Mutational Profile Enables the Identification of a High-Risk Subgroup in Myelodysplastic Syndromes with Isolated Trisomy 8.

Trisomy 8 (+8) is the most frequent trisomy in myelodysplastic syndromes (MDS) and is associated with clinical heterogeneity and intermediate cytogenetic risk when found in isolation. The presence of gene mutations in this group of patients and the prognostic significance has not been extensively analyzed. Targeted deep sequencing was performed in a cohort of 79 MDS patients showing isolated +8. The most frequently mutated genes were: TET2 (38%), STAG2 (34.2%), SRSF2 (29.1%) and RUNX1 (26.6%). The mutational profile identified a high-risk subgroup with mutations in STAG2, SRSF2 and/or RUNX1, resulting in shorter time to acute myeloid leukemia progression (14 months while not reached in patients without these mutations, p < 0.0001) and shorter overall survival (23.7 vs. 46.3 months, p = 0.001). Multivariate analyses revealed the presence of mutations in these genes as an independent prognostic factor in MDS showing +8 isolated (HR: 3.1; p < 0.01). Moreover, 39.5% and 15.4% of patients classified as low/intermediate risk by the IPSS-R and IPSS-M, respectively, were re-stratified as a high-risk subgroup based on the mutational status of STAG2, SRSF2 and RUNX1. Results were validated in an external cohort (n = 2494). In summary, this study validates the prognosis significance of somatic mutations shown in IPSS-M and adds STAG2 as an important mutated gene to consider in this specific subgroup of patients. The mutational profile in isolated +8 MDS patients could, therefore, offer new insights for the correct management of patients with a higher risk of leukemic transformation.

Clinicopathologic evaluation of cytopenic patients with isolated trisomy 8: a detailed comparison between idiopathic cytopenia of unknown significance and low-grade myelodysplastic syndrome.

The significance of an isolated trisomy 8 (+8) in the diagnosis of myelodysplastic syndrome (MDS) is not well established. It is common in MDS, but is not considered as an MDS-defining abnormality in the absence of morphologic dysplasia. We evaluated two groups of patients with isolated +8 and either low-grade MDS (LG-MDS) or idiopathic cytopenia of undetermined significance (ICUS). At presentation, ICUS patients had a lower platelet count (85.0 vs 163.5 × 109 cells/L; p = 0.02), while MDS patients had more frequent incidence of isolated anemia (64% vs 0%, p = 0.007). A subset (36%) of ICUS patients progressed to MDS or AML. These patients presented with more severe neutropenia (0.9 vs 3.1 × 103/µL, p = 0.01) and a trend toward a higher proportion (>50%) of +8 metaphases compared to those that did not progress (p = 0.05). Thus, ICUS patients with isolated +8 may progress to MDS and AML and deserve close clinical follow-up.