Somatic mutations and DNA methylation identify a subgroup of poor prognosis within lower-risk myelodysplastic syndromes

The MDS-RIGHT consortium presents a paper in the January 2025 issue of HemaSphere. The manuscript describes a comprehensive study of somatic mutations and DNA methylation in a large and clinically well-annotated cohort of treatment-naive patients with lower-risk myelodysplastic syndrome/neoplasm (LR-MDS) at diagnosis from The European MDS Registry and TRIAGE-MDS project, identifying distinct clusters based on both genetic profiling as well as genome wide methylation profiling. MDS is a chronic myeloid malignancy characterized by long-lasting anemia significantly affecting the clinical outcome and the quality of life.

The data set TRIAGE comprised 543 LR-MDS cases based on IPSS risk low or intermediate-1. The methylome and transcriptome studies were performed in a subset of 175 of these patients. Unsupervised clustering analyses identified six clusters based on genetic profiling which concentrate into four clusters on the basis of genome-wide methylation profiling. A significant overlap between the two clustering modes was observed. The four methylation clusters showed distinct methylation landscapes, genetic and clinical features and, more importantly, distinct outcomes.

This is an important study showing that genetic and DNA methylation features of LR-MDS at early stages may refine risk stratification, therefore offering the frame for a precocious therapeutic intervention.

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