Clinical Effect of Point Mutations in Myelodysplastic Syndromes

Abstract

BACKGROUND Myelodysplastic syndromes are clinically heterogeneous disorders characterized by clonal hematopoiesis, impaired differentiation, peripheral-blood cytopenias, and a risk of progression to acute myeloid leukemia. Somatic mutations may influence the clinical phenotype but are not included in current prognostic scoring systems. METHODS We used a combination of genomic approaches, including next-generation sequencing and mass spectrometry–based genotyping, to identify mutations in samples of bone marrow aspirate from 439 patients with myelodysplastic syndromes. We then examined whether the mutation status for each gene was associated with clinical variables, including specific cytopenias, the proportion of blasts, and overall survival. RESULTS We identified somatic mutations in 18 genes, including two, ETV6 and GNAS, that have not been reported to be mutated in patients with myelodysplastic syndromes. A total of 51% of all patients had at least one point mutation, including 52% of the patients with normal cytogenetics. Mutations in RUNX1, TP53, and NRAS were most strongly associated with severe thrombocytopenia (P<0.001 for all comparisons) and an increased proportion of bone marrow blasts (P<0.006 for all comparisons). In a multivariable Cox regression model, the presence of mutations in five genes retained independent prognostic significance: TP53 (hazard ratio for death from any cause, 2.48; 95% confidence interval [CI], 1.60 to 3.84), EZH2 (hazard ratio, 2.13; 95% CI, 1.36 to 3.33), ETV6 (hazard ratio, 2.04; 95% CI, 1.08 to 3.86), RUNX1 (hazard ratio, 1.47; 95% CI, 1.01 to 2.15), and ASXL1 (hazard ratio, 1.38; 95% CI, 1.00 to 1.89). CONCLUSIONS Somatic point mutations are common in myelodysplastic syndromes and are associated with specific clinical features. Mutations in TP53, EZH2, ETV6, RUNX1, and ASXL1 are predictors of poor overall survival in patients with myelodysplastic syndromes, independently of established risk factors. (Funded by the National Institutes of Health and others.)

CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients

“…The latter is also the preferred treatment of choice in AML associated with FLT3-ITD, whereas chemotherapy alone might be adequate for AML patients expressing NPM1 mutations without FLT3-ITD. 1 Similarly, the prognostic relevance of mutations in myelodysplastic syndromes 2 and primary myelofibrosis (PMF) 3 has been recognized but not yet implemented in clinical practice.…”

Evaluation of revised IPSS cytogenetic risk stratification and prognostic impact of monosomal karyotype in 783 patients with primary myelodysplastic syndromes

“…Acquired genetic lesions are frequently present in myelodysplastic syndromes (MDS) [1], with cytogenetic abnormalities noted in approximately 45% of patients at diagnosis [2]. Allogeneic stem cell transplant is potentially curative in MDS, but its utility is limited by the relatively high incidence of treatment-related mortality and morbidity [3].…”

Plasma circulating-microRNA profiles are useful for assessing prognosis in patients with cytogenetically normal myelodysplastic syndromes

“…6,9 Mutations in other myelodysplastic syndrome-related genes, especially TET2, ASXL1, TP53, and EZH2, were not tested in this study. 6,10 Using global profiling, we identified a list of differentially expressed plasma microRNAs in patients with myelodysplastic syndromes with different outcomes, among patients with different cytogenetic features, and between patients with myelodysplastic syndromes versus healthy individuals. For patients with a diploid karyotype and none of the common myelodysplastic syndromerelated mutations, admittedly a heterogeneous group, there are no known clinicopathologic or biologic markers that can further stratify these patients.…”

“…7,8 Alterations in apoptosis and proliferation have been implicated in the pathogenesis of myelodysplastic syndromes, and recurrent gene mutations have been associated with the disease progression and outcome. 9,10 In addition, gene expression studies have identified markers that appear to improve the accuracy of risk stratification or prognostication; 11 however, none of these markers have been included in the original or revised International Prognostic Scoring System. 12 MicroRNAs are a class of short (19-25 nucleotides), single-stranded RNA molecules that are components of the epigenetic machinery.…”