A novel prognostic model incorporating genetic profiling for myelodysplastic syndromes

Targeted and unbiased next-generation sequencing (NGS) has contributed to a better understanding of the molecular pathogenesis of myeloid neoplasms, including MDS. Discovery efforts have identified novel classes of mutated genes, while deep NGS approaches have yielded a better appreciation of clonal hierarchy, intercase variability, and intratumor heterogeneity. However, comprehensive analyses of sequences of more than 100 genes in large cohorts are rare. We determined the biological and prognostic significance of genetic aberrations in MDS by summarizing recent reports. In one major report, 944 patients with various MDS subtypes were screened for known or putative mutations or deletions in 104 genes, using targeted deep sequencing and array-based genomic hybridization. Of the 944 patients, 845 (89.5%) harbored at least one mutation (median, 3 per patient; range, 0-12). In total, 47 genes were significantly mutated, with TET2, SF3B1, ASXL1, SRSF2, DNMT3A, and RUNX1 mutated in >10% of the patients. Many mutations were associated with higher risk groups and/or blast elevation. Survival was investigated in 875 patients. By univariate analysis, 25 of the 47 genes affected survival (P<0.05). The status of 14 genes combined with conventional factors revealed a novel prognostic model "Model-1", separating the patients into four risk groups "low", "intermediate", "high", and "very high" with 3-year survival rates of 95.2, 69.3, 32.8, and 5.3%, respectively (P<0.001). Subsequently, a "gene-only model" (Model-2), constructed on the basis of 14 genes, also yielded four significant risk groups (P<0.001). Both models were reproducible in the validation cohort (n = 175 patients; P<0.001 each). Similar analysis in another large cohort can reproduce the results, which suggests that profiling of genetic alterations is useful as a clinical tool to improve the prediction of prognosis.