Abstract 3280: Interaction between genetic variants in mTOR and body size on breast cancer risk in African-American and European-American women

Abstract

Abstract Mammalian target of rapamycin (mTOR), a key protein in the phosphatidylinositol 3-kinase/Akt/mTOR (PI3K-AKT-mTOR) pathway promoting cell proliferation and angiogenesis, can be activated by overfeeding in animal models. However, epidemiological data on the mTOR pathway and breast cancer risk are very limited. We investigated the association of 13 single nucleotide polymorphisms (SNPs) in mTOR with breast cancer and potential effect modification of body size in the Women's Circle of Health Study (WCHS), a large case-control study in New York and New Jersey. Participants included 658 incident cases and 649 controls of European American background (EA) and 621 African-American (AA) cases and 744 matched controls, aged 20-75 y. Body size was approximated by body mass index (BMI) at recruitment measured by trained interviewers or obtained from self-report if the measurement was unavailable. Because allele frequencies varied between AAs and EAs, multivariable logistic regression was performed separately within groups, adjusting for age, family history, education, history of benign breast disease, cigarette smoking, proportion of European ancestry, and BMI (for main effects only). We observed higher risks of breast cancer associated with 3 SNPs in high linkage disequilibrium (r2 = 1) (rs2536 [3’-UTR], p=0.08; rs12116957 [intron], p=0.09; rs12125777 [intron], p=0.018) under a dominant genetic model among EA women. For rs12125777, variant allele carriers had a 71% higher breast cancer risk (odds ratio [OR]=1.71, 95% confidence interval (CI)=1.10-2.66) compared to non-carriers. The risk was more prominent among women who were overweight/obese (i.e., BMI ≥25 kg/m2; OR=3.34, 95% CI=1.67-6.69), compared to that among those with normal weight (OR=0.89, 95% CI=0.48-1.68; p-interaction=0.009). Compared to estrogen receptor (ER) positive cancers, the increased risk was more noticeable for ER negative cancers: the ORs comparing variant allele carriers to non-carriers were 2.68 (95% CI=1.24-5.79) overall, 8.49 (95% CI=2.85-25.3) among overweight/obese women, and 0.94 (95% CI=0.26-3.38) among normal-weight women; p-interaction=0.018. No association of genetic variants in mTOR with breast cancer was observed among AA women at a significant level of 0.1. Our findings suggest an etiologic role of overweight/obesity via promoting the mTOR pathway in breast carcinogenesis among EA women. Citation Format: Ting-Yuan D. Cheng, Jyoti Shankar, Gary Zirpoli, Song Yao, Michelle Roberts, Chi-Chen Hong, Elisa V. Bandera, Christine B. Ambrosone. Interaction between genetic variants in mTOR and body size on breast cancer risk in African-American and European-American women. [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 3280. doi:10.1158/1538-7445.AM2014-3280