Global DNA Methylation, Measured by the Luminometric Methylation Assay (LUMA), Associates with Postmenopausal Breast Cancer in Non-Obese and Physically Active Women

Introduction: Little is known about how modifiable lifestyle factors interact with the epigenome to influence disease. Body mass index (BMI, weight kg/height m2) and physical activity are associated with postmenopausal breast cancer, but the mechanisms are not well-understood. We hypothesized that BMI or physical activity may modify the association between markers of global DNA methylation and postmenopausal breast cancer risk. Methods: Resources from a population-based case-control study (~1300 postmenopausal women) were used to construct logistic regression models. We explored whether the association between breast cancer and global methylation, assessed using the luminometric methylation assay (LUMA) and long interspersed elements-1 (LINE-1) methylation in white blood cell DNA, was modified by BMI or recreational physical activity (RPA). Results: The LUMA-breast cancer association was modified by BMI (multiplicative p=0.03) and RPA (p=0.004). Non-obese women in the highest quartile of LUMA experienced a greater than two-fold increased risk of postmenopausal breast cancer (BMI<25kg/m2: OR=2.16; 95% CI=1.35, 3.57 and BMI 25-29.9kg/m2: OR=2.96; 95% CI=1.69, 5.19) compared to women in the lowest LUMA quartile. Similar increases in the LUMA-breast cancer association were observed among women who were physically active (moderate RPA: OR=2.62; 95% CI=1.44, 4.75 and high RPA: OR=2.62; 95% CI=1.53, 4.49). Estimates among obese and inactive women were less pronounced and imprecise. Although we observed statistical interactions (p<0.05) between BMI and RPA with LINE-1, we were unable to discern any clear associations with breast cancer. Conclusions: The association between LUMA and postmenopausal breast cancer risk may be modified by postmenopausal body size and physical activity.