Comparison of epigenetic aging in normal breast tissue from women with and without breast cancer.

Abstract

1522 Background: Age is one of the most important risk factors for developing breast cancer. However, why increasing age is associated with increasing incidence of breast cancer remains poorly understood. We hypothesize that accumulated epigenetic alterations in the breast contribute to the development of breast cancer, and that such changes accumulate more rapidly in the breast during the lifetime of women who develop breast cancer as compared to their healthy peers. We therefore sought to identify an epigenetic pattern of accelerated breast tissue “aging” in women with breast cancer. Methods: Samples of normal breast tissue were collected from four cohorts of women: age < 50 years with and without breast cancer, and age ≥50 years with and without breast cancer (BC). Samples were obtained from the Susan G. Komen Tissue Bank at IU Simon Cancer Center, reduction mammoplasties and adjuvant mastectomy specimens at Yale. The Illumina Human 450K BeadChip microarray was used to generate DNA methylation profiles. Data was analyzed using the “Epigenetic Clock”, a published biomarker of aging based on 353 specific CpGs in the human genome. Clinical data collected for each subject included: age, height, weight, ethnicity, medical and reproductive history, tobacco and alcohol use, family history of breast cancer, current medications, and tumor characteristics. Results: Normal breast tissue samples from 90 subjects were analyzed (age < 50 with BC = 22, age < 50 without BC = 30, age ≥50 with BC = 15, age ≥50 without BC = 23). Age range was 24-82 years and 18-82 years for cohorts with and without BC respectively. In the cohort with BC, 95% of tumors were estrogen receptor-positive. Overall, DNA methylation tissue age (DNAmAge) was strongly correlated with chronologic age (r = 0.88, p < 0.001). However, normal breast tissue from women with breast cancer demonstrated significantly accelerated DNAmAge as compared to healthy peers (p < 0.001). Conclusions: Normal breast tissue from women with breast cancer demonstrates evidence of an accelerated epigenetic "aging" process. DNAmAge of normal breast tissue may prove to be a useful tool in identifying those women at highest risk, and lend insight into novel mechanisms of breast cancer prevention.