Clinical Effect of Point Mutations in Myelodysplastic Syndromes

By R. Bejar, K. Stevenson, O. Abdel-Wahab, N. Galili, B. Nilsson, G. Garcia-Manero, H. Kantarjian, A. Raza, R. Levine, D. Neuberg and 1 more. New England Journal of Medicine, 2011

1,613 citations recorded by the source corpus.

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.)

Subfields: Genetics, Hematology

View Paper: https://www.semanticscholar.org/paper/198861d6ecbaa49249229804a88b0954126218bd

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. Michael R. Stratton
2. Benjamin L. Ebert
3. Moritz Gerstung
4. Peter J. Campbell

In Hematology

1. Michael R. Stratton
2. Benjamin L. Ebert

Citations in the corpus

• Age-related clonal hematopoiesis associated with adverse outcomes. (2014, neutral): “Sequencing studies have identified a set of recurrent mutations in several types of hematologic cancers.(12-24) However, the frequency of these somatic mutations in the general population is unknown.”
• Clinical and biological implications of driver mutations in myelodysplastic syndromes. (2013, result): “These findings replicate previous studies.(5,9,11,35-37,45,46) We assessed whether the effects on clinical outcome of a given gene differed by whether mutations were clonal or subclonal.”
• The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. (2016, neutral): “Aswith all the other myeloid neoplasms, a large amount of data has recently become available on recurring mutations in MDS. Targeted sequencing of a limited number of genes can detectmutations in 80% to 90% of MDS patients; the most commonly mutated genes in MDS are SF3B1, TET2, SRSF2, ASXL1,DNMT3A,”
• The role of mutations in epigenetic regulators in myeloid malignancies (2012, background): “As with DNMT3A, the prognostic relevance of TET2 mutations in MPN and MDS patients has not been clearly determined (45, 46).”
• Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. (2015, neutral): “…in MDS are associated with speci fi c clinicopathological presentations, such as the strong association of SF3B1 with ring sideroblasts, 22 ATRX with acquired a thalassemia, 23 RUNX1 with thrombocytopenia, 16 and TP53 with a complex karyotype, therapy-related disease, and dysgranulopoiesis.”
• Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. (2013, background): “The available evidence suggests that the integration of somatic mutations into prognostic scoring systems may provide more accurate risk stratification of individual patients and further refine clinical decision-making in MDS.(34,67) The spread of massive genotyping methods will soon make it possibl”