MYD88 L265P Somatic Mutation in Waldenström's Macroglobulinemia
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- 30 August 2012
- journal article
- research article
- Published by Massachusetts Medical Society in The New England Journal of Medicine
- Vol. 367 (9), 826-833
- https://doi.org/10.1056/nejmoa1200710
Abstract
Waldenström's macroglobulinemia is an incurable, IgM-secreting lymphoplasmacytic lymphoma (LPL). The underlying mutation in this disorder has not been delineated. We performed whole-genome sequencing of bone marrow LPL cells in 30 patients with Waldenström's macroglobulinemia, with paired normal-tissue and tumor-tissue sequencing in 10 patients. Sanger sequencing was used to validate the findings in samples from an expanded cohort of patients with LPL, those with other B-cell disorders that have some of the same features as LPL, and healthy donors. Among the patients with Waldenström's macroglobulinemia, a somatic variant (T→C) in LPL cells was identified at position 38182641 at 3p22.2 in the samples from all 10 patients with paired tissue samples and in 17 of 20 samples from patients with unpaired samples. This variant predicted an amino acid change (L265P) in MYD88, a mutation that triggers IRAK-mediated NF-κB signaling. Sanger sequencing identified MYD88 L265P in tumor samples from 49 of 54 patients with Waldenström's macroglobulinemia and in 3 of 3 patients with non–IgM-secreting LPL (91% of all patients with LPL). MYD88 L265P was absent in paired normal tissue samples from patients with Waldenström's macroglobulinemia or non-IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with multiple myeloma, marginal-zone lymphoma, or IgM monoclonal gammopathy of unknown significance. Inhibition of MYD88 signaling reduced IκBα and NF-κB p65 phosphorylation, as well as NF-κB nuclear staining, in Waldenström's macroglobulinemia cells expressing MYD88 L265P. Somatic variants in ARID1A in 5 of 30 patients (17%), leading to a premature stop or frameshift, were also identified and were associated with an increased disease burden. In addition, 2 of 3 patients with Waldenström's macroglobulinemia who had wild-type MYD88 had somatic variants in MLL2. MYD88 L265P is a commonly recurring mutation in patients with Waldenström's macroglobulinemia that can be useful in differentiating Waldenström's macroglobulinemia and non-IgM LPL from B-cell disorders that have some of the same features. (Funded by the Peter and Helen Bing Foundation and others.)Keywords
This publication has 34 references indexed in Scilit:
- The mutation spectrum revealed by paired genome sequences from a lung cancer patientNature, 2010
- Analysis of Genetic Inheritance in a Family Quartet by Whole-Genome SequencingScience, 2010
- How I treat Waldenström macroglobulinemiaBlood, 2009
- Risk of lymphoproliferative disorders among first-degree relatives of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia patients: a population-based study in SwedenBlood, 2008
- Long-term Evaluation of Three Multiple-Case Waldenström Macroglobulinemia FamiliesClinical Cancer Research, 2007
- Characterization of familial Waldenström's macroglobulinemiaAnnals of Oncology, 2005
- Immunoglobulin M Monoclonal Gammopathies of Undetermined Significance and Indolent Waldenström's Macroglobulinemia Recognize the Same Determinants of Evolution Into Symptomatic Lymphoid Disorders: Proposal for a Common Prognostic Scoring SystemJournal of Clinical Oncology, 2005
- Clinical characteristics and factors predicting evolution of asymptomatic IgM monoclonal gammopathies and IgM-related disordersLeukemia, 2004
- Long-term follow-up of IgM monoclonal gammopathy of undetermined significanceBlood, 2003
- Clinicopathological definition of Waldenstrom's macroglobulinemia: Consensus Panel Recommendations from the Second International Workshop on Waldenstrom's MacroglobulinemiaSeminars in Oncology, 2003