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Genetic Variants in the mTOR Pathway and Breast Cancer Risk in African American Women


Cheng, Ting-Yuan David; Ambrosone, Christine B.; Hong, Chi-Chen; Lunetta, Kathryn L.; Liu, Song; Hu, Qiang; Yao, Song; Sucheston-Campbell, Lara E.; Bandera, Elisa V.; & Ruiz-Narvaez, Edward A., et al. (2016). Genetic Variants in the mTOR Pathway and Breast Cancer Risk in African American Women. Carcinogenesis, 37(1), 49-55. PMCID: PMC5006112


The phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin (mTOR) pathway has been implicated in breast carcinogenesis. However, there has been no large-scale investigation of genetic variants in the mTOR pathway and breast cancer risk. We examined 28,847 single nucleotide polymorphisms (SNPs) in 61 mTOR pathway genes in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium of 3663 cases (1983 estrogen receptor-positive [ER+] and 1098 ER-negative [ER-]) and 4687 controls. Gene-level analyses were conducted using the adaptive rank truncated product (ARTP) test for 10,773 SNPs that were not highly correlated (r2<0.8), and SNP-level analyses were conducted with logistic regression. Among genes that were prioritized (nominal P<0.05, ARTP tests), associations were observed for intronic SNPs TSC2 rs181088346 (odds ratio [OR] of each copy of variant allele=0.77, 95% confidence interval [CI]=0.65-0.88 for all breast cancer) and BRAF rs114729114 (OR=1.53, 95% CI=1.10-1.87 for all breast cancer and OR=2.03, 95% CI=1.50-2.76 for ER- tumors). For ER not- tumors, intronic SNPs PGF rs11542848 (OR=1.38, 95% CI=1.15-1.66) and rs61759375 (OR=1.34, 95% CI=1.14-1.57) and MAPK3 rs78564187 (OR=1.26, 95% CI=1.11-1.43) were associated with increased risk. These SNPs were significant at a gene-wide level (Bonferroni-corrected P<0.05). The variant allele of RPS6KB2 rs35363135, a synonymous coding SNP, was more likely to be observed in ER- than ER+ tumors (OR=1.18, 95% CI=1.05-1.31, gene-wide Bonferroni-corrected P=0.06). In conclusion, specific mTOR pathway genes are potentially important to breast cancer risk and to the ER-negativity in AA women.


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Journal Article

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Cheng, Ting-Yuan David
Ambrosone, Christine B.
Hong, Chi-Chen
Lunetta, Kathryn L.
Liu, Song
Hu, Qiang
Yao, Song
Sucheston-Campbell, Lara E.
Bandera, Elisa V.
Ruiz-Narvaez, Edward A.
Haddad, Stephen A.
Troester, Melissa A.
Haiman, Christopher A.
Bensen, Jeannette T.
Olshan, Andrew F.
Palmer, Julie R.
Rosenberg, Lynn A.