Genetic Variants in Metabolic Signaling Pathways and Their Interaction with Lifestyle Factors on Breast Cancer Risk: A Random Survival Forest Analysis.

Genetic variants in the insulin-like growth factor-I (IGF-I)/insulin resistance axis may interact with lifestyle factors, influencing postmenopausal breast cancer risk, but these interrelated pathways are not fully understood. In this study, we examined 54 single-nucleotide polymorphisms (SNP) in genes related to IGF-I/insulin phenotypes and signaling pathways and lifestyle factors in relation to postmenopausal breast cancer, using data from 6,567 postmenopausal women in the Women's Health Initiative Harmonized and Imputed Genome-Wide Association Studies. We used a machine-learning method, two-stage random survival forest analysis. We identified three genetic variants ( rs2494740, rs2494744, and rs2498789) and two lifestyle factors [body mass index (BMI) and dietary alcohol intake] as the top five most influential predictors for breast cancer risk. The combination of the three SNPs, BMI, and alcohol consumption (≥1 g/day) significantly increased the risk of breast cancer in a gene and lifestyle dose-dependent manner. Our findings provide insight into gene-lifestyle interactions and will enable researchers to focus on individuals with risk genotypes to promote intervention strategies. These data also suggest potential genetic targets in future intervention/clinical trials for cancer prevention in order to reduce the risk for breast cancer in postmenopausal women. .