Epigenetic mortality predictors and incidence of breast cancer

Measures derived using blood DNA methylation are increasingly under investigation as indicators of disease and mortality risk. Three existing epigenetic age measures or “epigenetic clocks” appear associated with breast cancer. Two newly-developed epigenetic mortality predictors may be related to all-cancer incidence, but associations with specific cancers have not been examined in large studies. Using HumanMethylation450 BeadChips to measure blood DNA methylation in 2,773 cancer-free women enrolled in the Sister Study, we calculated two epigenetic mortality predictors: ‘GrimAgeAccel’ and the ‘mortality score’ (MS). Using Cox proportional hazard models, neither GrimAgeAccel nor the MS were associated with overall breast cancer incidence (GrimAgeAccel hazard ratio [HR]: 1.06, 95% confidence interval [CI]: 0.98-1.14, P=0.17; MS HR: 0.99, 95% CI: 0.92-1.07, P=0.85); however, a weak, positive association was observed for GrimAgeAccel and invasive breast cancer (HR: 1.08, 95% CI: 0.99-1.17, P=0.08). Stratification of invasive cancers by menopause status at diagnoses revealed the association was predominantly observed for postmenopausal breast cancer (HR: 1.10, 95% CI: 1.01, 1.20, P=0.04). Although the MS was unrelated to breast cancer risk, we find evidence that GrimAgeAccel may be weakly associated with invasive breast cancer, particularly for women diagnosed after menopause.