Ovarian Cancer Genecs€¢ Trans-vaginal ultrasound and CA-125 level • Consult with...
-
Upload
phungthuan -
Category
Documents
-
view
214 -
download
0
Transcript of Ovarian Cancer Genecs€¢ Trans-vaginal ultrasound and CA-125 level • Consult with...
OvarianCancerGeneMcs
BriganyDeGreef,MS,CGCLeeShulman,MD
CancerGene:csProgramNorthwesternMedicineSeptember9,2017
98
Disclosure
• IserveontheGene:cCounselingAdvisoryBoardforInvitaeLaboratories.
99
OvarianCancer
Non-GeneMc• Age• Nulliparity(neverbeingpregnant)• Familyhistoryofovariancancer
RiskFactors
GeneMc• BRCA1orBRCA2carrier• Lynchsyndrome(HNPCC)• Othersinglegenemuta:ons(rare)
OvarianCancerRiskinGeneralPopula:on
1outof72womenwilldevelopovariancancerintheirlife:me(1.4%)
OvarianCancerRisks
0
10
20
30
40
50 Rangesfrom5-50%
GeneralPopula:on
1.4%
Firstdegreerela:vewithovariancancer
Twofirstdegreerela:veswithovariancancer
GeneMuta:on
7%3-5%
OvarianCancer
Sporadic:~70%• Canceroccursbychanceorrelatedto
environmentalfactors• Generalpopula:oncancerrisk
Familial:~20%• Mul:plegenesand
environmentalfactors• Someincreaseincancerrisk
Hereditary:5-10%• Genemuta:onisinheritedinfamily• Significantincreasedcancerrisk
CausesofHereditarySuscep:bilitytoOvarianCancer
WalshTetal.Muta:onsin12genesforinheritedovarian,fallopiantube,andperitonealcarcinomaiden:fiedbymassivelyparallelsequencing.ProcNatlAcadSci2011;108:18032–7.
104
CluesforaHereditaryCancerSyndrome
• Earlyageofdiagnosis- Typicallydiagnosedundertheageof60
• Mul:pleprimarycancersinoneindividual- Suchasovariancancerandbreastcancer
• Individualwithovariancancerandfamilyhistoryofovarianand/orbreastcancertypicallydiagnosedundertheageof50
• Mul:plegenera:onsaffectedwithcancer• Rarecancers(i.e.malebreastcancer)• AshkenaziJewishancestry
HowCancerForms
SporadicCancer
HereditaryCancer
NormalCell Accumulatechangesormuta:onsover:me
TumorDevelopment
x x x xxx x xxx x
x xx xxx
PredisposedCell
Accumulatechangesormuta:onsover:me
TumorDevelopment
x xxxx
106
Whatarethese“genes”?
• Tumorsuppressorgenes• Carriedbybothmenandwomen• Twocopiesofeverygeneinourbody(~25,000)
WhatdoesamutaMonmean?AGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAA• Onecopyofgenecannolongerperformnormalfunc:onof“tumorsuppressing”
• Increasedriskofcancer
AGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCA
Inheritance
50%chancetopassonthenon-workingcopyofthe
gene
50%chancetopassonthe
workingcopyofthegene
108
HereditaryCancerSyndromes
AssociatedwithanIncreasedRiskforOvarianCancer
HereditaryBreastandOvarianCancerSyndrome(HBOC) LynchSyndrome Other/ModerateRiskGenesfor
OvarianCancer
Genes BRCA1andBRCA2 MLH1,MSH2,MSH2,PMS2,EPCAM BRIP1,RAD51C,RAD51D
OvarianCancerRisk 20-40% 10-15% 5-15%
OtherCancerRisks
Female/MaleBreast(50-60%,upto6%)Prostate(15%)Melanoma(5%)
Pancrea:c
Colon(upto70%)Uterine(40-60%)Gastric(upto13%)
UrinaryTract(upto7%)Pancrea:c(upto6%)
Unknown?
ManagementRecommendaMons CurrentlynoGuidelines
BasedonNCCNGuidelines2017
109
HereditaryCancerSyndromes
AssociatedwithanIncreasedRiskforOvarianCancer
HereditaryBreastandOvarianCancerSyndrome(HBOC) LynchSyndrome Other/ModerateRiskGenesfor
OvarianCancer
Genes BRCA1andBRCA2 MLH1,MSH2,MSH2,PMS2,EPCAM BRIP1,RAD51C,RAD51D
OvarianCancerRisk 20-40% 10-15% 5-15%
OtherCancerRisks
Female/MaleBreast(50-60%,upto6%)Prostate(15%)Melanoma(5%)
Pancrea:c
Colon(upto70%)Uterine(40-60%)Gastric(upto13%)
UrinaryTract(upto7%)Pancrea:c(upto6%)
Unknown?
ManagementRecommendaMons CurrentlynoGuidelines
BasedonNCCNGuidelines2017
110
HereditaryCancerSyndromes
AssociatedwithanIncreasedRiskforOvarianCancer
HereditaryBreastandOvarianCancerSyndrome(HBOC) LynchSyndrome Other/ModerateRiskGenesfor
OvarianCancer
Genes BRCA1andBRCA2 MLH1,MSH2,MSH2,PMS2,EPCAM BRIP1,RAD51C,RAD51D
OvarianCancerRisk 20-40% 10-15% 5-15%
OtherCancerRisks
Female/MaleBreast(50-60%,upto6%)Prostate(15%)Melanoma(5%)
Pancrea:c
Colon(upto70%)Uterine(40-60%)Gastric(upto13%)
UrinaryTract(upto7%)Pancrea:c(upto6%)
Unknown?
ManagementRecommendaMons CurrentlynoGuidelines
BasedonNCCNGuidelines2017
111
HereditaryCancerSyndromes
AssociatedwithanIncreasedRiskforOvarianCancer
HereditaryBreastandOvarianCancerSyndrome(HBOC) LynchSyndrome Other/ModerateRiskGenesfor
OvarianCancer
Genes BRCA1andBRCA2 MLH1,MSH2,MSH2,PMS2,EPCAM BRIP1,RAD51C,RAD51D
OvarianCancerRisk 20-40% 10-15% 5-15%
OtherCancerRisks
Female/MaleBreast(50-60%,upto6%)Prostate(15%)Melanoma(5%)
Pancrea:c
Colon(upto70%)Uterine(40-60%)Gastric(upto13%)
UrinaryTract(upto7%)Pancrea:c(upto6%)
Unknown?
ManagementRecommendaMons CurrentlynoGuidelines
BasedonNCCNGuidelines2017
112
HereditaryCancerSyndromes
AssociatedwithanIncreasedRiskforOvarianCancer
HereditaryBreastandOvarianCancerSyndrome(HBOC) LynchSyndrome Other/ModerateRiskGenesfor
OvarianCancer
Genes BRCA1andBRCA2 MLH1,MSH2,MSH2,PMS2,EPCAM BRIP1,RAD51C,RAD51D
OvarianCancerRisk 20-40% 10-15% 5-15%
OtherCancerRisks
Female/MaleBreast(50-60%,upto6%)Prostate(15%)Melanoma(5%)
Pancrea:c
Colon(upto70%)Uterine(40-60%)Gastric(upto13%)
UrinaryTract(upto7%)Pancrea:c(upto6%)
Unknown?
ManagementRecommendaMons CurrentlynoGuidelines
BasedonNCCNGuidelines2017
OvarianCancerRiskReduc:on
• Birthcontrolpills- 5yearsofuse:27%reduc:on- 15yearsofuse:60%reduc:on
• Firstfull-termpregnancy<age25;numberofpregnancies• Breast-feeding• Bilateraltuballiga:on/hysterectomy• Prophylac:coophorectomy- Riskofprimaryperitonealcancerremains
113
HBOCandLynchSyndrome
114
OvarianCancerRiskReduc:on
• Ovariancancer- Approximately15%life:meriskofovariancancer
• Currentlynoestablishedguidelines- Recommendriskreducingoophorectomyfollowingnaturalmenopause
• Othercancerrisks?- TBD
BRIP1,RAD51C,RAD51D
115
Prophylac:cSalpingectomywithDelayedOophorectomy
• RecentstudieshavesuggestedmajorityofovariancancerbeginsinfallopiantubesinwomenwithBRCA1/2muta:ons(~80%)
• RESEARCHcurrentlyongoingtoevaluateforremovaloffallopiantubesfirst- Delayssurgicalmenopausewhilehopefullyreducingovariancancerrisk- Removeovariesfewyearslater
• NOTSTANDARDOFCARE,onlybeingperformedonresearchbasisatthispoint
116
117
WhatifIalreadyhadnega:veBRCA1andBRCA2tes:ng?
AGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAAAGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAAAGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAAAGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAATTGCACCGTGACAGTCACGTAGTCACT
• SequencingAnalysis- Readsthrougheachlegeronebyone- Picksupapproximately95%ofmuta:onsinBRCA1/2
118
WhatifIalreadyhadnega:veBRCA1andBRCA2tes:ng?
AGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAAAGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAAAGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAAAGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAATTGCACCGTGACAGTCACGTAGTCACT
119
WhatifIalreadyhadnega:veBRCA1andBRCA2tes:ng?
AGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAAAGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAAAGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAAAGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAATTGCACCGTGACAGTCACGTAGTCACT
120
WhatifIalreadyhadnega:veBRCA1andBRCA2tes:ng?
AGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAAAGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAAAGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAAAGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAATTGCACCGTGACAGTCACGTAGTCACT
121
WhatifIalreadyhadnega:veBRCA1andBRCA2tes:ng?
AGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAAAGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAAAGCTGTTCAAAAATGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAAAGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAATTGCACCGTGACAGTCACGTGACT
• Dele:on/Duplica:onAnalysis- Looksforlargeamountsoflegersthataremissingoradded- Picksupapproximately5%ofmuta:onsinBRCA1orBRCA2
122
WhatifIalreadyhadnega:veBRCA1andBRCA2tes:ng?
• Genepanels…- Includesmorethanonegenerelatedtospecificindica:onsuchasovarian
cancer• Highriskgenes:Lynchsyndrome(MLH1,MSH2,MSH6,PMS2,EPCAM)• Moderateriskgenes:BRIP1,RAD51C,RAD51D• Andmanymore…
• Changingyearly,evenmonthly
Arethereothergenesrelatedtoovariancancer?
123
Gene:cTes:ng
• Mul:-GenePanelvsSingleGeneTes:ng- Mul:plecasesofcancerwithinafamily- Isolatedcaseofovariancancerdiagnosedatanyage- Iden:fiedfamilialmuta:on
• Gene:cTes:ngResults:- NoMuta:onFound- Pathogenic- Variantofuncertainsignificance(VUS)–inconclusive
124
Allofmygene:ctes:ngwasnega:ve,nowwhat?
• Managementbasedonpersonalandfamilyhistoryofcancer• Firstdegreefemalerela:ves(daughters,sisters,mothers):
• Considerovariancancerscreeningaspartofaresearchprotocol• NorthwesternOvarianCancerDetec:onandPreven:onProgram
• Trans-vaginalultrasoundandCA-125level
• Consultwithphysicians/gene:ccounselorsperiodicallyforupdatedgene:ctes:ngandrecommenda:ons
BenefitsofGene:cTes:ng
• Provideanexplana:onforyourpersonalorfamilyhistoryofcancer• Evaluateyourriskofdevelopingfuturecancers• Makeinformedmedicaldecisions,includingtreatment,surveillance,andpreven:veop:ons
• Poten:aluseofotherchemotherapyop:ons- PARPinhibitorsforBRCA1/2individuals
• Qualifyyouforpar:cipa:oninclinicaltrialsorresearchstudies• Iden:fyotherat-riskrela:vesforwhomgene:ctes:ngisrecommended• Alwayschangingandevolving–periodicallycheck-inwithgene:cs
125
DrawbackstoGene:cTes:ng
• Willresultsmakeadifferenceinmycare?• Maybeinconclusive• Riskfordevelopingcancernotalwaysestablished• Whatinterven:onsareavailable?• Psychosocialimplica:ons
126
127
TumorDNATes:ng
• Usesnextgenera:onsequencing(many,manygenes)• Tes:ngperformedtolookforDNAmuta:onswithincancercells/tumoronly- Differentfromgene:ctes:ng(tes:ngwejustreviewed)
• Typicallyperformedtolookfortreatmenttargetsorresponsetotreatment• Incidentallycanfindagene:cmuta:onthatyouwerebornwith(inheritedmuta:on)
• “New-er”soworkinprogressandrapidlyevolving…(staytuned)
HowCancerForms
SporadicCancer
HereditaryCancer
NormalCell Accumulatechangesormuta:onsover:me
TumorDevelopment
x x x xxx x xxx x
x xx xxx
PredisposedCell
Accumulatechangesormuta:onsover:me
TumorDevelopment
x xxxx
HowCancerForms
SporadicCancer
HereditaryCancer
NormalCell Accumulatechangesormuta:onsover:me
TumorDevelopment
x x x xxx x xxx x
x xx xxx
PredisposedCell
Accumulatechangesormuta:onsover:me
TumorDevelopment
x xxxx
HowCancerForms
SporadicCancer
HereditaryCancer
NormalCell Accumulatechangesormuta:onsover:me
TumorDevelopment
x x x xxx x xxx x
x xx xxx
PredisposedCell
Accumulatechangesormuta:onsover:me
TumorDevelopment
x xxxx
131
OtherConsidera:ons…
• Gene:cInforma:onNondiscrimina:onAct(GINA)passedin2008
• Familyplanningop:ons• Opennessorwillingnesstocommunicatewithfamilymembers- Familyleger
• PsychosocialImplica:ons
• Pa:entadvocacygroups
132
FamilyLegerExample
Dearfamily:
Iamwri:ngthislegertoinformyouthatIrecentlyhadgene:ctes:ngandwasdiagnosedwithacondi:oncalledhereditarybreastandovariancancersyndrome(HBOC)whichaffectsfamilies.Thislegercontainsinforma:onaboutHBOC,howitmightaffectyou,andhowtofindoutifyouhavethiscondi:onalso.
PeoplewhohaveHBOChaveincreasedcancerrisks.Specificallywomenhaveincreasedrisksforbreastcancerandovariancancer,andmenhaveincreasedrisksforprostatecancerandmalebreastcancer.ItisrecommendedthatanyonewithHBOChaveincreasedscreeningforthesecancerswhichhelpsdetectcancersearlierwhentheyaremoreeasilytreated,andinsomecases,preventthemaltogether.
Hereditarybreastandovariancancersyndromeiscausedbyamuta:oninagenethatcanbeinheritedinfamilies.Thespecificmuta:oniden:fiedinmewasintheBRCA*gene(***).Gene:ctes:ngisavailableforyoutoseeifyoucarrythissamemuta:on.Youcantakethislegertoyourdoctor,orcontactthegene:csteamatNorthwesternCancerGene:cstodiscussthisfurtherandfindouthowtogettestedinyourarea.Youcanalsofindagene:ccounselornearyoubygoingtothefollowingwebsite:www.nsgc.organdusingthe“FindaGene:cCounselor”tool.
Ifyouoryourdoctorshaveaddi:onalques:ons,theNorthwesternCancerGene:csteamwouldbehappytodiscussthisfurther.YoucanreachamemberoftheCancerGene:csTeamat312-472-0518or312-472-0523.Sincerely,
133
FindaGene:cCounselorNearyouhgp://www.aboutgene:ccounselors.com/
ThankYouEmail:[email protected]:(312)695-0320