Abstract 4444: DNA methylation age is accelerated in breast tissue of healthy women donors

Abstract

Abstract Background: Advanced age and cumulative estrogen exposure are well known risk factors for breast cancer. However, the mechanisms underlying the link between cellular senescence, chronic estrogen stimulation, increased cell cycling, and breast carcinogenesis are poorly understood. We examined epigenetic alterations that occur in the female breast with advancing age, and estrogen exposure. Methods: We utilized specimens from 49 women healthy tissue donors from the Komen Tissue Bank who donated both breast tissue and peripheral blood at two time points spaced at least 2 years apart. Ages of the donors ranged from 18-65 years and they were grouped by menopausal status (27 pre- and and 22 post-menopausal) and parity (21 nulliparous). We assessed epigenome-wide DNA methylation levels (Illumina 450K platform) from DNA extracted from breast and blood tissue, and calculated tissue “DNA methylation age (DNAm age)” based on methylation levels at 353 CpGs that have been shown to strongly correlate with chronologic age across tissues. We examined the relationship between this outcome and age and variables related to cumulative estrogen exposure, including age at menarche, gravidity, parity, and menopausal status. Results: DNAm age was highly correlated with chronological age in our sample (cor = 0.8, p<0.001), within both peripheral blood (cor = 0.94, p<0.001) and breast tissues (cor = 0.88, p<0.001). When we examine the residuals for each sample from our regression analysis of DNAm age versus chronological age, we find that age acceleration is significantly increased in breast relative to peripheral blood tissue (p<0.001). In a multivariate regression analysis, we found that earlier age at menarche (β = -0.62, p = 0.04) and higher gravidity (β = 0.95, p = 0.03) were associated with higher DNAm age. Conclusions: We find that DNAm age is accelerated in breast tissue compared with peripheral blood cells in a population of healthy donors to the Komen Tissue Bank. We further note a significant association between DNAm age and early menarche, and rising number of pregnancies, suggesting that cumulative cell cycling with menstrual cycles and the tissue plasticity occurring with pregnancy may contribute to accelerated epigenetic age in the female breast. Citation Format: Mary E. Sehl, Patricia A. Ganz, Steve Horvath. DNA methylation age is accelerated in breast tissue of healthy women donors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4444.