Genetics and Breast and Ovarian Cancer

1. Genetics and Breast and Ovarian Cancer An Introduction

2. Genetics and Breast Cancer • Inherited breast/ovarian cancer is an autosomal dominant condition • Occurs as a result of mutations in BRCA1 or BRCA2 genes • BRCA 1 - gene on chromosome 17 • BRCA 2 - gene on chromosome 13 BRCA 2 Chromosome 13 BRCA 1 Chromosome 17

3. Genetic Forms of Breast Cancer • Individuals with one copy of either mutated gene are at increased risk of breast and/or ovarian cancer. • ~60% lifetime risk breast cancer • ~10-40% lifetime risk ovarian cancer

4. Incidence of BRCA genes • BRCA1 • 3.5% Hispanic, • 1.3% to 1.4% African American, • 0.5% Asian American, • 2.2% to 2.9% non-Ashkenazi Caucasian, and • 8.3 % to 10.2% Ashkenazi Jewish. • BRCA2 • 2.6% African American and • 2.1% Caucasian

5. Heterozygous Individuals • Theoretically, heterozygous individuals with the BRCA 1 or 2 gene will have a normal allele on the other paired chromosome. • FYI…It would be unusual to be homozygous for BRCA 1 or 2

6. Heterozygous Individuals • HOWEVER….. • In most breast and ovarian cancers studied, in those carrying the mutation the normal allele on the homologous chromosome is deleted, • As a result there is a loss of all function of the BRCA 1 or 2 healthy gene product.

7. What do the BRCA genes code for? • The BRCA genes seem to code for tumor suppressor proteins • Needed to keep cells from becoming cancerous • BRCA gene products also play a role in: • DNA repair • Cell Cycle control • And other functions

8. Over 2000 different mutations have been identified in the BRCA genes • Not all have the same cancer risk • The cancer risk associated with each mutation depends on the impact of the mutation on the protein’s structure and function. • Most BRCA1 and BRCA2 mutations are predicted to produce a truncated protein product, and a loss of protein function.

9. Alexandra Best’s Story • Alexandra Best’s mother and grandmother died from breast cancer. • After visiting the doctor to voice her concerns, she discovered that researchers had traced the origins of her family's history of breast cancer back to three Italian brothers who emigrated to England in the 1850s. • Thirty-one members of her family had developed the disease since then - and the researchers said she was likely to be carrying the gene.

10. Alexandra’s Relatives –many generations back

11. What she did. • Alexandra was tested for the BRCA gene and found to carry it. • She decided to have a preventative mastectomy • During preparation for the operation a cancerous lump was found in her breast. • Lead to a double mastectomy and chemotherapy.

12. Alexandra’s extended family was tested and 11 were found to carry the BRCA gene • 8 have had preventative surgery • Another family tree for a real family follows.

13. Family positive for BRCA 1 deleterious mutation positive for mutation ** Preventive measure taken Ethel E. Laird Breast 28 Death 32 Marjorie Halt Ovarian 64,69 Death 69 Maryann Laird Breast 44, 46 Ovarian 63 Death 64 Paula (59) Breast 48 ** Barbara Breast 38, 40 Death 44 Susan Halt Davis (53) Breast 49 ** ** Linda Halt Nicholson (60) Steve Halt (57) ** BRCA I Neg Julianne BRCA I Neg Kevin (32) 2 Children Gina (30) Kristi (28) Amber (28) Jeffrey (40) No Children Richard Death 3-5-07 Age 25 Car accident Jennifer, 22