Abstract LB307: Epigenetic age in normal breast tissues and its association with breast cancer risk factors

Abstract Background: Chronological age is the most well-established risk factor for breast cancer; 80% of women diagnosed with breast cancer are aged 45 or older. This strong association is likely the result of age-related alteration in biological processes, including cellular senescence, telomere attrition, and epigenetic alteration, including DNA methylation. DNA-methylation-based age (mAge) estimates reflect biological age, and mAge provides insights into cumulative exposure to cancer risk factors, but there is limited understanding of how epigenetic age in normal breast tissue is related to breast cancer risk factors, including biological and epidemiological risk factors. Methods: We evaluated well-established DNA methylation age (mAge) estimates in the breast tissue of 91 cancer-free women, focusing on the first-generation mAge (Hannum and Horvath), mortality-related mAge (Grim and Pheno), and methylation-based-telomere-lengths (DNAmTL). Biomarkers that are potentially related to breast cancer risks were measured in breast tissue and blood, along with self-reported risk factors, including lifestyle, reproductive history, and family cancer history. Regression models, adjusted for chronological age, race, and body mass index (BMI), were used to estimate associations with a false discovery rate (FDR) at 0.05. Results: Higher BMI is significantly associated with older Hannum-mAge, Horvath-mAge, Grim-mAge, and longer DNAmTL. Grim-mAge and DNAmTL were positively associated with obesity biomarkers (adiponectin, IGF1, and IGFBP3 in breast tissue and blood), and reproductive-related markers (age at menarche and age at first use of oral contraceptives, age at first birth, and age at last birth). Additionally, Horvath-mAge was significantly associated with tissue Ki67, IGF1, and age at first use of oral contraceptives. A family history of breast cancer was significantly associated with shorter DNAmTL. Conclusion: We found associations between epigenetic age and various biological and epidemiological factors of breast cancer risk. Our findings support further studies to examine whether mAge, particularly Grim-mAge and DNAmTL, in normal breast tissue can predict the incidence of breast cancer and potentially can serve as a biomarker for personalized intervention, given that DNA methylation can be modified through lifestyle changes. Citation Format: Amarnath Singh, Joseph P. McElroy, Daniel Y. Weng, Sarah A. Reisinger, Cheryl Thompson, Freudenheim L. Jo, Peter G. Shields, Min-Ae Song. Epigenetic age in normal breast tissues and its association with breast cancer risk factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB307.