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

Abstract

Trisomy 8 (+ 8) is the most frequent trisomy in myelodysplastic syndromes (MDS) and is associated to clinical heterogeneity and intermediate cytogenetic risk when found isolated. 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 + 8isolated (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 high risk subgroup based on the mutational status of STAG2, SRSF2 and RUNX1. Results were validated in an external cohort (n = 2 494). In summary, the mutational profile in isolated + 8 MDS patients could offer new insights for the correct management of these patients.