Hereditary CancerPredispositionPatricia A. Ganz, MD
Cancer is a Genetic DiseaseNormalNormalTumorTumor
Cancer Arises From GeneMutationsGermline mutations Somatic mutationsSomatic mutationsSomaticSomaticmutation (eg,mutation (eg,breast)breast)MutatioMutation in eggn in eggororspermspermAll cellsAll cellsaffected inaffected inoffspringoffspringParentParent ChildChildll Present in egg or spermPresent in egg or spermll Are heritableAre heritablell Cause hereditaryCause hereditarycancer syndromescancer syndromesll Occur in nongermlineOccur in nongermlinetissuestissuesll Are nonheritableAre nonheritablell Later onsetLater onset
All Cancer is Genetic, Not All Cancer isInheritedFourth +mutationNormal cellFourth +mutationFirst mutationSecond mutationThird mutationMalignant cellFirst mutationSecond mutationThird mutationMalignant cellSporadic CancerSporadic Cancer Hereditary CancerHereditary Cancer
Hereditary Versus SporadicCancerSporadicSporadic•• Onset of breast cancer usually < 50Onset of breast cancer usually < 50•• Ovarian cancer at any ageOvarian cancer at any age(not always present)(not always present)•• Breast and ovarian cancer in the sameBreast and ovarian cancer in the sameindividualindividual•• Male breast cancerMale breast cancer•• Ashkenazi ancestryAshkenazi ancestryHereditaryHereditaryBr, 42Br, 42Ov, 71Ov, 71 Br, 45Br, 45Br, 71Br, 71Br, 63Br, 63•• None of the breastNone of the breastcancer is diagnosedcancer is diagnosedbefore 60 yrsbefore 60 yrs•• No ovarian cancerNo ovarian cancer•• No clear pattern on oneNo clear pattern on oneside of family or theside of family or theotherother
The Key to Identification: FamilyHistoryll Maternal andMaternal andpaternal familypaternal familyhistoryhistoryll Accurate riskAccurate riskassessmentassessmentll Effective geneticEffective geneticcounselingcounselingll AppropriateAppropriatemedical followmedical follow--upup
When to SuspectHereditary Cancer Syndrome• Cancer in 2 or more relatives(on same side of family)• Early age at diagnosis• Multiple primary tumors• Bilateral or multiple rare cancers• Constellation of tumors consistent withspecific cancer syndrome (eg, breast andovary)• Evidence of autosomal dominanttransmission• Ancestry
How Much Breast andOvarian Cancer Is Hereditary?SporadicSporadicFamily clustersFamily clustersHereditaryHereditaryOvarian CancerOvarian CancerBreast CancerBreast Cancer5%5%––10%10% >10%>10%15%15%20%20%
BRCA1 and BRCA2BRCA2BRCA2 BRCA1BRCA1Adapted fromAdapted from Tools for Understanding GeneticsTools for Understanding GeneticsNational Human Genome Research InstituteNational Human Genome Research InstituteOffice of Science Education and OutreachOffice of Science Education and Outreachwww.nhgri.nih.gov/DIR/VIPwww.nhgri.nih.gov/DIR/VIP
Inheritance Pattern: AutosomalDominant with Incomplete Penetrancell Penetrance is often incompletePenetrance is often incompletell May appear toMay appear to ““skipskip”” generationsgenerationsll Individuals inherit altered cancer susceptibilityIndividuals inherit altered cancer susceptibility gene,gene,not cancernot cancerNormalNormalCarrier, affectedCarrier, affectedwith cancerwith cancerSusceptible CarrierSusceptible CarrierSporadic cancerSporadic cancer
BRCA1-Associated Cancers:Lifetime RiskPossible increased risk of otherPossible increased risk of othercancers (eg, male breast, colon)cancers (eg, male breast, colon)Breast cancerBreast cancer 50%50%85% (often early age at onset)85% (often early age at onset)Second primarySecond primary breast cancerbreast cancer ~60%~60%Ovarian cancerOvarian cancer 40%40%60%60%
BRCA2-Associated Cancers:Lifetime RiskIncreased risk of prostate andIncreased risk of prostate andpancreatic cancers (magnitudepancreatic cancers (magnitudeunknown)unknown)breast cancerbreast cancer50%50%85%85%ovarian cancerovarian cancer10%10%27%27%male breast cancermale breast cancer6%6%Second primarySecond primary breast cancerbreast cancer ~50%~50%
BRCA1 and BRCA2 Mutations inthe Ashkenazi Jewish PopulationAn estimated 1 in 40 Ashkenazi JewsAn estimated 1 in 40 Ashkenazi Jewscarries acarries a BRCA1BRCA1 oror BRCA2BRCA2 mutationmutationRoa BB et al.Roa BB et al. Nat GenetNat Genet 14:185, 199614:185, 1996Oddoux C et al.Oddoux C et al. Nat GenetNat Genet 14:188, 199614:188, 1996Struewing JP.Struewing JP. N Engl J MedN Engl J Med 336:1401, 1997336:1401, 1997185delAG185delAGPrevalence = ~1%Prevalence = ~1%5382insC5382insCPrevalence = ~0.15%Prevalence = ~0.15%6174delT6174delTPrevalence = ~1.5%Prevalence = ~1.5%BRCA1BRCA1BRCA2BRCA2
Breast Cancer Management Options• Surveillance:– Self breast exam, Clinical breast exam, Mammogram,Breast MRI, and Breast Ultrasound.– MRI has been shown to have higher sensitivity in BRCAcarriers (77-91% for MRI vs. 33-36% for mammography)• Chemoprevention:– Tamoxifen• Prophylactic Surgery:– Bilateral Mastectomy is associated with ~90% reduction ofbreast cancer risk in women with BRCA mutations– Bilateral Salpingo-Oophorectomy is associated with ~50%reduction in breast cancer risk when done prior tomenopause.NEJM 2002;345:159-64. JAMA 2000; 283:617-24. J Clin Oncol 2005;23:8469-8476. JNCI 2001;93:1633-7.Lancet 2000;356:1876-1881. JAMA 2004;292:1317-1325.
Ovarian Cancer Management Options•• Surveillance: CASurveillance: CA--125, Pelvic exams, Transvaginal125, Pelvic exams, Transvaginalultrasoundultrasound““There are no data demonstrating that screening these highThere are no data demonstrating that screening these high--risk womenrisk womenreduces their mortality from ovarian cancer. Nonetheless, [the areduces their mortality from ovarian cancer. Nonetheless, [the abovebovescreening measures] are recommended...screening measures] are recommended...””--NIH Consensus Guidelines,NIH Consensus Guidelines,JAMA 1995;273:491JAMA 1995;273:491--77•• Chemoprevention:Chemoprevention: Oral ContraceptivesOral Contraceptives•• Prophylactic Bilateral SalpingoProphylactic Bilateral Salpingo--Oophorectomy:Oophorectomy: Ovarian cancer risk reduction of ~95%Ovarian cancer risk reduction of ~95% Breast cancer risk reduction of ~50% (premenopausal)Breast cancer risk reduction of ~50% (premenopausal)NEJM 2002;346(21):1609-1615.NEJM 2002;346(21):1616-1622.NEJM 1998;339:424-428.