Abstract 3272: Association between estrogen-metabolizing genetic risk scores and breast cancer risk

Purpose: Estrogens are metabolized by phase I enzymes to intermediate metabolites, which are conjugated by phase II enzymes to be excreted. Differences in estrogen metabolism by phase I and phase II enzymes may contribute to breast cancer risk. The levels and activities of these enzymes are controlled, in part, by genetic polymorphisms. We evaluated three genetic risk scores constructed to reflect the contributions of phase I, phase II and combined phase I/II estrogen-metabolizing activity in association with breast cancer risk. Methods: Data arise from 1296 White breast cancer cases and 1295 White controls enrolled in the Nashville Breast Health Study, a population-based case-control study conducted during 2001-2008. Telephone interviews obtained data on breast cancer risk factors. Saliva samples were obtained to determine genotypes for 12 functional variants in genes involved in estrogen metabolism (AHR, CYP1A1, CYP1A2, CYP3A4, NQO1, COMT, SULT1A1, UGT2B17, GSTM1 and GSTT1). Risk scores were formed according to the hypothesis that women with high phase I and II estrogen metabolizing profiles were at lower breast cancer risk, irrespective of menopausal status. Risk alleles in single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) were summed to form risk scores containing phase I, phase II or combined phase I/II genetic variants. The combined phase I/II estrogen metabolizing score used subjects in the quartile for highest phase II estrogen metabolizing as the reference group. All other participants were separated at the median according to phase I enzyme activity. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression to test associations between genetic scores and breast cancer risk. Likelihood ratio tests p-values were obtained for interactions between the phase I/II combined score and risk factors that may modify the association between endogenous estrogen metabolism and breast cancer, including age at menarche, menopausal status, age at menopause, body mass index and well-done red meat consumption. Results: Lower phase I and phase II estrogen metabolizing activity scores were associated with non-significant increased breast cancer risk. Women with low phase I/II estrogen metabolizing risk scores had an increased OR of 1.22 (CI: 1.01-1.47) compared to participants with high phase II estrogen metabolizing scores. Lower copy numbers of the UGT2B17 variant were associated with increased risk (OR: 1.16, CI: 1.03-1.30). No other individual CNVs or SNPs were associated with breast cancer risk. Effect modification was not observed by other risk factors (all P>0.05). Conclusions: Lower phase I and phase II metabolism activity as measured by functional genetic variants is associated with a modest increase in breast cancer risk; this relationship is not modified by established breast cancer risk factors. Citation Format: Shaneda N. Warren Andersen, Guoliang Li, Qiuyin Cai, Alicia Beeghly-Fadiel, Martha J. Shrubsole, Xiao-Ou Shu, Wei Zheng. Association between estrogen-metabolizing genetic risk scores and breast cancer risk. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3272. doi:10.1158/1538-7445.AM2014-3272