Scientific Publications

Categorized: Abstracts & Presentations, Hematology

Getting to the point: Somatic point mutations influence the clinical features and survival in myelodysplastic syndromes

According to the National Institutes of Health, the frequency and incidence of myelodysplastic syndromes (MDS) is increasing in the US population and is influenced by factors such as advancing age, the use of cytotoxic and mutagenic therapies for cancer, and greater exposure to environmental toxins. MDS is a heterogeneous group of disorders with some patients having an insidious onset of the disease, while others experience dramatic presentations including marrow failure or acute myeloid leukemia. The treatment is determined by the prognostic risk as determined by prognostic scoring systems, such as the International Prognostic Scoring System (IPSS) which incorporates the clinical features, bone marrow and peripheral blood findings, and karyotypic abnormalities. Approximately half of all patients have a normal karyotype. Single gene mutations are not currently considered in prognostic scoring systems but may be important in further defining MDS clinical phenotypes, risk stratification, and appropriate therapies.

Gene mutations reported to influence overall survival include: TP53, NRAS, RUNX1, TET2, and IDH1 and IDH2. Only TP53 gene mutations have been found to be associated with poor prognostic markers, such as a complex karyotype. Recent research reported by Bejar, et al. in the New England Journal of Medicine examined the influence that independent somatic point mutations may exert on the clinical phenotype and prognosis in a large group of patients with MDS.

The researchers identified somatic mutations in 18 genes, including two genes (ETV6 and GNAS) that were not previously reported to be mutated in MDS patients. Several of the somatic mutations correlated with features of a specific clinical phenotype which included certain cytopenias, blast percentage, cytogenetic abnormalities, and overall survival. RUNX1, TP53, and NRAS were strongly associated with severe thrombocytopenia and an increased proportion of bone marrow blasts. Mutations in one or more of these genes, TP53, EZH2, ETV6, RUNX1, and ASXL1, were identified in 137 of the 439 (31.2%) study patients and had prognostic significance independent of other established risk factors, predicting poor overall survival.

This study demonstrates that somatic point mutations are common in MDS, associated with specific clinical features, and predict poor overall survival, independent of other established risk factors. The findings support a role for identifying these specific mutations in explaining the heterogeneity of the myelodysplastic syndromes and improving the risk stratification of these patients for better therapeutic intervention.


Bejar, R., Stevenson, K., Abdel-Wahab, O., Galili, N., Nilsson, B., Garcia-Manero, G., Kantarjian, H., Raza, A., Levine, R. L., Neuberg, D., and Ebert, B. L. (2011). Clinical effect of point mutations in myelodysplastic syndromes. The New England Journal of Medicine, 364(26):2496-2506.

Kaneko H, Misawa S, Horiike S, Nakai H, Kashima K. TP53 mutations emerge at early phase of myelodysplastic syndrome and are associated with complex chromosomal abnormalities. Blood 1995;85:2189-93.

Kita-Sasai Y, Horiike S, Misawa S, et al. International prognostic scoring system and TP53 mutations are independent prognostic indicators for patients with myelodysplastic syndrome. Br J Haematol 2001;115:309-12.