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Breast Cancer Genetics and the Sephardic Jewish Woman Sephardic Community Center March 26, 2008

Breast Cancer Genetics and the Sephardic Jewish Woman Sephardic Community Center March 26, 2008. Heredity Predisposition to Breast and Ovarian Cancer Among Sephardic Jewish Women. Ruth Oratz, M.D. Harry Ostrer, M.D. NYU School of Medicine. Breast and Ovarian Cancer Statistics - 2008.

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Breast Cancer Genetics and the Sephardic Jewish Woman Sephardic Community Center March 26, 2008

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  1. Breast Cancer Genetics and the Sephardic Jewish Woman Sephardic Community Center March 26, 2008

  2. Heredity Predisposition to Breast and Ovarian Cancer Among Sephardic Jewish Women Ruth Oratz, M.D. Harry Ostrer, M.D. NYU School of Medicine

  3. Breast and Ovarian Cancer Statistics - 2008 In 2008, 243.000 Americans will be diagnosed with breast or ovarian cancer and 56,000 will die from their disease (Cancer is the second leading cause of death in U.S.) >150 deaths per day 5-10% of people with cancer have a significant family history, suggesting a genetic predisposition Jemal, et al, Cancer 2008. CA Cancer J Clin

  4. How is breast cancer diagnosed? • Palpable mass in the breast • Self examination • Physician examination • Breast Imaging • Mammogram • Sonogram (Ultrasound) • MRI • Biopsy • FNA • Core biopsy • Mammotome biopsy • Excisional biopsy

  5. Clinical Presentation of Breast Cancer - Biology • Breast cancer is not one disease • Spectrum of clinical presentations • Biology of breast cancer • Histology • Ductal • Lobular • In situ/Invasive • Molecular Features • ER/PR • Her 2 neu • Proliferation Index

  6. Clinical Presentation of Breast Cancer - Stage • TNM Classification • Tumor size • Lymph node involvement • Spread beyond local area • Treatment based on stage and biology • Surgery • Radiation therapy • Systemic therapy • Hormonal therapy • Chemotherapy • Biologic therapy

  7. What are risk factors ? • Anything that affects your chance of getting a disease, such as cancer. • Smokinglung cancer • Sun exposure skin cancer • Relationship between having risk factors and getting disease • Different kinds of risk factors.: • Age, gender – can’t be changed • Environmental • Behavioral - diet, exercise • Some factors influence risk more than others, • Risk for breast cancer can change over time

  8. Risk Factors for Breast Cancer Personal history of breast cancer Age Time of menarche Time of menopause Age of first term pregnancy Hormone Replacement Therapy/Oral Contraceptives Abnormal breast biopsy Previous chest irradiation Obesity/Physical Activity Alcohol

  9. Family history as a Risk Factor for Breast Cancer

  10. Family History and Breast Cancer • Breast cancer risk is higher among women whose close blood relatives have this disease • 20%-30% of women with breast cancer have a family history • One first degree relative (mother, sister, daughter) • Doubles risk • Two first degree relatives • 5 fold increase • Male with breast cancer

  11. Genetic mutations contribute to cancer development

  12. Genetic Basis of Cancer5-6 Hits in the Tumor Cell DNA Risk Factors Radiation Smoking Dietary carcinogens Heritable mutations Chromosomal loss or rearrangement Somatic mutations

  13. What is the Evidence for aHereditary Predisposition to Cancer?Twin Studies Concordance rates % MZ DZ > Hereditary Breast 14 9 Colorectum (men) 9 8  Colorectum (women) 16 6 Environmental Ovary 5 1 Dizygotic twins Monozygotic twins Prostate 21 6 Lichtenstein P. N Engl J Med. 343:78-85, 2000

  14. Factors Suggestive of Hereditary Cancer More than one affected individual in the same family, frequently in succeeding generations Early age of onset Multiple primary tumors Non-random associations (i.e. breast and ovary) Male breast cancer

  15. Percentage of Cancer that is Hereditary Jemal, et al, Cancer 2004. CA Cancer J Clin 2004; 54:8-29

  16. Breast Cancer Risk Estimates Based on Family History Affected relative Age of affected relative Cumulative risk (%) by age 80 One first degree <50 13-21 >50 9-11 Two second degree <50 10-14 >50 8-9 Two first degree Both < 50 35-48 Both >50 11-24 Two second degree Both < 50 21-26 Both > 50 6-16 Hoskins, et al. JAMA273:577, 1995, adapted from Claus et al. Cancer 73:643, 1994

  17. Inherited Susceptibility to Breast Cancer • 5% - 10% of breast cancer may be caused by inherited susceptibility • Genes related to increased risk of breast cancer • BRCA 1 • BRCA 2 • ATM • CHEK 2 • P53 (Li-Fraumeni Syndrome) • PTEN (Cowden Syndrome)

  18. Genes Conferring High Risk for Breast and Ovarian Cancer

  19. BRCA GENES • BRCA 1 - chromosome 17 • BRCA 2 – chromosome 13 • Mutations in these genes are the most common ones associated with breast & ovarian cancer • Tumor suppressor genes – normally help to prevent cancers from developing • Mutations (abnormalities) in the gene lead to dysfunction – allowing or promoting cancer development

  20. Presumed Effects of Heritable BRCA1 and BRCA2 Mutations DNA damage BRCA1 or BRCA2 mutation Normal BRCA1 or BRCA2 failed DNA repair DNA repair Normal p53 p53 mutation cancer cell death

  21. Does everyone with a BRCA mutation develop cancer? Some individuals with BRCA mutations never develop cancer This can make the cancer appear to skip generations Persons with a mutation, regardless of whether they develop cancer, have a 50/50 chance to pass the mutation on to the next generation.

  22. BRCA GENES – Patterns of Inheritance Family Tree Pedigree

  23. Family with Multiple Cases of Breast and Ovarian Cancer Ov CA Ov CA 50 Br CA 63 Ov CA36

  24. Hereditary Breast Ovarian Cancer Syndrome (BRCA1 / BRCA2) Early age onset breast cancer (often before age 50) Family history of both breast and ovarian cancer Family history of male breast cancer Increased chance of bilateral cancers or an individual with both breast and ovarian cancer Increased incidence of tumors of other specific organs

  25. BRCA mutations BRCA 1 mutations 36 percent to 85 percent lifetime risk for breast cancer (in females) 40 percent to 60 percent lifetime risk for second breast cancer (not reappearance of first tumor) 20 percent to 60 percent lifetime risk for ovarian cancer increased risk for other cancer types, such as prostate cancer BRCA 2 mutations 36 percent to 85 percent lifetime risk for breast cancer (in females) 6 percent lifetime risk for breast cancer (in males) up to 27 percent lifetime risk for ovarian cancer increased risk for other cancer types, such as pancreatic, prostate, laryngeal, stomach cancer, and melanoma

  26. Genetic Counseling? • Genetic counseling • Trained professional • – genetic counselor, physician • Make the right diagnosis • Determine which, if any, test is appropriate • Provide a precise estimate of risk • Provide accurate information about results, prevention, surveillance, treatment • Extend testing to family members

  27. Genetic Counseling for Cancer Risk: Who Should Be Tested? • Test the proband first. • If positive, offer testing to other family members • Do not recommend screening or random testing

  28. Who should consider genetic testing for BRCA mutations ? • Affected individuals • Early age breast cancer • Family history breast/ovarian cancer • Breast & Ovarian cancer in same individual • Unaffected individuals • No personal cancer history • Known mutation carrier in family • High risk family history

  29. What is Genetic Testing? • Blood sample is taken • Genes (DNA) in blood is analyzed • Specific mutation • Multisite 3 mutations • 3 most common mutations found in Ashkenazi Jewish populations • Gene sequencing

  30. How Do We Use the Information: Increased Surveillance Breast cancer Self-exam Mammography Ultrasound/MRI Colon cancer Colonoscopy Ovarian cancer Ultrasound CA125 Prostate cancer Digital exam PSA Ultrasound

  31. Breast Cancer Surveillance • Screening • Diagnosis • Monitor for recurrence • Watch for contralateral breast cancer • Techniques • Self Exam • Physician Exam • Mammogram • Ultrasound • MRI

  32. How Do We Use the Information: Risk-Reducing Surgery or Chemoprevention? Breast cancer Hormonal manipulation Prophylactic mastectomy Colon cancer Diet Aspirin/NSAID Total colectomy Ovarian cancer Hormonal manipulation Prophylactic oophrectomy Prostate cancer Hormonal manipulation Diet

  33. Ovarian Cancer: Screening and Prevention • Detection • History & Physical Exam • Family History • Transvaginal Pelvic Sonogram • ? CA 125 • ? New serum markers • Clinical trials • Risk Reduction • Prophylactic BSO

  34. Family with Multiple Cases of Breast and Ovarian Cancer Ov CA 50 Br CA 63 Ov CA36

  35. Event-Free Survival By Mutation Status from Robson, et al. J Clin Oncol 16:1642-1649, 1998

  36. Second Malignancies in BRCA1/2 Carriers Mutation carriers 12 contralateral BC 3 ovarian neoplasia 1 AML No Mutation 5 contralateral BC 0 ovarian neoplasia 1 endometrial carcinoma

  37. Benefit of Risk-Reducing Surgery Rebbeck, New Engl J Med. 346:1616-22, 2002

  38. Protections Against Genetic Discrimination NYS Insurance Law. § 2615. Genetic testing written informed consent. “No authorized insurer or person acting on behalf of an authorized insurer shall request or require an individual proposed for insurance coverage to be the subject of a genetic test without receiving the written informed consent of such individual prior to such testing, in advance of the test.” NYS Civil Rights Law. § 79-l. Confidentiality of records of genetic tests. “No person shall perform a genetic test on a biological sample taken from an individual without the prior written informed consent of such individual.” Americans with Disabilities Act. Prohibits discrimination against a person who is regarded as having a disability. Health Insurance Portability and Accountability Act. Prohibits group health plans from using any health status-related factor, including genetic information, as a basis for denying or limiting eligibility for coverage or for increasing premiums. Support GINA http://www.genome.gov/PolicyEthics/LegDatabase/pubMapSearch.cfm

  39. Knowledge is power Sir Francis Bacon - 1597 Religious Meditations

  40. BRCA mutations in Jewish Populations

  41. Are there mutations specific to the Jewish Population ? MULTISITE 3 MUTATIONS Account for the majority of inherited breast and ovarian cancer in people of Ashkenazi Jewish descent If there is a mutation that is responsible for the cancer in an Ashkenazi Jewish family, approximately 90 % of the time it will be one of these 3 mutations • BRCA 1 • 187delAG (185delAG) • 5385insC • BRCA 2 • 6174delT

  42. * *

  43. de Oñate’s Expedition Left encampment at Rio Conchos on February 7, 1598 ~129 soldiers plus women, children, and servants Arrived San Juan (near Santa Fe) July, 1598

  44. Chronology 1598: de Oñate settles San Juan 1609: de Paralta founds Santa Fe 1609 - 1680: continued expansion 1680: Pueblo revolt 1693: Spanish retake New Mexico 1851: Beaubien founds San Luis, CO

  45. BRCA mutations in the San Luis Valley Hispanic population 19 breast and ovarian cancer patients, self-identified as Hispanic, with San Luis Valley ancestry All met American Society of Clinical Oncologists Genetic Testing for Cancer Predisposition Inclusion Criteria All denied knowledge of Jewish ancestry Underwent clinical DNA sequencing of BRCA1 and BRCA2 genes by Myriad Genetics Laboratory, Inc.

  46. San Luis Valley BRCA1/2 Results • 10 patients tested positive for a BRCA1 or BRCA2 mutation/variant • 6 185delAG BRCA1 mutation (5 breast cancer, 1 ovarian cancer) • 1 E1339X deleterious mutation in BRCA1 • 1 1205del56 deleterious mutation in BRCA1 • 1 D596H variant in BRCA2 • 1 I2490T variant in BRCA2

  47. 185delAG BRCA1 mutation Found in ~1% of the Ashkenazi Jewish population Other Ashkenazi Jewish mutations (5382insC BRCA1 and 6174delT BRCA2) not seen so far in San Luis Valley 185delAG reported in Spanish, with AJ haplotype (indicating a common ancestor)

  48. What about Sephardic Populations ?

  49. Major Migrations in Jewish History 300 date B.C.E.. 1900 1500 1100 700 Destruction of 2nd Temple Jewish captives to Rome DFNB1, FMF, G6PD, CF BRCA1, BRCA2, FIX, FV&VIII, LRRK2 Abraham migrates from Ur in the Chaldees to Hebron in Canaan Kingdom of David and Solomon Assyrian conquest and exile Hebrew Exodus from Egypt Babylonian conquest and exile Hasmonean Jewish Kingdom Establishment ofCohanim Y lineage HEXA

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