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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