Genetic Epidemiology of Breast Cancer

1. Genetic Epidemiology of Breast Cancer Susan Neuhausen, PhD Epidemiology Div., Dept. Medicine University of California Irvine Irvine, CA USA

2. Risk factors for disease Inherited (exposure) Genotypes Somatic (outcome) Physical and biologic agents, e.g., chemical exposures, drugs, infectious agents Exposures Lifestyle, e.g., smoking, alcohol use, nutrition, # pregnancies Sex Age Demographics Ethnicity Genotypes Exposures Interactions Demographics, e.g., age, sex

3. SEER US incidence rates for breast cancer, 1988-1992

4. Age-specific incidence of breast cancer for different population groups Based on Cancer Incidence in Five Continents

5. Familial risks

6. Importance of identifying genes • Objectives • To understand the etiology of the disease • To develop more accurate models for risk estimation • Purpose • To develop more specific strategies and therapies • To target individuals at highest risk of developing cancer (or other diseases being studied) for preventative strategies, surveillance,etc.

7. General classes of genes causing susceptibility to disease

8. 21 20 22 23 25 26 19 1 2 3 4 5 6 7 8 9 10 11 14 15 16 17 18 24 27 BRCA1 and BRCA2 BRCA1 20 19 21 18 22 3 10 12 14 9 17 23 1 11 2 5 6 7 8 13 15 16 24 5382insC 185delAG BRCA2 Identified mutation 6174delT

9. Founder effect A high frequency of a mutant gene in a population founded by a small ancestral group Ancestral group Generations later One random mutation Mutation spread throughout population

10. Examples of recurrent mutations found in BRCA1 and BRCA2

11. What factors modify the risk of developing cancer, the type of cancer, and the age at which it develops? • Genotype-phenotype correlations • OCCR region in BRCA2 and BRCA1 • Gene-environment interactions • Oral contraceptive use • Parity, Age at menarche • Prophylactic oophorectomy • Gene-gene interactions • Androgen receptor • AIB1 • RAD51

12. Breast and ovarian cancer risks by location From Thompson & Easton, J Mammary Gland Biol Neoplasia 9:221. 2004

13. Age specific penetrance differs by ascertainment From Thompson & Easton, J Mammary Gland Biol Neoplasia 9:221. 2004

14. There is substantial inter-individual variability in cancer risk among BRCA1 and BRCA2 mutation carriers • Even among those carrying the same deleterious mutation, there is large variation in age at diagnosis and cancer type • This suggests that there are additional genetic and environmental factors that modify risk

15. Collaborative group of BRCA1/2 mutation carriers for modifier studies Baylor-Dallas Baylor-Houston City of Hope Creighton Dana Farber Duke Fox Chase Georgetown Mayo Northwestern UChicago UC Irvine UCLA UPenn UT Southwestern UToronto UVienna Candidate Modifiers: IGF (UC Irvine) Candidate Modifiers: DNA repair (UPenn) BRCA1/2 Cohort 2434 carriers and 1600DNAs** Candidate Modifiers: TBA Novel Modifiers Detection (Penn)

16. Breast cancer families due to BRCA1 and BRCA2

17. Efforts to find additional high penetrance breast cancer susceptibility genes • Study families known not to have BRCA1 or BRCA2 mutations • No ovarian or male breast cancer in the family • At least three cases of breast cancer diagnosed <60 years • Helpful to stratify by • Gene expression • Comparative genomic hybridization • Tumor histology • Other cancer types

18. Putative BRCA3 loci • 8p12-p22 • Seitz et al., 1997; 3-point LOD = 3.30 in 2 German families • Rahman et al., 2000; 31 BC families. No linkage evidence • 13q21 • Kainu et al., 2000. Scandanvian families. 2-point LOD of 2.8; multipoint HLOD of 3.46. Tumors had LOH at 13q21-q22. • Thompson et al., 2002. 128 families- no linkage evidence • Other linkage evidence from BCLC: 149 families w/>3 BC cases • Best LOD of 2.4 on 2p in families with 4+ cases <age 50 • CONCLUSION: No gene is likely to account for a large fraction of the breast cancer families. Likely multiple genes with small contributions

19. Polygenic model of cancer risk Cases Population

20. Association studies • A marker locus is associated with a disease if the distribution of genotypes at the marker locus in disease-affected individuals differs from the distribution in the general population • A specific allele may be positively associated (over-represented in affecteds) or negatively associated (under-represented)

21. CHEK2 1100delC and breast cancer • CHEK2 encodes a G2/M checkpoint kinase. • 1100delC variant abolishes the kinase activity • 1.4% frequency in controls in Europe; 0.4% in US • Meijers-Heijboer and BrCa Consortium first reported an association with breast cancer • 2-fold increased risk for breast cancer • Attributable risk of 9% for male breast cancer, based on families with male breast cancer • Vajterostp et al. 2002 confirmed 2-fold increased risk BC • Male breast cancer: Neuhausen et al., 2004; Syrjakoski et al., 2004 found no increased risk • CONCLUSION: 2-fold increased risk in women with a family history

22. ATM and breast cancer risk • Carriers of mutations in ATM suffer from ataxia-telangiectasia (AT) • Protein is activated in response to DNA damage by ionizing radiation • Female heterozygotes are at a 3-4 fold increased risk of breast cancer • Inconclusive results of ATM missense mutations and breast cancer risk

23. Summary of six breast cancer susceptibility genes Other associations have been reported but not replicated From Thompson & Easton. 2004. J Mammary Gland Biol Neoplasia 9:221.

24. Contribution of known genes to breast cancer BRCA1 BRCA2 TP53,PTEN, STK11 ATM/CHEK2 Other genes, familial not genetic

25. Association studies to identify additional low to moderate penetrance genes • Need large numbers • Genome-wide using 100+K SNPs • Targeted pathways, e.g. • Insulin-like growth factor • Estrogen metabolism • Inflammation • DNA repair • Incorporation of additional factors into models for analysis • Lifestyle factors • Gene x gene interactions • Gene x environment interactions

26. Considerations for association studies • Study Design: case-control, cohort, family- based • Choice of cases • Choice of controls • Choice of genes and pathways • Selection of genetic variants • Statistical issues

27. Multi-Step Carcinogenesis A 21th Century View: