Abstract

Background: DNA methylation (DNAm)–based marker of aging, referred to as 'epigenetic age' or 'DNAm age' is a highly accurate multi-tissue biomarker for aging, associated with age-related disease risk, including cancer. Breast cancer (BC), an age-associated disease, is associated with older DNAm age and epigenetic age acceleration (age accel) at tissue levels. But this raises a question on the predictability of DNAm age/age accel in BC development, emphasizing the importance of studying DNAm age in pre-diagnostic peripheral blood (PB) in BC etiology and prevention. Methods: We included postmenopausal women from the largest study cohort and prospectively investigated BC development with their pre-diagnostic DNAm in PB leukocytes (PBLs). We estimated Horvath's pan-tissue DNAm age and investigated whether DNAm age/age accel highly correlates with risk for developing subtype-specific BC and to what degree the risk is modified by hormones and lifestyle factors. Results: DNAm age in PBLs was tightly correlated with age in this age range, and older DNAm age and epigenetic age accel were significantly associated with risk for developing overall BC and luminal subtypes. Of note, in women with bilateral oophorectomy before natural menopause experiencing shorter lifetime estrogen exposure than those with natural menopause, epigenetic age accel substantially influenced BC development, independent of obesity status and exogeneous estrogen use. Conclusions: Our findings contribute to better understanding of biologic aging processes that mediate BC carcinogenesis, detecting a non-invasive epigenetic aging marker that better reflects BC development, and ultimately identifying the elderly with high risk who can benefit from epigenetically targeted preventive interventions.