPAA)followingproctocolectomy.AnnSurg2006;244(1):18–26ChambersWM,McCMortensenNJ.Shouldilealpouch-analanastomosisincludemucosectomy?ColorectalDis2007;9(5):384–92FazioVW,KiranRP,RemziFH,etal.Ilealpouchanalanastomosis.AnnSurgAzizO,AthanasiouT,FazioVW,etal.Meta-analysisofobservationalstudiesofileorectalversusilealpouch–analanastom

osisforfamilialadenomatouspolypo-sis.BrJSurg2006;93(4):407–17SoraviaC,KleinL,BerkT,etal.Comparisonofilealpouch-analanastomosisandileorectalanastomosisinpatientswithfamilialadenomatouspolyposis.DisColonRectum1999;42(8):1028–33[discussion1033–4]OlsenKO,JuulS,BulowS,etal.Femalefecunditybeforeandafteroperationforfamilialadenomatouspolyposis.BrJSurg2003;90(2):227–31BurtR,NeklasonDW.Genetictestingforinheritedcoloncancer.Gastroenter-ology2005;128(6):1696–716Rodriguez-MorantaF,Rodriguez-AlonsoL,GuardiolaCaponJ.Serratedpolypo-sissyndrome.CirEsp2014;92(10):643–4RostyC,ParryS,YoungJP.Serratedpolyposis:anenigmaticmodelofcolorectalcancerpredisposition.PathologResInt2011;2011(4):1–13SnoverDC,AhnenDJ,BurtRW,etal.Serratedpolypsofthecolonandrectumandserrated(“hyperplastic”)pol-yposis.In:BosmanST,CarneiroF,HrubanRH,etal,editors.WHOClassificationoftumoursofthedigestivesystem.Berlin:Springer-Verlag;2010LangnerC.Serratedandnon-serratedprecursorlesionsofcolorectalcancer.DigDis2015;33(1):28–37KanthP,BronnerMP,BoucherKM,etal.Genesignatureinsessileserratedpolypsidentifiescoloncancersubtype.CancerPrevRes(Phila)2016;9(6):AndersonJC.Pathogenesisandmanagementofserratedpolyps:currentstatusandfuturedirections.GutLiver2014;8(6):582–9RostyC,WalshMD,WaltersRJ,etal.Multiplicityandmolecularheterogeneityofcolorectalcarcinomasinindividualswithserratedpolyposis.AmJSurgPatholElorzaG,EnrsJM,BujandaL,etal.Phenotypecharacteristicsofpatientswithcolonicserratedpolyposissyndrome:astudyof23cases.CirEspGalaMK,MizukamiY,LeLP,etal.Germlinemutationsinoncogene-inducedsenescencepathwaysareassociatedwithmultiplesessileserratedadenomas.Gastroenterology2014;146(2):520–9HuiVW,SteinhagenE,LevyRA,etal.Utilizationofcolonoscopyandpathologyreportsforidentifyingpatientsmeetingtheworldhealthorganizationcriteriaforserratedpolyposissyndrome.DisColonRectum2014;57(7):846–50Wells&Wise ButterlyL,RobinsonCM,AndersonJC,etal.Serratedandadenomatouspolypdetectionincreaseswithlongerwithdrawaltime:resultsfromtheNewHampshirecolonoscopyregistry.AmJGastroenterol2014;109(3):417–26PohlH,SrivastavaA,BensenSP,etal.Incompletepolypresectionduringcolo-noscopy:resultsofthecompleteadenomaresection(CARE)study.Gastroenter-ology2013;144(1):74–80.e1HassanC,RepiciA,RexDK.Serratedpolyposissyndrome:riskstratificationorreduction?Gut2016;65(7):1070–2HereditaryColorect