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

Abstract

Simple Summary Trisomy 8 (+8) is one of the most frequent cytogenetic alterations found in myelodysplastic syndromes (MDS). MDS patients harboring isolated +8 show clinical heterogeneity, and life expectancy varies between several months and several years after diagnosis. We aimed to investigate whether the mutational profile of isolated +8 MDS patients could help to clarify the heterogeneous prognosis of these patients. In fact, we found that mutations in STAG2, SRSF2 and RUNX1 are independent prognostic factors, enough to define the course of the disease in terms of overall survival and leukemic transformation in isolated +8 MDS. Therefore, these findings might help to identify patients at a high risk of evolving disease and open new horizons by changes in the management of a high subset of patients within MDS with isolated +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.