Abstract IA022: Harnessing epigenetic profiles in MDS for the development of predictive biomarkers

Abstract While significant progress has been made in understanding the genetic landscape of MDS, less is known about the epigenetic makeup of this disease and how this may impact biology and response to azacitidine (AZA). To address this, we performed genomic, epigenomic, and transcriptomic analyses on CD34+ cells from a multicenter cohort of 94 intermediate or higher-risk MDS patients treated with AZA who had documented responses. DNA methylation (DNAme) by ERRBS, gene expression (GE) by RNA-seq, mutational profiling, and detailed clinical, cytogenetic, and laboratory data were documented. Supervised and unsupervised analyses revealed that aberrant DNAme in MDS is not distributed randomly but rather is highly correlated with disease phenotypes, capturing clinically relevant heterogeneity, beyond what is identified by methodologies used in the past that focused solely on promoter regions. Moreover, this epigenetic information can be harnessed for the development of robust biomarkers predictive of AZA response and integrative approaches combining clinical, mutation, GE and DNAme data can further improve the predictive performance of these biomarkers, with an AUC score=0.94. Citation Format: Maria E Figueroa. Harnessing epigenetic profiles in MDS for the development of predictive biomarkers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr IA022