w w w . j c o l . o r g . b r
Journal
of
Coloproctology
Original
Article
Current
evidence
for
universal
molecular
testing
for
colorectal
cancer
patients
Fábio
Guilherme
Campos
a,∗,
Marleny
Novaes
Figueiredo
a,
Carlos
Augusto
Real
Martinez
b,caUniversidadedeSãoPaulo(USP),FaculdadedeMedicina,DepartamentodeGastroenterologia,DivisãodeCirurgiaColorretal,São
Paulo,SP,Brazil
bUniversidadeSãoFrancisco(USF),ProgramadePós-graduac¸ãoemCiênciasdaSaúde,Braganc¸aPaulista,SP,Brazil cUniversidadeEstadualdeCampinas(Unicamp),FaculdadedeCiênciasMédicas,SãoPaulo,SP,Brazil
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Articlehistory:
Received6June2017 Accepted26June2017 Availableonline11July2017
Keywords:
LynchSyndrome Genetics Screening Colorectalcancer Testing
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c
t
Background:RiskassessmentforLynchSyndromemaybeacomplexandchallengingtask. DemonstrationofgermlinemutationshasthebenefitsofconfirmingLynchSyndrome diag-nosisandmayalsoprovidescreeningandsurgicalorientationforaffectedmembersand relieffornon-affectedrelatives.
Objective:ThepresentpaperaimedtocriticallyreviewthecriteriatodiagnoseLynch Syn-drome,focusingtheattentiononthenewperspectiveofadoptinguniversalscreeningfor patientsdiagnosedwithcolorectalcancer.
Methods:Weperformedaliteraturereviewabouttherationaleandpreliminaryresultsof universaltestingforLynchSyndrome.
Results:TheuseofselectiveeligibilitycriteriatodeterminewhoshouldundergoLynch Syn-drometestingmayfailinasubstantialproportionofcases.Moreover,universalstrategy isfeasible,cost-effectiveandmoresensitivethanpreviousmethods.However,therestill existproblemsregardingclinicalpracticeimplementationandcomplianceeitherbymedical doctorsandpatients.
Conclusions:Standardguidelinesforcolorectalcancerscreeningarenot idealtoprovide earlydetectionofLynchSyndromepatients.Andalthoughuniversalscreeninghasbeen associatedwithanincreasedidentificationofLynchSyndromepatients,asuccessful imple-mentationofthisapproachisstilllimitedbythelackofclinicalexpertiseamongphysicians, andalsorequiresstandardizationoftheexistingprotocolsforroutinegeneticscreening.
©2017SociedadeBrasileiradeColoproctologia.PublishedbyElsevierEditoraLtda.This isanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/
licenses/by-nc-nd/4.0/).
∗ Correspondingauthor.
E-mail:fgmcampos@terra.com.br(F.G.Campos).
http://dx.doi.org/10.1016/j.jcol.2017.06.003
Evidências
atuais
para
testes
moleculares
universais
para
pacientes
com
câncer
colorretal
Palavras-chave:
SíndromedeLynch Genética
Triagem Câncercolorretal Testes
r
e
s
u
m
o
Introduc¸ão: Aavaliac¸ãoderiscoparasíndromedeLynch(SL)podesertarefacomplexae desafiadora.Ademonstrac¸ãodemutac¸õesnalinhagerminalresultaembenefícios,comoa confirmac¸ãododiagnósticodeSLetambémpodeproporcionarorientac¸õesparaatriageme procedimentoscirúrgicosparaosmembrosafetados,alémdetrazeralívioparaosparentes nãoafetados.
Objetivo: Esteartigoteveporobjetivooferecerumarevisãocríticadoscritériosparao diag-nósticodeSL,comenfoquenaatenc¸ãosobrea novaperspectivadeadoc¸ãodatriagem universalparapacientesdiagnosticadoscomcâncercolorretal(CCR).
Métodos: Procedemosaumarevisãodaliteraturacomênfasenasjustificativaseresultados preliminaresdetestesuniversaisparaSL.
Resultados:Ousodecritériosseletivosdequalificac¸ão,comvistasadeterminarquemdeveria passarporumtesteparaSL,podesermalsucedidoemsubstancialpercentualdecasos.Foi tambémconstatadoqueaestratégiauniversaléexequível,combomcusto-benefícioecom maiorsensibilidade,emcomparac¸ãocomosmétodospreviamenteutilizados.Contudo, aindaexistemproblemasconcernentesàsuaimplementac¸ãonapráticaclínicaetambém nacooperac¸ãodemédicosedepacientes.
Conclusões:Asorientac¸õespadronizadasparaatriagemdeCCRnãosãoideais,emtermosde seobteraimediatadetecc¸ãodepacientescomSL.Poroutrolado,emboraatriagemuniversal tenhasidoassociadaaumaumentonaidentificac¸ãodepacientescomSL,abem-sucedida implementac¸ãodessaabordagemficaaindalimitadapelapoucaexperiênciaclínicaentreos médicose,alémdisso,tambémháanecessidadedepadronizac¸ãodosprotocolosexistentes paraatriagemgenéticaderotina.
©2017SociedadeBrasileiradeColoproctologia.PublicadoporElsevierEditoraLtda.Este ´eumartigoOpenAccesssobumalicenc¸aCCBY-NC-ND(http://creativecommons.org/
licenses/by-nc-nd/4.0/).
Introduction
Thecomprehensionandinterpretation ofmolecular mech-anisms involved in colorectal cancer (CRC) carcinogenesis haveimproved alot duringthe recent decades.In the era ofpersonalizedmedicine,thetranslationofalltheacquired knowledgeintoclinicalpracticerepresentsamajoradvance and a very important tool in screening and management ofthe disease.1 In this setting,stratification ofpatients at riskthroughdetectionofgermlinemutationsimplicatedin hereditarysyndromesiscrucialasitmayinfluenceclinical decision-makingandcancersurveillancefortheirrelatives. ThisisespeciallytruetoLynchSyndrome(LS)patients,the mostcommonhereditaryCRCsyndrome(onein35patients withCRC),comprising3–5%ofallCRCburdens.2–4
Since Aldred Scott Warthin concluded that there was “some influence of heredity on cancer” in his 1895 manuscript,5LShasbeentheobjectofmanyinvestigations andreceiveddifferentnomenclatureovertime(cancerfamily syndrome,hereditarynonpolyposis colorectalcancer).Nowadays, theeponymLSrendersanhomagetoDr.HenryLynchafter his1966seminalpaperthatcomprehensivelydescribedthis conditionashavinganautosomal-dominantinheritance pat-ternandanearlyageofonset(averageageatonset<45years) andinvolvingadenocarcinomasofthecolon,endometrium, andstomach.6
Main
characteristics
of
Lynch
Syndrome
LSisadisordercausedbyagermlinemutationsinamismatch repair(MMR) gene(MLH1,MSH2, MSH6andPMS2) or dele-tion inthe epithelial cell adhesionmolecule(EPCAM) gene leading tothe closelylinkedMSH2 lossofexpression. Pro-teinsrelatedtothesegenesmayrecognizenucleotidesthat havebeeninadequatelyincorporated.Thus,theabsence(or inactivation) ofsuchproteinsare leadstoaccumulationof cellularmutationsandavariablelifetimeriskofCRC.7 Con-sequently,CRCscreeninginthispopulationisfundamental, asthosepatientsdevelopCRCearlierthannormalsubjects (meanage44–61years).InMLH1andMSH2mutationcarriers, thisriskapproaches30–74%ofpatients,whilelowerfigures werereportedamongwomen(30–52%),inpatientswithMSH6
(10–22%)orPMS2(15–20%)mutations.8
Therealsoexistsamodestincreasedriskofextracolonic cancersarisinginthe stomach,ovaries,smallbowel, hepa-tobiliaryepithelium,urinarytractandsebaceousglands.8,11 Particularly,femaleswithLShavea28–60%lifetimeriskfor endometrialcancer(EC),sotheyareadvisedtoperformannual pelvicexamination/endometrialsamplingafter30–35yearsof age.10,11
Overtheyears,manyinstitutionshaveabandoned tradi-tionalscreeningprogramsinfavorofauniversal screening approach.Forthisreason,itisnownecessarytodiscussissues abouttheviabilityofperformingandimplementingstrategies ofuniversaltumorscreeningforallCRCpatients.
Problems
and
limitations
to
identify
Lynch
Syndrome
patients
TheidentificationofpatientscarryingMMRgenemutations isofcrucialimportanceforcancersurveillanceand preven-tivemeasures. AlthoughpatientswithCRCor ECrepresent the most effective way to identifyLS, specific educational programsdirectedtothegeneralpopulationandphysicians wouldprobablyincreasetheirawarenessregardinghereditary CRC,withpositiveeffectsonLSidentification.
RiskassessmentforLSmaybeacomplexand challeng-ingtaskevenforphysiciansspecializedinfamilialcancer,as theybelieveLSisprobablyunderdiagnosed.12Thisperception comesfromthe recognitionthatalmost 28%ofLSpatients maybemissedduetothelowsensitivityandefficiencyofthe currentusedstrategies.13–15 Moreover,LSdiagnosispresents otherlimitationsregardingterminology,patientacceptance, publichealthimplicationsandcostofgenetictests. Neverthe-less,someofthesebarriershavebeensurpassedindifferent ranges.
Firstofall,wehavetoknowwhatwearetalkingabout. Differentterminologyisusedtoseparatepatientswith dis-tinct clinicalfeatures when comparedtoLS.16 Thus, while hereditarynon-polyposis colorectal cancer definespatients presentingAmsterdamcriteria,LSisreservedonlyforthose exhibitingMMRorEPCAMgenemutations.Toaddmore con-fusion,patientspresentingmicrosatelliteinstability(MSI)or immunohistochemistry(IHC)abnormalitiesbutnogermline mutations are referred as Lynch-like syndrome. And finally, thosewithAmsterdamcriteriawithoutMSIintumortestare classifiedasFamilialColorectalCancerTypeX.
LSpatientsmay beidentifiablewiththeaid ofdifferent approachessuchasclinical data,predictionmodels, tumor testing,germlinetesting,and universaltesting.10 Tradition-ally, indications foreither tumor or germline testing were basedoncriteriaderivedfromexpertconsensus(Amsterdam Criteriaor BethesdaGuidelines). TheAmsterdam Criteria17 requirestheattainmentofadetailedfamilyhistoryand sen-sitivity is less than 50%, besides being broadened in 1999 toincorporateextracolonictumors.4,18 Due tolossof iden-tification ofagreatnumber ofmutationcarriers, Bethesda guidelines were proposed in 1997and revised in 200419 to includefamilyhistoryandspecificpathologicfeaturesofCRC. Theywere lessrestrictive andpresentedsensitivitygreater than72%.4
ItiswellrecognizedthatsomeLSfamiliesmaynotmeet both criteria and guidelines. Conversely, despite meeting them, some families will not express germline alterations in any MMR genes. Moreover,family history isnot always available.Consequently,theirusehaverenderedcriticismand limitedimplementationofthesecriteriainclinicalpractice.
Thedemonstrationofgermlinemutationsbytumor test-inghasthebenefitsofconfirmingLSdiagnosisand,doingso, itmayprovidescreeningandsurgicalorientationforaffected members andrelieffornon-affectedrelatives.7 Tumor test-ing ismadebypolymerase chainreaction (PCR)toidentify MSI,and/orIHCtodetectproteinproductsexpressedbyMMR genes.
MSItumorswithlossofMLH1proteinarelikelysecondary tosomaticevents,whilelossofMSH2, MSH6or PMS2 pro-teins are likely from a germline mutation.7 As 10–15% of sporadicCRCsmayalsoexhibitMSI,MSI+patientswithno MLH1expressionaresuggestedtoundergoadditionaltumor testing (BRAF),asthis occursin75%ofcasesasaresultof somaticpromoterhypermethylation.20Thereisastrong con-cordancebetweenbothtests,withspecificitycloseto90%.21 WhileMSIanalysispresents93%sensitivityindetectingMMR deficiencyinMMRmutationcarriers,IHC testingallowsfor targetmutationanalysis.10
Rationaleandperspectivesofuniversaltesting
Occasionally, the consequenceofanunexpectedCRC diag-nosis in a young patient in a non-suspected LS family is inappropriate management (partial resection of colon, non-indicationofaprophylactichysterectomyorlackof extra-colonictumorsscreening).Moreover,relativesatriskwould not be advised to undergo genetic testing. This scenario explainswhytheideaofexploringsystematictestingforLS independentofclinicalcriteriahasgainedincreasing accep-tanceintheliterature.
ThestrategyofscreeningallcasesofnewlydiagnosedCRC forLShasbeenreferredtoas“universalscreening”.4,22–26In 2005,Hampeletal.24reportedthatamong2.8%ofLSpatients diagnosedbyuniversalscreening,halfofthemhadmorethan 50yearsofage,and25%didnotmeeteitherAmsterdamor the revised Bethesdacriteria. Later in2009, the Evaluation ofGenomicApplicationsinPracticeandPrevention(EGAPP) Working Group (EWG) incorporated the suggestion of the JerusalemWorkshoptoperformroutinegenetictestingforall CRCsinpatientsyoungerthan70years.27Thisindependent group(EWG)formedbymultidisciplinaryexpertspublished anevidence-basedrecommendationtoperformscreeningfor LSonallnewlydiagnosedCRCbyPCR-basedMSItestingor IHC,inordertoreducemorbidityandmortalityamongtheir relatives.28
Progressively,the 2009 EGAPP proposition received sup-portfrom manyexpertswhobelieved thatimplementation ofuniversalLSscreeningonapopulationlevelisworth pur-suing.Ithasbeendemonstratedthatthebenefitsoutweighs harms,20,32,33andthatitishighlycost-effective.22,23 Follow-ingthistendency,someleadingcancerinstitutionsandpublic healthagenciescreatedtheLynchSyndromeScreening Net-work(LSSN)in2011.ThemainpurposewastoimplementLS screeningforbothCRCandECs.Accordingtothisproject,the involvedentitiesareencouragedtoshareresources,protocols anddata;moreover,accesstoexpertsinLSscreeningshould befacilitated.34
Thefeasibilityandeffectivenessofsuchprogramarewell observed in an interesting publication from the Cleveland Clinic,wheretheImplementationofuniversalMSI/IHC,along witheffectivemultidisciplinarycommunicationandplansof responsibilityforpatientcontact,resultedinincreased iden-tificationofpatientswithLS.32
InEurope, the Mallorca group(formed by35 specialists from13countries)recentlypublishedtherevisedguidelines fortheclinicalmanagementofLS,recommendingtoperform analysisofallCRCyoungerthan70yearsbyIHCofthefour MMR proteins (MLH1/MSH2/MSH6/PMS2) or MSI.35 Tumors thatdemonstratelossofMLH1shouldundergoBRAFtesting orMLH1promoterhypermethylationanalysis.Thisstatement wasfurtherincorporatedintheupdatedNCCNguidelinesfor Genetic/Familial-RiskAssessment.36
TheUSMulti-SocietyTaskForceonCRChasalsoendorsed this change toward universal LS screening.10 This group emphasizedtheneedforappropriateinfrastructureandthe opportunity to perform the tumor testing on preoperative biopsyspecimens,inordertofacilitatetumortesting. Proba-bly,thislevelIIIevidencemayhelpstandardizetheexisting protocols for routine LSgenetic screening withinUS, as a previousevaluationin2010showedavariablescenario char-acterizedbythe use different combinations ofpreliminary tumortesting(e.g.,MSIonly,IHConly,MSIandIHC,andIHC withBRAF),aswellasnon-uniformpatient/familyconsentand follow-upprocedures.36
However, it should be acknowledged that a success-ful implementation of such recommendations might face manychallenges.Firstly,the mostsignificantbarrieristhe general lack of clinical expertise regarding genetic tests among physicians Laura Valle, fact that raises the need forimprovingtheawarenessandcomprehensionofgenetic testsamongcancercareproviders.37Forthismatter, educa-tionalmaterialcontainingupdatedinformationshouldbealso developed.Secondly, indicationofthese testsrequires pre-and post-counseling, inorder todiscuss and explain clini-cal,psychosocial,financial,andethicalissuesthatmaycome upduringthis process.10 Thus,cooperationand integration amongtheinvolvedspecialists(gastroenterologist,colorectal surgeon,gynecologists,geneticist,geneticcounselor, oncol-ogist, etc.) is essential. Other important issues include populationaccess, costsand protocols standardization.11,32 Additionally,oneshouldrecognizethatestimatesofbenefit mightbecompromisedinfamilieswithlowerpenetranceand laterageofonset(suchasMSH6andPMS2mutationcarriers). In summary,standard guidelines forCRC screening are not safe to provide early detection or prevention for LS
malignancies, mainly becausethey usuallyoccur atyoung ages.Otherwise,theuniversalLSscreeningstrategyismore sensitive than previous methods and may have several potential benefits. Unfortunately, the many difficulties to implementitinclinicalpracticehasmadecompliancewith thisideaspottyatbest.25Thescientificcommunityand gov-ernmentinstitutionsshouldfocustheireffortstodiscusshow universal screeningshould beperformed, rather than if it shouldbedone.Thetaskistopushresearchandclinical set-tingfeasibilitytothepopulationlevel.Forthefuture,thereis alsohopeforgreateravailabilityanddecreasedcostsofpanel testingforgermlinemutationsingenesinvolvedin carcino-genesis.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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e
s
1.PritchardCC,GradyWM.Colorectalcancermolecularbiology
movesintoclinicalpractice.Gut.2011;60:116–29.
2.BarnetsonRA,TenesaA,FarringtomSM,NichollID,
CetnarskyjR,PorteousME,etal.Identificationandsurvivalof
carriersofmutationsinDNAmismatch-repairgenesincolon
cancer.NEnglJMed.2006;354:2751–63.
3.Pi ˜nolV,CastellsA,AndreuM,Castellví-BelS,AlendaC,LlorX,
etal.,GastrointestinalOncologyGroupoftheSpanish
GastroenterologyAssociation.Accuracyof
immunohistochemistryfortheidentificationofpatientswith
hereditarynonpolyposiscolorectalcancer.JAMA.
2005;293:1986–94.
4.HampelH,FrankelWL,MartinE,ArnoldM,KhandujaK,
KueblerP,etal.FeasibilityofscreeningforLynchSyndrome
amongpatientswithcolorectalcancer.JClinOncol.
2008;26:5783–8.
5.WarthinAS.Hereditywithreferencetocarcinomaasshown
bythestudyofthecasesexaminedinthepathological
laboratoryoftheUniversityofMichigan,1895–1913.Arch
InternMed.1913;12:546–55.
6.LynchHT,ShawMW,MagnusonCW,LarsenAL,KrushAJ.
Hereditaryfactorsincancer.Studyoftwolargemidwestern
kindreds.ArchInternMed.1966;117:206–12.
7.BaiocchiGL,PortolaniN,VermiW,BaronchelliC,GhezaF,
ZognoC,etal.LynchSyndromefromasurgeonperspective:
retrospectivestudyofclinicalimpactofmismatchrepair
proteinexpressionanalysisincolorectalcancerpatientsless
than50yearsold.BMCSurg.2014;14:9.
8.SehgalR,SheahanK,O’ConnellPR,HanlyAM,MartinST,
WinterDC.LynchSyndrome:anupdatedreview.Genes.
2014;5:497–507.
9.DeJongAE,MorreauH,vanPuijenbroekM,EilersPH,Wijnen
J,NagengastFM,etal.Theroleofmismatchrepairgene
defectsinthedevelopmentofadenomasinpatientswith
HNPCC.Gastroenterology.2004;126:42–8.
10.GiardielloFM,AllenJI,AxilbundJE,BolandCR,BurkeCA,Burt
RW,etal.Guidelinesongeneticevaluationandmanagement
ofLynchSyndrome:aconsensusstatementbytheUS
Multi-SocietyTaskForceoncolorectalcancer.DisColon
Rectum.2014;57:1025–48.
11.BellcrossCA,BedrosianSR,DanielsE,DuquetteD,HampelH,
JaspersonK,etal.ImplementingscreeningforLynch
cancer:summaryofapublichealth/clinicalcollaborative
meeting.GenetMed.2012;14:152–62.
12.TranøG,WasmuthHH,SjursenW,HofsliE,VattenLJ.
Awarenessofheredityincolorectalcancerpatientsis
insufficientamongclinicians:aNorwegianpopulation-based
study.ColorectalDis.2009;11:456–61.
13.JuliéC,TrésalletC,BrouquetA,VallotC,ZimmermannU,
MitryE,etal.Identificationindailypracticeofpatientswith
LynchSyndrome(hereditarynonpolyposiscolorectalcancer):
revisedBethesdaguidelines-basedapproachversus
molecularscreening.AmJGastroenterol.2008;103:2825–35.
14.vanLierMG,LeenenCH,WagnerA,RamsoekhD,DubbinkHJ,
vandenOuwelandAM,etal.,LIMOStudyGroup.Yieldof
routinemolecularanalysesincolorectalcancerpatients
≤70yearstodetectunderlyingLynchSyndrome.JPathol.
2012;226:764–74.
15.Pérez-CarbonellL,Ruiz-PonteC,GuarinosC,AlendaC,Payá
A,BreaA,etal.Comparisonbetweenuniversalmolecular
screeningforLynchSyndromeandrevisedBethesda
guidelinesinalargepopulation-basedcohortofpatientswith
colorectalcancer.Gut.2012;61:865–72.
16.ValleL.Geneticpredispositiontocolorectalcancer:wherewe
standandfutureperspectives.WorldJGastroenterol.
2014;20:9828–49.
17.VasenHF,WatsonP,MecklinJP,LynchHT.Newclinicalcriteria
forhereditarynonpolyposiscolorectalcancer(HNPCC,Lynch
Syndrome)proposedbytheInternationalCollaborativegroup
onHNPCC.Gastroenterology.1999;116:1453–6.
18.SalovaaraR,LoukolaA,KristoP,KääriäinenH,AhtolaH,
EskelinenM,etal.Population-basedmoleculardetectionof
hereditarynonpolyposiscolorectalcancer.JClinOncol.
2000;18:2193–200.
19.UmarA,BolandCR,TerdimanJP,SyngalS,delaChapelleA,
RüschoffJ,etal.RevisedBethesdaGuidelinesforhereditary
nonpolyposiscolorectalcancer(LynchSyndrome)and
microsatelliteinstability.JNatlCancerInst.2004;96:261–8.
20.delaChapelleA,PalomakiG,HampelH.IdentifyingLynch
Syndrome.IntJCancer.2009;125:1492–3.
21.PalomakiGE,McClainMR,MelilloS,HampelHL,Thibodeau
SN.EGAPPsupplementaryevidencereview:DNAtesting
strategiesaimedatreducingmorbidityandmortalityfrom
LynchSyndrome.GenetMed.2009;11:42–65.
22.MvunduraM,GrosseSD,HampelH,PalomakiGE.The
cost-effectivenessofgenetictestingstrategiesforLynch
Syndromeamongnewlydiagnosedpatientswithcolorectal
cancer.GenetMed.2010;12:93–104.
23.LadabaumU,WangG,TerdimanJ,BlancoA,KuppermannM,
BolandCR,etal.StrategiestoidentifytheLynchSyndrome
amongpatientswithcolorectalcancer:acost-effectiveness
analysis.AnnInternMed.2011;155:69–79.
24.HampelH,FrankelWL,MartinE,ArnoldM,KhandujaK,
KueblerP,etal.ScreeningfortheLynchSyndrome(hereditary
nonpolyposiscolorectalcancer).NEnglJMed.
2005;352:1851–60.
25.PeresJ.ToscreenornottoscreenforLynchSyndrome.JNatl
CancerInst.2010;102:1382–4.
26.HampelH.Point:justificationforLynchSyndromescreening
amongallpatientswithnewlydiagnosedcolorectalcancer.J
NatlComprCancerNetw.2010;8:597–601.
27.BolandCR,ShikeM.ReportfromtheJerusalemworkshopon
LynchSyndrome-hereditarynonpolyposiscolorectalcancer.
Gastroenterology.2010;138,2197.e1–7.
28.EvaluationofGenomicApplicationsinPracticePrevention
(EGAPP)WorkingGroup.RecommendationsfromtheEGAPP
WorkingGroup:genetictestingstrategiesinnewlydiagnosed
individualswithcolorectalcanceraimedatreducing
morbidityandmortalityfromLynchSyndromeinrelatives.
GenetMed.2009;11:35–41.
29.HampelH.Genetictestingforhereditarycolorectalcancer.
SurgOncolClinNAm.2009;18:687–703.
30.CanardG,LefevreJH,ColasC,CouletF,SvrcekM,LascolsO,
etal.ScreeningforLynchSyndromeincolorectalcancer:are
wedoingenough?AnnSurgOncol.2012;19:809–16.
31.MoreiraL,BalaguerF,LindorN,delaChapelleA,HampelH,
AaltonenLA,etal.EPICOLONConsortium.Identificationof
LynchSyndromeamongpatientswithcolorectalcancer.
JAMA.2012;308:1555–65.
32.HealdB,PlesecT,LiuX,PaiR,PatilD,MolineJ,etal.
Implementationofuniversalmicrosatelliteinstabilityand
immunohistochemistryscreeningfordiagnosingLynch
Syndromeinalargeacademicmedicalcenter.JClinOncol.
2013;31:1336–40.
33.WardRL,HicksS,HawkinsNJ.Population-basedmolecular
screeningforLynchSyndrome:implicationsforpersonalized
medicine.JClinOncol.2013;31:2554–62.
34.MangeS,BellcrossC,CragunD,DuquetteD,GormanL,
HampelH,etal.Creationofanetworktopromoteuniversal
screeningforLynchSyndrome:theLynchSyndrome
screeningnetwork.JGenetCouns.2015;24:421–7.
35.VasenHF,BlancoI,Aktan-CollanK,GopieJP,AlonsoA,Aretz
S,etal.Revisedguidelinesfortheclinicalmanagementof
LynchSyndrome(HNPCC):recommendationsbyagroupof
Europeanexperts.Gut.2013;62:812–23.
36.NationalComprehensiveCancerNetworkNCCNPractice GuidelinesinOncology.Availablefrom:http://www.nccn.org.
37.RybakC,HallMJ.InterpretationofgenetictestingforLynch
Syndromeinpatientswithputativefamilialcolorectalcancer.