Application of Next Generation Sequencing for Prognostic Stratification in Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by a deregulation of blood cell formation with cytopenia in varying degrees and frequently develop into acute myeloid leukemia (AML). Next generation sequencing (NGS) has significantly contributed to diagnosis and prognostication in patients with MDS. To explore the role of acquired mutations in MDS biology and clinical features, we performed mutational profiling of 111 genes in 125 patients with MDS based on target-sequencing. The results showed that 89% of patients had one or more carcinogenic mutations. Mutation frequencies of several genes, including ASXL1 (16.8%), RUNX1 (14.4%) and TET2 (12%), were above 10% in MDS patients. According to univariate analysis in 108 patients with survival data, mutations of GATA1/2, TP53 and DNMT3A were identified as adverse prognostic factors for overall survival (OS), while RUNX1, KRAS/NRAS, SRSF2 and TET2 mutations were determined as unfavorable factors for progression free survival (PFS). By multivariate COX regression analysis, mutations of KRAS/NRAS, GATA1/2 and DNMT3A were independent risk factors for OS, whereas IDH1/2 gene mutations were favorable factors for PFS. By evaluation of the clinical benefit of hypomethylating agents (HMAs), it showed that for patients harboring mutations associated DNA methylation or not and receiving HMAs treatment or not, the order of the outcome from good to bad was gene^WT with non-HMAs, gene^WT with HMAs, gene^mutwith HMAs and gene^mutwith non-HMAs. Therefore, target-sequencing of mutational spectrum is a feasible and highly promising prediction method for prognostic evaluation in patients with MDS, which would contribute to personalized therapeutic decisions.