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NRAS mutations with low allele burden have independent prognostic significance for patients with lower risk myelodysplastic syndromes

Leukemia volume 27, pages 2077–2081 (2013)Cite this article

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Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by inefficient hematopoiesis, cytopenias and an increased risk of progression to acute myeloid leukemia.1 Common prognostic scoring methods, such as the International Prognostic Scoring System for MDS (IPSS), use clinical features and karyotypic abnormalities to stratify patients into risk groups that form the basis for clinical treatment guidelines.2 However, more than half of all MDS patients display a normal karyotype and patients with identical chromosomal abnormalities often have varied clinical outcomes. Therefore, additional prognostic indicators that can refine prognosis in MDS patients could help determine the optimal form and timing of therapy. Recent analysis of bone marrow aspirates from 439 MDS patients using various methods, including mass-extend mass spectrometry-based genotyping (MALDI), revealed that somatic point mutations in specific genes are associated with clinical features and are independent prognostic factors.3 Of these patients, 295 were classified as low/intermediate-1 IPSS risk, yet some displayed an unexpectedly short survival even in the absence of adverse prognostic mutations.

The clinical heterogeneity in MDS patients is partially explained by the diversity of genetic abnormalities acquired by their disease cells.4 For example, somatic mutations in specific genes such as NRAS and TP53 are associated with clinical features and overall survival in patients with MDS.5, 6, 7 However, even within individual patients, these mutations are not uniformly distributed. The abnormal cells in the bone marrow of patients with MDS evolve over time giving rise to sub-clonal populations. Different sub-clones that have acquired and selected for additional genetic abnormalities therefore often coexist. Mutations present in a small fraction of cells can retain important clinical significance, for example, low-level TP53 mutations have been associated with resistance to therapy using lenalidomide.8

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Acknowledgements

We acknowledge the contribution of Ben Legendre at Transgenomic Inc. for his help with administrative aspects of the work. This work was supported by the Innovative Molecular Analysis Technologies Program of the NCI, Grants CA-111994 and CA-151164 (GMM); P01-CA108631, R01-HL082945, and a Leukemia and Lymphoma Society Scholar Award (BLE); and an ASH Scholar Award and NIDDK Grant 1K08DK091360 (RB). The contents of this manuscript do not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

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Authors and Affiliations

  1. Department of Radiation Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston,, MA, USA

    D M Murphy & G Mike Makrigiorgos

  2. Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston,, MA, USA

    K Stevenson & D Neuberg

  3. Division of Hematology and Oncology, UCSD Moores Cancer Center, La Jolla, CA, USA

    R Bejar

  4. Transgenomic Inc, Omaha, NE, USA

    Y Shi, C Cubrich, K Richardson & P Eastlake

  5. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    G Garcia-Manero & H Kantarjian

  6. Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    B L Ebert

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Correspondence to B L Ebert or G Mike Makrigiorgos.

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Murphy, D., Bejar, R., Stevenson, K. et al. NRAS mutations with low allele burden have independent prognostic significance for patients with lower risk myelodysplastic syndromes. Leukemia 27, 2077–2081 (2013). https://doi.org/10.1038/leu.2013.160

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