Translational Sciences Section, Jonsson Comprehensive Cancer Center, School of Nursing, University of California, Los Angeles, Los Angeles, California.
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Cancer Res. 2019 May 15;79(10):2784-2794. doi: 10.1158/0008-5472.CAN-18-3688. Epub 2019 Apr 1.
Obesity-insulin connections have been considered potential risk factors for postmenopausal breast cancer, and the association between insulin resistance (IR) genotypes and phenotypes can be modified by obesity-lifestyle factors, affecting breast cancer risk. In this study, we explored the role of IR in those pathways at the genome-wide level. We identified IR-genetic factors and selected lifestyles to generate risk profiles for postmenopausal breast cancer. Using large-scale cohort data from postmenopausal women in the Women's Health Initiative Database for Genotypes and Phenotypes Study, our previous genome-wide association gene-behavior interaction study identified 58 loci for associations with IR phenotypes (homeostatic model assessment-IR, hyperglycemia, and hyperinsulinemia). We evaluated those single-nucleotide polymorphisms (SNP) and additional 31 lifestyles in relation to breast cancer risk by conducting a two-stage multimodal random survival forest analysis. We identified the most predictive genetic and lifestyle variables in overall and subgroup analyses [stratified by body mass index (BMI), exercise, and dietary fat intake]. Two SNPs ( rs17254590 and rs117911989), exogenous factors related to lifetime cumulative exposure to estrogen, BMI, and dietary alcohol consumption were the most common influential factors across the analyses. Individual SNPs did not have significant associations with breast cancer, but SNPs and lifestyles combined synergistically increased the risk of breast cancer in a gene-behavior, dose-dependent manner. These findings may contribute to more accurate predictions of breast cancer and suggest potential intervention strategies for women with specific genetic and lifestyle factors to reduce their breast cancer risk. SIGNIFICANCE: These findings identify insulin resistance SNPs in combination with lifestyle as synergistic factors for breast cancer risk, suggesting lifestyle changes can prevent breast cancer in women who carry the risk genotypes.
肥胖与胰岛素之间的关联一直被认为是绝经后乳腺癌的潜在危险因素，而胰岛素抵抗 (IR) 基因型和表型之间的关联可以通过肥胖-生活方式因素来改变，从而影响乳腺癌的风险。在这项研究中，我们在全基因组水平上探讨了 IR 在这些途径中的作用。我们确定了 IR 遗传因素，并选择了生活方式来为绝经后乳腺癌生成风险概况。我们利用来自妇女健康倡议数据库的基因型和表型研究的绝经后妇女的大型队列数据，我们之前的全基因组关联基因-行为相互作用研究确定了 58 个与 IR 表型相关的基因座（稳态模型评估-IR、高血糖和高胰岛素血症）。我们通过进行两阶段多模态随机生存森林分析，评估了这些单核苷酸多态性 (SNP) 和另外 31 种生活方式与乳腺癌风险的关系。我们在总体和亚组分析（按体重指数 (BMI)、运动和饮食脂肪摄入量分层）中确定了最具预测性的遗传和生活方式变量。两个 SNP（rs17254590 和 rs117911989）、与终生累积暴露于雌激素、BMI 和饮食酒精摄入相关的外源性因素是整个分析中最常见的影响因素。个体 SNP 与乳腺癌没有显著关联，但 SNP 和生活方式联合协同地以基因-行为、剂量依赖的方式增加了乳腺癌的风险。这些发现可能有助于更准确地预测乳腺癌，并为具有特定遗传和生活方式因素的女性提供潜在的干预策略，以降低其乳腺癌风险。
这些发现确定了胰岛素抵抗 SNP 与生活方式相结合是乳腺癌风险的协同因素，这表明生活方式的改变可以预防携带风险基因型的女性发生乳腺癌。
