1. The Genetics of Breast and Ovarian Cancer Susceptibility Patricia Tonin, PhD Associate Professor Depts. Medicine, Human Genetics & Oncology McGill University McGill University Health Centre patricia.tonin@mcgill.ca

2. How common is hereditary cancer? 85% Hereditary - known genes Hereditary - unknown genes Sporadic - Most cancers are caused by unknown factors likely due to a combination of genetic and environmental factors! 5% 10% 1,055 2,100 17,945

3. Cancer 1994. 73:643-651.

4. Seminars in Surgical Oncology 2000. 18:281-286

5. *Breast cancer risk to age 50 years : 30% for BRCA carriers compared with 2% for general population!!!!!!

6. Features of Families with Genetic Predisposition Cancer occurs in first, second or third degree relatives in relation to cancer case Minimum of 3 cases per family Cancers occur in same branch of the family Maternal OR Paternal Average age of diagnosis is often younger than average age of diagnosis of all cancers of same site (< 55 yrs of age) Mendelian mode of inheritance Autosomal dominant

7. Autosomal Dominant Mode of Inheritance

8. BRCA Positive Family

9. Management of High Risk Women [> 30 years of age < 50 years of age] Screening Mammography (MRI?) –yearly Pelvic examination, CA125 serum test, transvaginal ultrasonography –every 6 months Cancer prevention Breast cancer –prophylactic mastectomy –chemoprevention? Ovarian cancer: –prophylactic oophorectomy

11. Breast cancer families that feature an ovarian cancer case most likely harbor BRCA1 mutations

13. Breast cancer families that feature no ovarian cancer cases and/or a male breast cancer case most likely harbor a BRCA2 mutation

16. Genetic Testing Commercially available via Myriad Genetics Provided at no cost to the individual but on a per case basis via genetic counsel ling centers in Quebec Time-line - very good (~ 1 month) Testing not comprehensive??? Research laboratories Provided at no cost to the individual Time-line is usually longer (> 3 months) Testing may be more comprehensive

17. Assessing Sequence Variants NO FUNCTIONAL ASSAY! Deleterious mutation Predicted change in function based on deduced amino acid sequence Segregates with cancer cases in families Sequence variant of unknown significance Polymorphism No net change in amino acid sequence Does not segregates with cancer cases in families Frequency in unaffected controls and breast cancer cases is similar

18. When a deleterious mutation is found Mutation detection is offered to other members of the family to assess risk based on carrier status Management strategies discussed based on carrier status Mutation analysis can distinguished carriers (highest risk) from non-carriers (lowest risk) and thus improved risk assessment of members of this family

19. BRCA Positive Family

20. When NO sequence variant is found Risk assessment remains based on family history of cancer alone. Mutation analysis has not improved assessment for family members in this situation as a genetic test cannot distinguish highest risk from lowest risk individuals in this family

21. BRCA Positive Family Risk estimates is based on empiric risk estimate ‘tables’. No BRCA Mutation Found 35-48%

22. Genetic Testing Confirmation of cancer cases in family Pathology reports Death certificates Individuals to test Breast cancer case, preferably youngest age of diagnosis in family (<55 years) Ovarian cancer case (any age) Male breast cancer Obligate carrier (example, father of affected daughters) DNA/RNA Samples tested Peripheral blood leukocytes Paraffin embedded or archived tissues discouraged

23. BRCA analysis facilitated by common mutations found at high frequency in well defined populations

26. Genetic Testing at McGill: Genetic Counseling Service Per case basis by referral Family history of cancer Specific mutation analysis: Panel of common mutations for Ashkenazi Jewish population or French Canadian population Previously identified mutation Myriad Genetic Testing: Other populations Mutation-negative cases (Ashkenazi Jewish or French Canadian)

27. Are there guidelines for BRCA mutation analysis?

29. Summary 85% of breast cancers ‘sporadic’ 15% of breast cancers occur in context of family history of breast cancer attributable to transmission of highly penetrant gene 5-10% attributed to germline mutations in BRCA1 and BRCA2 ~1% other known genes ~5% unknown genes Mutation analysis and interpretation facilitated by Nature mutations Common mutations found in well defined populations