The spectrum of genetic mutations in myelodysplastic syndrome: Should we update prognostication?

Abstract

The natural history of patients with myelodysplastic syndrome (MDS) is dependent upon the presence and magnitude of diverse genetic and molecular aberrations. The International Prognostic Scoring System (IPSS) and revised IPSS (IPSS‐R) are the most widely used classification and prognostic systems; however, somatic mutations are not currently incorporated into these systems, despite evidence of their independent impact on prognosis. Our manuscript reviews prognostic information for TP53, EZH2, DNMT3A, ASXL1, RUNX1, SRSF2, CBL, IDH 1/2, TET2, BCOR, ETV6, GATA2, U2AF1, ZRSR2, RAS, STAG2, and SF3B1. Mutations in TP53, EZH2, ASXL1, DNMT3A, RUNX1, SRSF2, and CBL have extensive evidence for their negative impact on survival, whereas SF3B1 is the lone mutation carrying a favorable prognosis. We use the existing literature to propose the incorporation of somatic mutations into the IPSS‐R. More data are needed to define the broad spectrum of other genetic lesions, as well as the impact of variant allele frequencies, class of mutation, and impact of multiple interactive genomic lesions. We postulate that the incorporation of these data into MDS prognostication systems will not only enhance our therapeutic decision making but lead to targeted treatment in an attempt to improve outcomes in this formidable disease.