Clinical Implications of Genetic Mutations in Myelodysplastic Syndrome

Abstract

Myelodysplastic syndrome (MDS) is clonal disorder characterized by ineffective hematopoiesis and a tendency to evolve into acute myeloid leukemia (AML). Genetic studies have enabled the identification of a set of recurrently mutated genes central to the pathogenesis of MDS, which can be organized into a limited number of cellular processes, including RNA splicing, epigenetic and traditional transcriptional regulation, and signal transduction. The sequential accumulation of mutations drives disease evolution from asymptomatic clonal hematopoiesis to frank MDS, and, ultimately, to secondary AML. This detailed understanding of the molecular landscape of MDS, coupled with the emergence of cost- and time-effective methodologies for DNA sequencing has led to the introduction of genetic studies into the clinical realm. Here, we review recent advances in our genetic understanding of MDS, with a particular focus on the emerging role for mutational data in clinical management as a potential tool to assist in diagnosis, risk stratification, and therapeutic decision-making.

Fig 1.

The recurrently mutated genes in myelodysplastic syndrome (MDS) can be organized into a limited number of biologic categories. Estimated mutation frequencies within an unselected population of patients with MDS are displayed, with examples of the most commonly implicated genes in each category listed to the right of each bar. Data are from Papaemmanuil et al, Haferlach et al, and R.C. Lindsley (personal communication, October 2016).

Fig 2.

The spectrum of clonal myeloid disorders and their defining clinical features. The sequential acquisition of somatic mutations drives the evolution of asymptomatic clonal hematopoiesis through CCUS to frank MDS and sAML. CHIP, originally defined by Steensma et al, encompasses individuals who possess a somatic mutation in a gene associated with myeloid malignancy but do not meet diagnostic criteria for another hematologic neoplasm. Of note, only a minority of patients at each stage along this spectrum proceed to the next; for example, CHIP evolves into frank MDS at a rate of 0.5% to 1% per year. CBC, complete blood cell count; CCUS, clonal cytopenias of undetermined significance; CHIP, clonal hematopoiesis of indeterminate potential; MDS, myelodysplastic syndrome; sAML, secondary acute myeloid leukemia.

Fig 3.

Somatic mutations in any of TP53, EZH2, RUNX1, ASXL1, or ETV6 identify patients with reduced overall survival within each of the IPSS-R lower risk categories. Patients and mutational data were originally described in Bejar et al. Survival curves compare patients with one or more mutations in TP53, EZH2, RUNX1, ASXL1, or ETV6 (yellow lines) with patients within the same IPSS-R category without mutations in these five genes (blue lines). Adapted from Bejar et al and used with permission. IPSS-R, International Prognostic Scoring System, Revised.

Fig 4.

TP53 mutations are associated with reduced overall survival in MDS and identify a subset of patients with complex karyotypes who have poor outcomes. (A) Survival analysis of 439 patients with MDS comparing those with somatic TP53 mutations (yellow line; n = 33) with those without TP53 mutations (blue line, n = 406). (B) Overall survival of patients with complex cytogenetics who have TP53 mutations (yellow line; n = 26) compared with those who lack TP53 mutations (blue line; n = 31). Adapted from Bejar et al and used with permission. MDS, myelodysplastic syndrome.