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Genetic Epidemiology of Breast Cancer Susan Neuhausen, PhD Epidemiology Div., Dept. Medicine University of California Irvine Irvine, CA USA Risk factors for disease Genotypes Inherited (exposure) Somatic (outcome) Exposures Physical and biologic agents, e.g., chemical exposures, drugs, infectious agents Lifestyle, e.g., smoking, alcohol use, nutrition, # pregnancies Demographics Interactions Sex Age Ethnicity Genotypes Exposures Demographics, e.g., age, sex SEER US incidence rates for breast cancer, 1988-1992 120 Non-Hispanic Cauc Hispanic African American Alaska Native Amer Indian Chinese Japanese Vietnamese Hawaiian 100 80 60 40 20 0 Rates per 100,000 Age-specific incidence of breast cancer for different population groups Based on Cancer Incidence in Five Continents Familial risks Family members Increased risk Personal history 1 first-degree relative 2 first-degree relatives First-degree with bilateral 3-4 fold increased risk 2-fold 5-fold 6-fold 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. General classes of genes causing susceptibility to disease Class Variant frequency Absolute risk Attributable Examples risk Rare variants Low High Low BRCA1, BRCA2 Common variants High Low High AR, NAT2 BRCA1 and BRCA2 3 9 10 12 5 6 7 8 BRCA1 11 Identified mutation 15 19 20 21 18 22 17 23 16 24 5382insC BRCA2 10 14 13 185delAG 1 2 3 45 6 7 8 9 12 11 19 14 15 16 17 18 6174delT 20 21 22 23 25 26 24 27 Founder effect A high frequency of a mutant gene in a population founded by a small ancestral group Ancestral group One random mutation Generations later Mutation spread throughout population Examples of recurrent mutations found in BRCA1 and BRCA2 Population Mutation Ashkenazi Jews BRCA1 185delAG, 5382insC; BRCA2 6174delT Icelanders BRCA2 995delC Dutch BRCA1 IVS12-1643del3835; BRCA2 5573insA Norwegians BRCA1 1136insA and 1675delA Swedes BRCA1 3171ins5, Poles BRCA1 5382insC; C61G, 4153delA 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 Breast and ovarian cancer risks by location From Thompson & Easton, J Mammary Gland Biol Neoplasia 9:221. 2004 Age specific penetrance differs by ascertainment From Thompson & Easton, J Mammary Gland Biol Neoplasia 9:221. 2004 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 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) BRCA1/2 Cohort 2434 carriers and 1600DNAs** Candidate Modifiers: DNA repair (UPenn) Candidate Modifiers: TBA Novel Modifiers Detection (Penn) Breast cancer families due to BRCA1 and BRCA2 Family group BRCA1 BRCA2 Other All Families 4+ BrCa (n=237) 52% 32% 16% 4-5 BrCa (female only) (n=83) 28% 5% 67% 6+ BrCa (female only) (n=34) 21% 60% 19% Br and Ovarian Ca (n=94) 81% 14% 5% Male BrCa in family (n=26) 16% 76% 8% From Ford et al., 1998 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 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 Polygenic model of cancer risk 0.45 0.4 0.35 DENSITY 0.3 Cases 0.25 0.2 Population 0.15 0.1 0.05 0 0.001 0.01 0.1 1 RISK 10 100 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) 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 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 Summary of six breast cancer susceptibility genes Gene Pop’n carrier frequency Risk of BC by 70 yrs (95% CI) BRCA1 BRCA2 CHEK2 ATM 1 in 860 1 in 740 1 in 90 1 in 100 65% (44-78%) 45% (31-56%) 11% (9-14%) 23% (13-39%) TP53 PTEN 1 in 5,000 1 in 250,000 50-60% by 45 yrs 30-50% Other associations have been reported but not replicated From Thompson & Easton. 2004. J Mammary Gland Biol Neoplasia 9:221. Contribution of known genes to breast cancer BRCA1 BRCA2 TP53,PTEN, STK11 ATM/CHEK2 Other genes, familial not genetic 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 Considerations for association studies • Study Design: case-control, cohort, familybased • Choice of cases • Choice of controls • Choice of genes and pathways • Selection of genetic variants • Statistical issues Multi-Step Carcinogenesis A 21th Century View: