The extent to which physical activity reduces breast cancer risk through changes in global DNA methylation is unknown. We systematically identified studies that investigated the association between: (i) physical activity and global DNA methylation; or (ii) global DNA methylation and breast cancer risk. Associations were quantified using random-effects models. Heterogeneity was investigated through subgroup analyses and the Q-test and I 2 statistics. Twenty-four studies were reviewed. We observed a trend between higher levels of physical activity and higher levels of global DNA methylation [pooled standardized mean difference = 0.19; 95% confidence interval (CI), -0.03-0.40; P = 0.09] which, in turn, had a suggestive association with a reduced breast cancer risk (pooled relative risk = 0.70; 95% CI, 0.49-1.02; P = 0.06). In subgroup analyses, a positive association between physical activity and global DNA methylation was observed among studies assessing physical activity over long periods of time (P = 0.02). Similarly, the association between global DNA methylation and breast cancer was statistically significant for prospective cohort studies (P = 0.007). Despite the heterogeneous evidence base, the literature suggests that physical activity reduces the risk of breast cancer through increased global DNA methylation. This study is the first to systematically overview the complete biologic pathway between physical activity, global DNA methylation, and breast cancer. Cancer Epidemiol Biomarkers Prev; 27(11); 1320-31. ©2018 AACR.
©2018 American Association for Cancer Research.