STAG2 and SRSF2 Mutations Might Define Prognosis of MDS Patients With Isolated Trisomy 8

Isolated trisomy 8 is a karyotypic abnormality frequently found in hematological neoplasms. It is found in 10% of myelodysplastic syndromes (MDS) with cytogenetic aberrations. It is classified as an intermediate risk subgroup in MDS IPSS-R (Revised International Prognostic Scoring System) because of the heterogeneous clinical course of the patients.The aim of this study was to determine whether mutational profile could be useful to improve the risk reclassification of MDS with isolated trisomy 8.In a cohort of 591 MDS patients, we included 38 patients with isolated trisomy 8 confirmed through karyotype and FISH. We carried out next generation sequencing in bone marrow samples of these patients with an in-house custom panel with more than 100 myeloid-related genes. NGS files were processed with our own pipeline. Statistical analysis was performed with SPSS.A total of 102 somatic mutations were found in our cohort. The most frequently mutated genes were TET2, STAG2, ASXL1 and SRSF2. Interestingly, the mutational profile allows the differentiation of two subtypes of isolated trisomy 8: patients with mutations in either SRSF2 or STAG2 (n=16), and those without mutations in these genes (n=22). Both groups presented similar clinical characteristics. However, patients with STAG2 and/or SRSF2 mutations had a shorter time to progression to AML and lower overall survival than patients without these mutations (p<0.05). Surprisingly, the risk for AML progression and the overall survival of patients with STAG2/SRSF2 alterations was similar to those MDS classified as high risk in IPSS-R (p>0.05). Similarly, patients with trisomy 8 without these mutations did not show significant differences in survival and progression to AML when compared to the group of MDS with low IPSS-R risk (p>0.05).This study demonstrates, for the first time, that mutational profile of MDS with isolated trisomy 8 allows these patients to be reclassified into two groups based on the presence or absence of mutations in STAG2 and/or SRSF2. These alterations are clearly associated with an adverse prognosis. Therefore, we suggest the need to study the mutational profile of these patients in order to reclassify them on the prognostic scale.