Abstract 4096: Altered epigenetic aging in leukocytes with detectable mosaic chromosomal alterations

Abstract Background: Mosaic chromosomal alterations (mCAs), including autosomal mCAs, mosaic loss of chromosome X (mLOX), and mosaic loss of chromosome Y (mLOY) are types of age-related detectable clonal hematopoiesis (CH) in the blood and are associated with hematologic cancer risk. Epigenetic age, measured by DNA methylation-based clocks, can be used to estimate epigenetic age acceleration and could offer insights into the etiology of hematologic cancer; however, the relationship between mCAs and epigenetic age acceleration remains poorly understood. Methods: DNA methylation was analyzed in 482 blood-derived samples from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial using the Illumina EPIC array. Quality control and normalization were implemented using the Chip Analysis Methylation pipeline (ChAMP) and epigenetic aging metrics were derived using the DNA Methylation Age Calculator. T-tests were conducted to evaluate differences in age acceleration and age-adjusted logistic regression was used to investigate differences in estimated abundance of immune cells by mCA type. Results: In total, 115 analyzed PLCO participants had autosomal mCAs, 68 had mLOX, 38 had mLOY, and 261 were mCA-free. Participants with mLOY exhibited the highest mean chronologic age (67.50 years) and the highest smoking prevalence (68.52% ever smokers). Across all samples, DNA methylation age demonstrated a moderate correlation with chronologic age (r=0.57, p<8.38×10-43, 95% CI:0.51-0.63). A trend toward higher epigenetic age acceleration was observed in individuals with detectable mCAs compared to mCA-free individuals (mean difference=1.17, p=0.05), with females having detectable mLOX displaying the highest age acceleration (mean difference=1.82, p=0.031). Notable alterations in methylation-estimated immune cell abundance were observed in individuals with detectable mCAs including elevations in CD4 T cells, natural killer cells, monocytes and granulocytes. Additionally, 2 probes, were differentially methylated in individuals with mCAs relative to mCA-free individuals, both located near the FOXI2 gene. Conclusion: We observe epigenetic age acceleration in individuals with detectable mCAs, indicating epigenetic age acceleration could be a contributor to or consequence of mCAs in the hematopoietic compartment. Methylation-based evaluation of immune cell abundance identified increases in both lymphoid and myeloid cell types in individuals with mCAs, supporting prior findings of altered immune function in individuals with mCAs. Citation Format: Corey D. Young, Derek W. Brown, Charles Breeze, Rebecca L. Kelly, Kara M. Barnao, Aubrey K. Hubbard, Weiyin Zhou, Amy A. Hutchinson, Belynda D. Hicks, Aurélie L. Vogt, Wen-Yi Huang, Steven C. Moore, Stephen J. Chanock, Mitchell J. Machiela. Altered epigenetic aging in leukocytes with detectable mosaic chromosomal alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4096.