mTOR 通路候选基因与肥胖在黑人女性乳腺癌风险中的相互作用：妇女健康研究。
mTOR pathway candidate genes and obesity interaction on breast cancer risk in black women from the Women's Circle of Health Study.
机构信息
Department of Epidemiology, University of Florida, Gainesville, FL, USA.
Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.
出版信息
Cancer Causes Control. 2023 May;34(5):431-447. doi: 10.1007/s10552-022-01657-9. Epub 2023 Feb 15.
BACKGROUND
Obesity is known to stimulate the mammalian target of rapamycin (mTOR) signaling pathway and both obesity and the mTOR signaling pathway are implicated in breast carcinogenesis. We investigated potential gene-environment interactions between mTOR pathway genes and obesity in relation to breast cancer risk among Black women.
METHODS
The study included 1,655 Black women (821 incident breast cancer cases and 834 controls) from the Women's Circle of Health Study (WCHS). Obesity measures including body mass index (BMI); central obesity i.e., waist circumference (WC) and waist/hip ratio (WHR); and body fat distribution (fat mass, fat mass index and percent body fat) were obtained by trained research staff. We examined the associations of 43 candidate single-nucleotide polymorphisms (SNPs) in 20 mTOR pathway genes with breast cancer risk using multivariable logistic regression. We next examined interactions between these SNPs and measures of obesity using Wald test with 2-way interaction term.
RESULTS
The variant allele of BRAF (rs114729114 C > T) was associated with an increase in overall breast cancer risk [odds ratio (OR) = 1.81, 95% confidence interval (CI) 1.10-2.99, for each copy of the T allele] and the risk of estrogen receptor (ER)-defined subtypes (ER+ tumors: OR = 1.83, 95% CI 1.04,3.29, for each copy of the T allele; ER- tumors OR = 2.14, 95% CI 1.03,4.45, for each copy of the T allele). Genetic variants in AKT, AKT1, PGF, PRKAG2, RAPTOR, TSC2 showed suggestive associations with overall breast cancer risk and the risk of, ER+ and ER- tumors (range of p-values = 0.040-0.097). We also found interactions of several of the SNPs with BMI, WHR, WC, fat mass, fat mass index and percent body fat in relation to breast cancer risk. These associations and interactions, however, became nonsignificant after correction for multiple testing (FDR-adjusted p-value > 0.05).
CONCLUSION
We found associations between mTOR genetic variants and breast cancer risk as well as gene and body fatness interactions in relation to breast cancer risk. However, these associations and interactions became nonsignificant after correction for multiple testing. Future studies with larger sample sizes are required to confirm and validate these findings.
背景
肥胖已知会刺激哺乳动物雷帕霉素靶蛋白（mTOR）信号通路，肥胖和 mTOR 信号通路都与乳腺癌的发生有关。我们研究了 mTOR 通路基因与肥胖之间的潜在基因-环境相互作用与黑人女性乳腺癌风险的关系。
方法
该研究包括来自妇女健康研究圈（WCHS）的 1655 名黑人女性（821 例乳腺癌新发病例和 834 例对照）。由经过培训的研究人员获得肥胖测量值，包括体重指数（BMI）；中心肥胖，即腰围（WC）和腰臀比（WHR）；以及体脂分布（脂肪量、脂肪量指数和体脂百分比）。我们使用多变量逻辑回归研究了 20 个 mTOR 通路基因中 43 个候选单核苷酸多态性（SNP）与乳腺癌风险的关系。接下来，我们使用 Wald 检验和双向交互项检验了这些 SNP 与肥胖测量值之间的相互作用。
结果
BRAF（rs114729114 C > T）的变异等位基因与整体乳腺癌风险增加相关[比值比（OR）= 1.81，95%置信区间（CI）1.10-2.99，每增加一个 T 等位基因]，以及雌激素受体（ER）定义的亚型（ER+肿瘤：OR= 1.83，95%CI 1.04，3.29，每增加一个 T 等位基因；ER-肿瘤 OR= 2.14，95%CI 1.03，4.45，每增加一个 T 等位基因）。AKT、AKT1、PGF、PRKAG2、RAPTOR、TSC2 中的基因变异与整体乳腺癌风险以及 ER+和 ER-肿瘤的风险呈显著相关（p 值范围为 0.040-0.097）。我们还发现了几个 SNP 与 BMI、WHR、WC、脂肪量、脂肪量指数和体脂百分比之间与乳腺癌风险的相互作用。然而，在进行多重测试校正（FDR 调整后的 p 值>0.05）后，这些关联和相互作用变得不显著。需要更大样本量的未来研究来证实和验证这些发现。
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