Pf533 mutations on Cohesin Complex Are Associated to a Poor Prognosis in Low‐risk Myelodysplastic Syndromes Patients

Abstract

Background:Mutations in cohesin complex genes have been described commonly in several types of cancer, with an incidence of 8% in myeloid diseases and myelodysplastic syndromes (MDS), and have been linked to marrow fibrosis by our group in a prior publication (Ramos F et al. Oncotarget 2016). However, their clinical impact is still undetermined.Aims:To identify mutations in cohesin complex genes in MDS patients by next generation sequencing (NGS) and to analyze their implications at clinical level (correlation with clinical characteristics and outcome).Methods:A cohort of 850 myeloid samples was analyzed by targeted deep sequencing (Nextera Rapid Capture Custom Enrichment) using an Illumina ® custom panel of 117 myeloid‐related genes, including cohesin complex genes: STAG1, STAG2, SMC1A, SMC3 and RAD21. A final selection of 324 patients with clinical, biological and follow‐up data were selected.Results:The median age was 75 years (p10‐p90: 57–84); 59% were male. According to the WHO 2008 classification most of the patients had RCMD (40%), and RAEB 1–2 (30%), while 11% had a MDS associated with isolated del(5q), and the remaining subtypes RCUD, RARS, U‐MDS were observed in less than 10% each. Regarding IPSS‐R, the majority of patients had very low (27%) and low (44%) risk, with 85% of the series having normal karyotype or clonal alterations of very good or good risk. The median follow‐up was 2.5 years (range 0.01–15.6) and during this time 50% of patients died and 30% progressed to acute myeloid leukemia (AML).NGS study identified a 9.3% of patients with mutations in cohesin complex genes: STAG2 (6.5%), SMC3 (1.5%) and SMC1A (1.2%). In the global cohort, mutations in cohesin genes were associated with RAEB‐1 and RAEB‐2 subtypes (p = 0.003), intermediate IPSS‐R (p = 0.010), intermediate cytogenetic risk (p = 0.026) and a lower platelet count (p = 0.004). In addition, cohesin‐mutated patients showed a shorter overall survival (3 vs. 5 years, p = 0.06). Moreover, mutations in these genes were associated with a higher rate of progression to AML (p = 0.004) and a shorter time to AML progression (1.5 vs. 9.1 years, p < 0.001).To further study the negative impact of these mutations, analyses were carried out for each IPSS‐R groups, separately. Interestingly, in low IPSS‐R patients, these analyses showed that cohesin mutations were the sole factor significantly associated with an earlier progression to AML (p < 0.001), while hemoglobin, platelet and neutrophil count, blasts in bone marrow and cytogenetic were not related to the outcome (Table 1). In addition, in the multivariate analysis, the presence of cohesin mutations was associated with a shorter overall survival in this subgroup of patients (HR = 0.291 (95% CI, 0.113–0.752); p = 0.011) (Table 2).Summary/Conclusion:Mutations in cohesin complex genes (mainly STAG2) are associated with a worse prognosis due to a higher rate of AML evolution and a shorter time to progression to AML in the global cohort. Of note, mutations in the cohesin complex were associated with a potential prognostic impact in low risk IPSS‐R subgroup. Therefore, analysis of these mutations, especially in this subgroup of patients, should be carried out.image