P029 | Sex-based differential DNA methylation signatures in myelodysplastic neoplasms

Introduction. Disparities in MDS incidence, mutational landscape, and treatment outcomes based on sex are increasingly evident in Myelodysplastic Neoplasms (MDS). However, underlying epigenetic mechanisms remain elusive. We previously performed an in-depth analysis on sex-based disparities in lower-risk (LR)-MDS, showing significant differences in mutational burden and landscape, including mutations in epigenetic regulator genes e.g. TET2 (enriched in males) and DNMT3A (enriched in females), with a trend of reduced response to erythropoietin stimulating agents (ESAs) in the latter. We hypothesized that the epigenomic landscape in MDS not only is influenced by prevalence of specific somatic mutations; but might also be sex-specific and could partially explain previously observed clinical differences.Methods. We performed genome-wide DNA methylation profiling using Illumina EPIC v2.0 arrays on bone marrow mononuclear cells (BMNCs) from 141 LR-MDS patients (according to IPSS-R). Raw IDAT files were processed with SeSaMe in R. Quality control excluded 44.950 probes with detection p > 0.05 in >10% of samples, samples with >10% failed probes, and SNP/sex-chromosome probes. Sex-stratified differential methylation analysis identified autosomal DMRs using limma and DMRcate (λ = 1000, C = 2, FDR < 0.05). DMRs were annotated to genomic features and classified as hyper- or hypomethylated in females. Epigenetic age acceleration (EAA) was calculated using Horvath, Hannum, PhenoAge, GrimAge (v1/v2), and principal component (PC)-based clocks to assess sex-specific biological aging.Results. Sex-stratified differential methylation analysis of 141 LR-MDS cases (46 females, 95 males) identified 751 significantly differentially methylated CpGs (FDR