Impact of mutational variant allele frequency on prognosis in myelodysplastic syndromes.

Abstract

The clinical relevance of variant allele frequency (VAF) of recurrent mutations in myelodysplastic syndromes (MDS) has been increasingly reported. However, the prognostic value of mutational VAF across the genetic spectrum of MDS has not been extensively evaluated. In this study, we profiled the mutational spectrum of 382 newly diagnosed MDS patients using targeted next-generation sequencing. Exploratory analysis found that mutational VAF of some genes including <i>TET2</i>, <i>TP53</i>, and <i>SF3B1</i> had significant associations with patient survival. Specifically, <i>TET2</i> VAF ≥ 32% (HR 1.69, P = 0.025) and <i>TP53</i> VAF ≥ 27% (HR 3.58, P < 0.001) were independently associated with shorter overall survival (OS). In contrast, <i>SF3B1</i> VAF ≥ 15% had an independent association with better prognosis (HR 0.52, P = 0.048). In addition, high <i>TET2</i> VAF was associated with an increased response to hypomethylating agents relative to low <i>TET2</i> VAF (P = 0.009). Patients with high <i>TP53</i> VAF more often possessed complex karyotypes than those with low VAF (P = 0.034). And patients with high <i>SF3B1</i> VAF were more frequently classified as MDS with ring sideroblasts (MDS-RS) category than those with low VAF (P = 0.012). Meanwhile, we found that for some other genes like <i>EZH2</i> and <i>NRAS</i>, once their mutations appeared, it meant poor survival regardless of mutational VAF. These findings suggest that mutational VAF of certain genes should be considered into the routine prognostic prediction and risk stratification of MDS patients.