Abstract 948: Investigation of breast cancer susceptibility loci in the PAGE study

Abstract

Abstract Introduction: Recent genome-wide association studies (GWAS) of breast cancer have identified single nucleotide polymorphisms (SNPs) in more than 20 loci associated with increased risk of breast cancer, primarily in European-descent populations. Yet, the biological mechanisms underlying most of these genetic variants as well as their effect sizes in other populations differing by race/ethnicity remains unknown. We investigated breast cancer associations with previously reported SNPs in white and African American (AA) women from the Population Architecture using Genomics and Epidemiology (PAGE) study. Methods: We selected 28 common SNPs reported in breast cancer GWAS or candidate-gene association studies representing 21 different breast cancer susceptibility loci for our analysis. These SNPs were genotyped in 5878 white and 904 AA postmenopausal women sampled from the Women's Health Initiative Study, which is part of the PAGE consortium. Invasive breast cancer cases (n = 1366 in whites and n=226 in AA) were identified prospectively and confirmed via medical records review. We coded SNPs using additive genetic models and used logistic regression to estimate per allele odds ratios (OR) and 95% confidence intervals (CI). Race/ethnicity-specific models were adjusted for age; adjustment for risk factors such as body mass index, current smoking and postmenopausal hormone therapy (HT) were also investigated. Results: In whites, we observed statistically significant (p<0.05) associations for 14 of 28 SNPs; strongest associations were seen for SNPs in 10q26.13/FGFR2 and 16q12.1/TOX3, with p<0.0001. In AA, 5 of the 28 SNPs located in 1p11.2/NOTCH, 5q11.2/MAP3K1, 10q26.13/FGFR2, and 11p15.5/LSP1 were associated with breast cancer at p<0.05, while an additional 4 were marginally significant at p<0.07. FGFR2 has been strongly implicated as a breast cancer susceptibility locus, though a causal variant has not yet been identified (Udler et al., 2009). Our ORs of ∼1.2 in whites are consistent with prior reports. Additionally, we observed elevated odds of breast cancer, OR (95%CI) = 1.3(1.0-1.7), in AA for a SNP in this locus, rs2981578 (G allele). Conclusions: We confirm prior breast cancer associations in postmenopausal white women and report associations in 4 loci that extend to AA women. Our next steps will be to evaluate associations by cancer subtype and expand investigations in AA to include additional genotype data and women from the other PAGE studies. These results in women differing by race/ethnicity contribute to future research on breast cancer etiology by providing data that can be used to inform the identification and fine mapping of causal breast cancer variants. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 948. doi:10.1158/1538-7445.AM2011-948