* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Hereditary Cancer Syndromes - Roswell Park Cancer Institute
Survey
Document related concepts
Genetic testing wikipedia , lookup
Gene expression programming wikipedia , lookup
Genetic engineering wikipedia , lookup
Artificial gene synthesis wikipedia , lookup
History of genetic engineering wikipedia , lookup
Medical genetics wikipedia , lookup
Polycomb Group Proteins and Cancer wikipedia , lookup
Quantitative trait locus wikipedia , lookup
Population genetics wikipedia , lookup
Frameshift mutation wikipedia , lookup
Public health genomics wikipedia , lookup
Point mutation wikipedia , lookup
Cancer epigenetics wikipedia , lookup
Designer baby wikipedia , lookup
Nutriepigenomics wikipedia , lookup
Microevolution wikipedia , lookup
BRCA mutation wikipedia , lookup
Transcript
HereditaryCancerSyndromes NicoletaVoian,MD,MPH DirectorClinicalGeneticsService RoswellParkCancerInstitute [email protected] February23,2016 CommonGeneticsTerms –Gene:AhereditaryunitconsistingofasequenceofDNAthatoccupiesa specificlocationonachromosomeanddeterminesaparticularcharacteristic inanorganism. –Locus:specificareaonchromosomewherethegeneisfound –Trait:Adistinguishingfeature,ageneticallydeterminedcharacteristicor condition. –Allele:Versionsofagene –Genotype:thegeneticmakeupofanorganism –Phenotype:thephysicalappearanceofanorganism –Pleiotropy:theabilityofagenetoaffectanorganisminmanyways –PolygenicInheritance:additiveeffectof2ormoregenesonaphenotypic character –Phenocopy:theobservedresultofanenvironmentallyinduced,nongenetic alterationofaphenotypetoaformthatresemblestheexpressionofaknown geneticmutation. GeneticHeterogeneity • Geneticheterogeneity:Anumberofsimilaror identicalphenotypesarecausedbydifferent genotypes – mutationsatdifferentloci(differentgenes) • locusheterogeneity – Hearingloss – maybetheresultofdifferentmutationsatthesame locus(samegene) • allelicheterogeneitymeansthatdifferentmutationswithina singlegenelocus(formingmultipleallelesofthatgene)cause thesamephenotypicexpression. • Forexample,thereareover1000knownmutantallelesofthe CFTRgenethatcausecysticfibrosis. VariationinthePhenotype • Penetrance – theprobabilitythatagenewillhaveANYphenotypicexpression • itisanallornoneconcept • ifsomepeoplewithanappropriategenotypefailtoexpressthe phenotype,thereisreducedpenetrance • Expressivity – Severityofthemanifestationsofthephenotype – whenphenotypicseverityvariesamongthosewithidentical genotypes,variableexpressivityisshown • Pleiotropy – Multiplephenotypiceffectsofasinglegeneorgenepair – whentheeffectsarenotobviouslyrelated Genotypevs.Phenotype ▪ Samegenotype(geneticmakeup)differentphenotype(observedfeatures) – Pleiotropy(singlegeneinfluencesmultiplephenotypictraits) • Ex.MSH6associatedw/colonca,endometrialca,ovarianca,etc. – Expressivity(differentdegreesofpresentation) • Ex.APCgenemutations–classicvs.attenuatedform ▪ Samephenotypedifferentgenotype ▪Ex.Breastcancerassociatedw/mutationsinBRCA,PTEN,TP53orsporadic GoalsofPedigreeAnalysis 1. Determine(suggest)themodeofinheritance: autosomaldominant,(AD),autosomal recessive(AR),sex-linked,mitochondrial. 2. Determinetheprobabilityofinheritingagene mutationfortheoffspring. ObtainingaFamilyHistory • 4generations–listallmaternalandpaternal relatives,whetherornottheyhavehadcancer – Limitedfamilystructure(<2femalesoverage45onone sideofthefamily)forHBOC Ageatcancerdiagnosis Pathology Ageatdeath/causeofdeath Historyofoophorectomyorhysterectomy,CRC polyps-includingnumberandpathology • Ancestry • • • • BasicSymbols ModesofInheritance • Autosomal Dominant: affects both males and females in all generations. • Examples: Achondroplasia, Huntington disease, Neurofibromatosis types 1 & 2, and many, many more! ModesofInheritance ⦿ AutosomalRecessive:offspringof2carrierparentscan beaffected.Usuallyonlyseeninonegeneration.Males andfemalesaffectedandtransmit. • Consanguinitymaybeapparentinparentsofaffected child. – Examples:CysticFibrosis,PKU,Wilson’sdisease,andmany more! ModesofInheritance ⦿ X-linkedrecessive:onlysonsofheterozygousmothers (carriers)canbeaffected,thereisnofathertoson transmission.Alldaughtersofanaffectedmalewillbe carriers. ● Examples:Duchennemusculardystrophy,HemophiliaAand B ● Femalesmayrarelybeaffectedduetonon-random inactivationofXchromosome ModesofInheritance ⦿ X-linkeddominant:Malesandfemalescanbe affected.Alldaughtersofaffectedfathersare affected.Nomaletomaletransmission. ● Example- ○ Hypophosphatemicrickets(X-linkedhypophosphatemic rickets):increasedphosphatewastingatproximal tubule(kidney) ModesofInheritance Mitochondrial:TransmissionONLY throughthemother.Mitochondria areonlyinheritedfromthemother. Alloffspringofaffectedmothers areaffected. ⦿ ● Variableexpressiondueto heteroplasmy ● TheeffectamutationinmtDNAwill haveonacell'sfunctionwill thereforedependonthenumberof mutantorganellesinacell comparedtothenumberofnormal, or"wildtype",present.Inthis respect,eachcellisanalogoustoan organisminwhichsomaticmutation canproducemosaicism.Herethe mixtureofgenotypesistermed heteroplasmy. Exampleofafamilytreeshowingmembersofafamilyinwhichrunsaninheritanceofamitochondrialcondition (Adaptedfrom:GreenwoodGeneticCentre(1995):CounselingAidsforgeneticists.GreenwoodGeneticCentre,USA) GeneralPrinciples ■ ■ ■ Causesofcancer InheritancePatterns Importanceofdiagnosingageneticdisorder All cancer is genetic, not all cancer is hereditary. Cancer ▪Familialcancer~15-20% • • • • Morecasesofaspecifictype(s) ofcancerwithinafamilythan expected,butnospecificpattern ofinheritance Ageofonsetvariable Mayresultfromchance clusteringofsporadiccases Mayresultfromcommon geneticbackground(low penetrancegene),similar environmentand/orlifestyle factors ▪Hereditarycancer~5-10% • • • • • • Earlydiagnosis Bilateralcancers Multipleprimariesinanindividual Multipleaffectedfamilymembers Spanninganumberofgenerations Rarecancers(ovariancancer,malebreastcancer) ▪Sporadiccancer~65-70% • • Typicalageofonset(olderage) Evenifthereismorethanonecase inthefamily,thereisnoparticular patternofinheritance HereditaryCancerSyndromesand PublicHealth • ~5-10%ofallcancers(withsomeexceptions) • Highriskofmultipleprimaries • Occuratyoungerage • Multiplefamilymembersaffected • Earlyidentificationwouldbenefitfrompreventivecareoptions (Some)HereditaryCancerSyndromes • HereditaryBreastandOvarianCancerSyndrome(BRCA1and BRCA2) • HNPCC/LynchSyndrome(MMRgenes–MLH1,MSH2,MSH6, PMS2,andnon-MMRgeneEPCAM) • FAP,AFAPandMAP(APCandMYH) • Malignantmelanoma(CDKN2A,CDK4) • HereditaryDiffuseGastricCancer(CDH1) • VonHippelLindau(VHL) • CowdenSyndrome(PTEN) • Neurofibromatosistype1andtype2(NF1andNF2) • Li-FraumeniSyndrome(TP53) • Multipleendocrineneoplasiatype1(MEN1) • Multipleendocrineneoplasiatype2(RET) HereditaryBasisofCancer • Mostinheritedcancersyndromesareautosomal dominant-AD(e.g.HBOC,HNPCC,FAP/AFAP, Cowden,Li-Fraumeni) • Fewareautosomalrecessive-AR(e.g.MYHPolyposis,FanconiAnemia) GeneticCancerRiskAssessment ComponentandActivities Select and offer test Provide informed consent Provide pretest counseling Identify atrisk patients http://www.docviewer.org/view.php?url=http://drubin.bsd.uchicago.edu/powerpoint/ Rubin_DT_2007_Ethical_issues_in_genetics.ppt&t=Ethical Issues in Genetics Disclose results Provide posttest counseling and follow-up BenefitsandLimitationsofTesting Benefits • • • • Offerspersonalizedhereditary cancerriskassessment Canprovideinformationtohelp makemedicalmanagement decisionstoreducecancerrisk Importantinformationforfamily members Reducedanxietyandstress Limitations • • Testingdoesnotdetectallcauses ofhereditarycancer Anegativeresultismosthelpful whenthereisaknownmutationin thefamily HereditaryBreastandOvarianSyndrome associatedwithmutationsinthe BRCA1/2genes BRCA1/2genes: MutationPenetrance CancerTypeInheritedRiskGeneralPopulationRisk • Breast-female45-84%*11-12% -maleupto8%<1% • Ovarianandovarianrelated11-62%1.5-2% • Prostate20%16.2% • Thereisalsoanincreasedincidenceofmelanomaand/orpancreaticcancerinsomefamilies. *Womenwhohavealreadyhadbreastcancerhaveuptoa20%risktodevelopanewprimarybreast cancerwithin5yearsoftheirinitialdiagnosis,anduptoa60%riskintheirlifetime. RoleofBRCA1&2genes • Tumorsuppressorgenes • PrimarilyexecutingtheDNAdouble-strand breakrepairbyhomologousrecombination HBOC(associatedwithmutationsinBRCA1/2genes)pedigree sciencedirect.com GeneticTestingResults • Positive -Deleterious(harmful)mutationidentified • Negative - Interpretationdiffersifamutationhaspreviouslybeen identifiedinthefamily • Mutationknown–truenegative(cancerriskasgeneralpopulation) • Mutationunknown–uninformative(cancerriskincreasedcomparedwith generalpopulation,butlessthanifhavingaBRCAmutation) • Variantofunknownsignificance - ThetestidentifiedachangeintheBRCA1/2genesbutisnotclearifthechange isharmfulornot. ManagingHereditaryBreastandOvarian CancerRisk ManagementofBRCACarriers Increasedsurveillance – Forbreastcancer,ovariancancer,prostatecancer, melanomaandpancreaticcancer Medication – E.g.Tamoxifen,raloxifen(forbreastcancer) – Oralcontraceptives(reducetheriskofovariancancer) Risk-reducingsurgery – Bilateralmastectomy,bilateralsalpingo-oophorectomy Newtherapy: PARPinhibitors • Twogenesaresaidtobeinasyntheticlethal relationshipifamutationineithergenealoneisnot lethalbutmutationsinbothcausethedeathofacell. • InhibitionofPARP[poly(adenosine-disposphateribose)polymerase]appearstoselectivelykillcells whichlackfunctionalBRCA. PARPfunction AnnFolkins,KarunaGarg,TeriLongacre.GynecologicFamilialCancerSyndromes: WhatthePracticingPathologistNeedstoKnow.2011AnnualMeeting–LasVegas,NV PARPInhibitors • FDAapprovedforadvancedovarian cancer(certainconditionsneedtobemet) • Therearecurrentlyanumberofongoingclinical studiesinBRCA1/2mutationcarriersutilizing variousPARPinhibitorsinbreast,prostate, pancreaticcancerpatients ColorectalCancerGenetics Sporadic Familial RareCRCsyndromes HNPCC(2-5%) FAP(1%) AdaptedfromBurt,RW.InheritanceandGeneticTestingforColonCancer Lynchsyndrome(LS)or Hereditarynon-polyposiscolorectalcancer • Germlinemutationsinoneoffourmismatchrepair(MMR) genes(MLH1,MSH2,MSH6,andPMS2). • MLH1andMSH2germlinemutationsaccountfor approximately90%; • MSH6mutations~7%-10%;and • PMS2mutationsinfewerthan5%. • GermlinedeletionsinEPCAM(notamismatchrepairgene) inactivateMSH2inabout1%ofindividualswithLynch syndrome. http://www.ncbi.nlm.nih.gov/books/NBK1211/ CancerRisksinIndividualswithLynchSyndromeAge≤70Years ComparedtotheGeneralPopulation CancerType GeneralPopulationRisk LynchSyndrome (MLH1andMSH2heterozygotes) Risk MeanAgeofOnset Colon 5.5% 52%-82% 44-61years Endometrium 2.7% 25%-60% 48-62years Stomach <1% 6%-13% 56years Ovary 1.6% 4%-12% 42.5years Hepatobiliarytract <1% 1.4%-4%% Notreported Urinarytract <1% 1%-4% ~55years Smallbowel <1% 3%-6% 49years Brain/centralnervous system <1% 1%-3% ~50years Sebaceousneoplasms <1% 1%-9% Notreported Aarnioetal[1999],Vasenetal[2002],AmericanCancerSociety[2002],Hampeletal[2005],Pontietal[2006],Southetal[2008],Watsonetal[2008],barrowetal [2009],Barrowetal[2009],Stoffeletal[2009] Lynchsyndrome-MMRgenes TheDNAmismatchrepair(MMR)mechanisminhumans. CurrentGenomics,2009,Vol.10,No.2 AmsterdamCriteria: ClinicalDiagnosisofLynchsyndrome(3-2-1) AmsterdamCriteria – Threeormorefamilymembers,oneofwhomisafirst-degreerelativeoftheothertwo, withaconfirmeddiagnosisofcolorectalcancer – Twosuccessiveaffectedgenerations – Oneormorecoloncancersdiagnosedbeforeage50years – FAP(FamilialAdenomatousPolyposis)excluded AmsterdamIICriteria – Threeormorefamilymembers,oneofwhomisafirst-degreerelativeoftheothertwo, withHNPCC-relatedcancers** – Twosuccessiveaffectedgenerations – OneormoreoftheHNPCC-relatedcancersdiagnosedbeforeage50years – FAPexcluded **Colorectal,endometrial,stomach,smallintestinal,hepatobiliary,renalpelvic,orureteral Vassen, HF, et al. Dis Colon Rectum 1991;34:424-5. Vasen HFA, et al. Gastroenterology 1999;116:1453-6. BethesdaGuidelines: ScreeningforLynchsyndrome (criteriaformicrosatelliteinstabilitytesting) Colorectalcancer ▪ Underage50 ▪ WithasynchronousormetachronousLynch(HNPCC)tumor ▪ Underage60withhistologyconsistentwithLynch(HNPCC)syndrome ▪ tumorinfiltratinglymphocytes,Crohn-likereaction,mucinous/ signetringdifferentiation,medullarygrowthpattern ▪ Withafirst-degreerelativewhohasanHNPCCtumor<50 ▪ With2ormorefirstorsecond-degreerelativeswithHNPCCtumor Rodriguez-Bigas, et al. J Natl Cancer Inst 1997;89:1758-62. Umar A, et al. J Natl Cancer Inst 2004;96:261-8. PedigreeofaLynchsyndromefamily FrederikJHesWorldJournalofSurgicalOncology20086:21doi:10.1186/1477-7819-6-21 MicrosatelliteInstabilityTesting – Musthavetumorandnormaltissue(ornormalcontrol–bloodsample) – Mosteffectivewhencombinedwithclinicalinformation – StudiesofLynchsyndrome-associatedadenomassuggesta slightlylowerrateofMSIcomparedtoinvasivecancers, withapproximately80%ofadenomasbeingMSI-high • • • – Approximately20%-30%ofendometrialcancersexhibitMSI,andaswithcolon cancersthemajorityaretheresultofsomaticMLH1promotermethylation MSI-highifmorethantwo(or>30%)ofthemarkersshowinstability MSI-lowifone(or<30%)ofthemarkersshowinstability MSI-stableif0(or0%)ofthemarkersshowinstability http://www.ncbi.nlm.nih.gov/books/NBK1211/ Immunohistochemistry(IHC) • StainarchivedtumortissueforMMRproteins • Missingproteinindicateswhichgenetosequence – MLH1andPMS2 – MSH2andMSH6 • MLH1canbelostbymethylationorbysomaticmutations GeneticsinMedicine,Jan2009,EGAPPRecommendationStatement,Volume11,Number1 ManagementofLynchsyndrome • Increasedsurveillance – Colorectal,endometrial,ovarian,urinarytract • Riskreducingsurgery – endometrial,ovarian • Doessurveillancehelp?? – DetectionofCRCatanearlierstage,toa63% reductionoftheriskofCRCandtoasignificant reductionofthemortalityassociatedwithCRC Vasen,etal,JMG,2007;44;353-62. What’snew? • NextGenerationsequencing: ahigh-throughputsequencingmethodthat parallelizethesequencingprocess,producing thousandsormillionsofsequencesatonce. StadlerZK,JClinOncol.2010Sep20;28(27):4255-67 Advances in Genetic Testing: Next Generation Sequencing (NGS) Panels • Currently over 10 clinical laboratories in US offer gene panel tests for hereditary cancer syndromes • Syndrome-specific test(e.g. BRCA1 and BRCA2 for HBOC) • Cancer-specific that include high penetrance gene panel • Cancer-specific including high- and moderatepenetrance genes • Comprehensive cancer panels(genes associated with multiple hereditary cancer syndromes) Next Generation Sequencing (NGS) Panels Strengths • Allows the analysis of several genes concurrently • May identify a cause/cancer syndrome that would not have otherwise been identified through single-gene testing • Cost and time effective Limitations • Lack of evidence-based management guidelines for many of the rare syndromes(or gene mutations) • High likelihood for Variants of Unknown Significance • Several genes may not have clinical relevance to personal and family history • NGS panels should be offered only in consultation with a cancer genetics professional(NCCN and SGO) IssuesinGeneticCounseling/Testing • Bloodsample(orothertissuesample) • Non-directivecounseling • Informedconsent -Positive,negative,variantofuncertainsignificance • InsuranceDiscrimination/GeneticPrivacyLaws -HIPAA,StateLawsGoverningGeneticDiscrimination, GeneticInformationNon-DiscriminationAct(GINA) • Minors • Uninformativenegativetestresult • Familyimplications • Supportgroupinformation ThankYou! ContactInformation ClinicalCancerGenetics RoswellParkCancerInstitute Phone:716-845-8400 1-877-ASK-RPCI Fax:716-845-5720