Key Points

  • Specific gene mutation combinations correlate with morphologic MDS/MPN subtypes and help to elucidate the heterogeneity in these neoplasms.

  • Patients with MDS/MPN-U display different clinically distinct molecular profiles that mimic the ones observed in other MDS/MPN

Over 90% of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) harbor somatic mutations in myeloid-related genes, but still, current diagnostic criteria do not include molecular data. We performed genome-wide sequencing techniques to characterize the mutational landscape of a large and clinically well-characterized cohort including 367 adult MDS/MPN: chronic myelomonocytic leukemia (CMML, n=119), atypical chronic myeloid leukemia (aCML, n=71), MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T, n=71) and MDS/MPN unclassifiable (MDS/MPN-U, n=106). A total of 30 genes were recurrently mutated in ≥3% of the cohort. Distribution of recurrently mutated genes and clonal architecture differed among MDS/MPN subtypes. Statistical analysis revealed significant correlations between recurrently mutated genes, as well as genotype-phenotype associations. We identified specific gene combinations that associated with distinct MDS/MPN subtypes and that were mutually exclusive with most of the other MDS/MPN (e.g. TET2-SRSF2 in CMML, ASXL1-SETBP1 in aCML or SF3B1-JAK2 in MDS/MPN-RS-T). Patients with MDS/MPN-U were the most heterogeneous and displayed different molecular profiles that mimicked the ones observed in other MDS/MPN subtypes and that had an impact on the outcome of the patients. Specific gene mutations also had an impact on the outcome of the different MDS/MPN, which may be relevant for clinical decision-making. Overall, the results of this study help to elucidate the heterogeneity found in these neoplasms, which can be of use in the clinical setting of MDS/MPN.

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