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Hereditary Cancer Predisposition


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Patricia A. Ganz, MD
February 13, 2013

Published in: Health & Medicine
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Hereditary Cancer Predisposition

  1. 1. Hereditary Cancer Predisposition Patricia A. Ganz, MD
  2. 2. Cancer is a Genetic Disease NormalNormal TumorTumor
  3. 3. Cancer Arises From Gene Mutations Germline mutations Somatic mutationsSomatic mutations SomaticSomatic mutation (eg,mutation (eg, breast)breast) MutatioMutatio n in eggn in egg oror spermsperm All cellsAll cells affected inaffected in offspringoffspring ParentParent ChildChild ll Present in egg or spermPresent in egg or sperm ll Are heritableAre heritable ll Cause hereditaryCause hereditary cancer syndromescancer syndromes ll Occur in nongermlineOccur in nongermline tissuestissues ll Are nonheritableAre nonheritable ll Later onsetLater onset
  4. 4. All Cancer is Genetic, Not All Cancer is Inherited Fourth + mutation Normal cell Fourth + mutation First mutation Second mutation Third mutation Malignant cell First mutation Second mutation Third mutation Malignant cell Sporadic CancerSporadic Cancer Hereditary CancerHereditary Cancer
  5. 5. Hereditary Versus Sporadic Cancer SporadicSporadic •• 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 same individualindividual •• Male breast cancerMale breast cancer •• Ashkenazi ancestryAshkenazi ancestry HereditaryHereditary Br, 42Br, 42 Ov, 71Ov, 71 Br, 45Br, 45 Br, 71Br, 71 Br, 63Br, 63 •• None of the breastNone of the breast cancer is diagnosedcancer is diagnosed before 60 yrsbefore 60 yrs •• No ovarian cancerNo ovarian cancer •• No clear pattern on oneNo clear pattern on one side of family or theside of family or the otherother
  6. 6. The Key to Identification: Family History ll Maternal andMaternal and paternal familypaternal family historyhistory ll Accurate riskAccurate risk assessmentassessment ll Effective geneticEffective genetic counselingcounseling ll AppropriateAppropriate medical followmedical follow--upup
  7. 7. When to Suspect Hereditary 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 with specific cancer syndrome (eg, breast and ovary) • Evidence of autosomal dominant transmission • Ancestry
  8. 8. How Much Breast and Ovarian Cancer Is Hereditary? SporadicSporadic Family clustersFamily clusters HereditaryHereditary Ovarian CancerOvarian CancerBreast CancerBreast Cancer 5%5%––10%10% >10%>10% 15%15% 20%20%
  9. 9. BRCA1 and BRCA2 BRCA2BRCA2 BRCA1BRCA1 Adapted fromAdapted from Tools for Understanding GeneticsTools for Understanding Genetics National Human Genome Research InstituteNational Human Genome Research Institute Office of Science Education and OutreachOffice of Science Education and Outreach
  10. 10. Inheritance Pattern: Autosomal Dominant with Incomplete Penetrance ll Penetrance is often incompletePenetrance is often incomplete ll May appear toMay appear to ““skipskip”” generationsgenerations ll Individuals inherit altered cancer susceptibilityIndividuals inherit altered cancer susceptibility gene,gene, not cancernot cancer NormalNormal Carrier, affectedCarrier, affected with cancerwith cancer Susceptible CarrierSusceptible Carrier Sporadic cancerSporadic cancer
  11. 11. BRCA1-Associated Cancers: Lifetime Risk Possible increased risk of otherPossible increased risk of other cancers (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%
  12. 12. BRCA2-Associated Cancers: Lifetime Risk Increased risk of prostate andIncreased risk of prostate and pancreatic cancers (magnitudepancreatic cancers (magnitude unknown)unknown) breast cancerbreast cancer 50%50%85%85% ovarian cancerovarian cancer 10%10%27%27% male breast cancermale breast cancer 6%6% Second primarySecond primary breast cancerbreast cancer ~50%~50%
  13. 13. BRCA1 and BRCA2 Mutations in the Ashkenazi Jewish Population An estimated 1 in 40 Ashkenazi JewsAn estimated 1 in 40 Ashkenazi Jews carries acarries a BRCA1BRCA1 oror BRCA2BRCA2 mutationmutation Roa BB et al.Roa BB et al. Nat GenetNat Genet 14:185, 199614:185, 1996 Oddoux C et al.Oddoux C et al. Nat GenetNat Genet 14:188, 199614:188, 1996 Struewing JP.Struewing JP. N Engl J MedN Engl J Med 336:1401, 1997336:1401, 1997 185delAG185delAG Prevalence = ~1%Prevalence = ~1% 5382insC5382insC Prevalence = ~0.15%Prevalence = ~0.15% 6174delT6174delT Prevalence = ~1.5%Prevalence = ~1.5% BRCA1BRCA1 BRCA2BRCA2
  14. 14. 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 BRCA carriers (77-91% for MRI vs. 33-36% for mammography) • Chemoprevention: – Tamoxifen • Prophylactic Surgery: – Bilateral Mastectomy is associated with ~90% reduction of breast cancer risk in women with BRCA mutations – Bilateral Salpingo-Oophorectomy is associated with ~50% reduction in breast cancer risk when done prior to menopause. 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.
  15. 15. Ovarian Cancer Management Options •• Surveillance: CASurveillance: CA--125, Pelvic exams, Transvaginal125, Pelvic exams, Transvaginal ultrasoundultrasound ““There are no data demonstrating that screening these highThere are no data demonstrating that screening these high--risk womenrisk women reduces their mortality from ovarian cancer. Nonetheless, [the areduces their mortality from ovarian cancer. Nonetheless, [the abovebove screening 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.
  16. 16. Genetic Predisposition Testing Is a Multi-Step Process ProvideProvide postpost--testtest counselingcounseling andand followfollow--upup IdentifyIdentify atat--riskrisk patientspatients ProvideProvide pretestpretest counselingcounseling ProvideProvide informedinformed consentconsent Select andSelect and offer testoffer test DiscloseDisclose resultsresults
  17. 17. • Anxiety/fear • Guilt • Self-esteem • Depression • Stigmatization • Grief • Anticipatory loss • Changes in family dynamics • How/when to inform at risk children/relatives Psychological Issues in Testing
  18. 18. Genetic Testing Has Implications for the Entire Family • Consider the impact of testing on all family members • Ultimately, testing is the individual’s choice
  19. 19. Questions???