Abstract 7010: A pan-tissue investigation of epigenetic aging in association with genetic risk for cancer among European descendants

Abstract Epigenetic age (EA) is recognized as a valuable biomarker of aging. The discrepancy between epigenetic and chronological age (CA), termed epigenetic age acceleration (EAA), has been associated with increased mortality from various age-related diseases, including cancer. However, previous studies primarily focused on the EA in blood cells, resulting in a notable gap in understanding the EA in cancer-relevant tissues and its relationship to cancer development. To examine if genetic risks for seven distinct cancers are associated with EAA in cancer-relevant tissues and blood cells, we utilized Illumina EPIC-array-based DNA methylation data and whole genome sequencing (WGS) -derived genotype data of 659 normal tissue and 42 whole blood samples from 315 European-ancestry subjects in the Genotype-Tissue Expression (GTEx) project. EA was estimated across 30 female breast, 167 colon, 41 kidney, 163 lung, 118 ovary, 96 prostate, 44 testis, and 42 whole blood samples via seven established epigenetic clocks: HorvathAge, GrimAge, GrimAge2, HannumAge, PhenoAge, Zhang-BLUP-Age, and Zhang-EN-Age. EAA was calculated as the residual of EA regressed on CA. For each participant, a polygenic risk score (PRS) was computed to assess the genetic risk for each cancer, using validated cancer-specific PRSs for European populations from the Polygenic Score Catalogue. Linear regression analysis was performed to evaluate the association between cancer PRS and EAA, adjusting for body mass index, sex (where applicable), cigarette smoking, and WGS platform and library construction protocol. All EA estimates of cancer-relevant tissues and blood cells exhibited significant correlations with CA (maximum P=2. 44 × 10−3). Among them, GrimAge, known for its strong predictive capacity for mortality, had the most pronounced correlation with CA, with Spearman coefficients ranging from 0. 80 in blood cells to 0. 98 in breast tissues. A higher prostate cancer PRS was significantly associated with increased EAA in normal prostate tissues measured by PhenoAge (β=2. 49; P=0. 01), Zhang-BLUP-Age (β=1. 71; P=0. 02), HannumAge (β=1. 36; P=0. 04), and GrimAge (β=0. 73; P=0. 04). In addition, a higher PRS for renal cell carcinoma showed a significant association with increased GrimAge acceleration in normal kidney tissues (β=0. 82; P=0. 02). Moreover, breast and lung cancer PRSs were significantly associated with increased EAA in blood cells. Specifically, breast cancer PRS was associated with Zhang-BLUP-Age acceleration (β=0. 99; P=0. 04), while lung cancer PRS showed associations with HannumAge (β=1. 78; P=0. 01) and Zhang-EN-Age acceleration (β=0. 94; P=0. 02). Our results suggest a potential connection between genetic susceptibility to certain cancers and accelerated aging in relevant tissues and/or blood cells before cancer onset. Future large-scale studies are needed to substantiate and expand upon our findings. Citation Format: Yaxin Chen, Yawen Qi, Gang Wang, Yufang Xie, Yaohua Yang, Weimin Li. A pan-tissue investigation of epigenetic aging in association with genetic risk for cancer among European descendants abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 7010.