Pattern of somatic mutations in patients with Waldenström macroglobulinemia or IgM monoclonal gammopathy of undetermined significance

We analyzed MYD88 and CXCR4 mutation status of 260 patients with Waldenström macroglobulinemia or IgM monoclonal gammopathy of undetermined significance using allele-specific real time quantitative polymerase chain reaction and Sanger sequencing, respectively. A subgroup of 119 patients was further studied with next-generation sequencing of 11 target genes (MYD88, CXCR4, ARID1A, KMT2D, NOTCH2, TP53, PRDM1, CD79B, TRAF3, MYBBP1A, and TNFAIP3). MYD88 (L265P) was found at diagnosis in 91% of patients with Waldenström macroglobulinemia and in 60% of patients with IgM monoclonal gammopathy of undetermined significance using allele-specific polymerase chain reaction analysis. MYD88 mutations other than the classical L265P (V217F, S219C and M232T) were found in four cases by next-generation sequencing. Waldenström macroglobulinemia patients with wild-type MYD88 had a distinct clinical phenotype characterized by less bone marrow infiltration (P=0.01) and more frequent extramedullary involvement (P=0.001) compared to patients with mutated MYD88. Patients with wild-type MYD88 did not show additional mutations in the other target genes. CXCR4 mutations were found by Sanger sequencing in 22% of patients with Waldenström macroglobulinemia. With next-generation sequencing, a CXCR4 mutation was detected in 23% of patients with Waldenström macroglobulinemia and 9% of those with IgM monoclonal gammopathy of undetermined significance. Asymptomatic Waldenström macroglobulinemia patients harboring a CXCR4 mutation had a shorter treatment-free survival (51 months) than that of patients with wild-type CXCR4 (median not reached) (P=0.007). Analysis of variant allele frequencies indicated that CXCR4 mutations were present in the dominant clone in the majority of cases. Recurrent somatic mutations of KMT2D were found in 24% of patients with Waldenström macroglobulinemia and 5% of patients with IgM monoclonal gammopathy of undetermined significance and were primarily subclonal.

[1]  S. Ferrero,et al.  Minimal Residual Disease in Indolent Lymphomas: A Critical Assessment , 2018, Current Treatment Options in Oncology.

[2]  B. Quesnel,et al.  TP53 Mutation and Its Prognostic Significance in Waldenstrom's Macroglobulinemia , 2017, Clinical Cancer Research.

[3]  S. Treon,et al.  To select or not to select? The role of B‐cell selection in determining the MYD88 mutation status in Waldenström Macroglobulinaemia , 2017, British journal of haematology.

[4]  S. Treon,et al.  Transcriptome sequencing reveals a profile that corresponds to genomic variants in Waldenström macroglobulinemia. , 2016, Blood.

[5]  R. Advani,et al.  Clonal architecture of CXCR4 WHIM‐like mutations in Waldenström Macroglobulinaemia , 2016, British journal of haematology.

[6]  S. Treon,et al.  MYD88 Mutations and Response to Ibrutinib in Waldenström's Macroglobulinemia. , 2015, The New England journal of medicine.

[7]  L. Quintanilla‐Martinez,et al.  MYD88 L265P and CXCR4 mutations in lymphoplasmacytic lymphoma identify cases with high disease activity , 2015, British journal of haematology.

[8]  R. Advani,et al.  Ibrutinib in previously treated Waldenström's macroglobulinemia. , 2015, The New England journal of medicine.

[9]  B. Quesnel,et al.  Genomic Landscape of CXCR4 Mutations in Waldenström Macroglobulinemia , 2014, Clinical Cancer Research.

[10]  A. Roccaro,et al.  C1013G/CXCR4 acts as a driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic lymphoma. , 2014, Blood.

[11]  S. Rodig,et al.  The WHIM-like CXCR4S338X somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom’s Macroglobulinemia , 2014, Leukemia.

[12]  Dereje D. Jima,et al.  The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells. , 2014, Blood.

[13]  S. Treon,et al.  Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia. , 2014, Blood.

[14]  S. Treon,et al.  The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. , 2014, Blood.

[15]  M. Calaminici,et al.  Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma , 2013, Nature Genetics.

[16]  Manel Juan,et al.  Landscape of somatic mutations and clonal evolution in mantle cell lymphoma , 2013, Proceedings of the National Academy of Sciences.

[17]  M. Cazzola,et al.  MYD88 (L265P) mutation is an independent risk factor for progression in patients with IgM monoclonal gammopathy of undetermined significance. , 2013, Blood.

[18]  N. Gray,et al.  A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia. , 2013, Blood.

[19]  M. Cazzola,et al.  Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenstrom's macroglobulinemia and related lymphoid neoplasms. , 2013, Blood.

[20]  N. Munshi,et al.  MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction. , 2013, Blood.

[21]  N. Gutiérrez,et al.  MYD88 L265P is a marker highly characteristic of, but not restricted to, Waldenström’s macroglobulinemia , 2013, Leukemia.

[22]  A. Sivachenko,et al.  Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples , 2013, Nature Biotechnology.

[23]  L. Staudt,et al.  MYD88 L265P somatic mutation in IgM MGUS. , 2012, The New England journal of medicine.

[24]  B. Quesnel,et al.  MYD88 L265P mutation in Waldenstrom macroglobulinemia. , 2012, Blood.

[25]  N. Harris,et al.  MYD88 L265P somatic mutation in Waldenström's macroglobulinemia. , 2012, The New England journal of medicine.

[26]  S. Pileri,et al.  The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development , 2012, The Journal of experimental medicine.

[27]  T. Therneau,et al.  Progression in smoldering Waldenstrom macroglobulinemia: long-term results. , 2012, Blood.

[28]  Steven J. M. Jones,et al.  Frequent mutation of histone modifying genes in non-Hodgkin lymphoma , 2011, Nature.

[29]  M. DePristo,et al.  A framework for variation discovery and genotyping using next-generation DNA sequencing data , 2011, Nature Genetics.

[30]  Joseph M. Connors,et al.  Oncogenically active MYD88 mutations in human lymphoma , 2011, Nature.

[31]  R. Pfeiffer,et al.  Differential characteristics of Waldenström macroglobulinemia according to patterns of familial aggregation. , 2010, Blood.

[32]  S. Treon,et al.  IgA and IgG hypogammaglobulinemia in Waldenström’s macroglobulinemia , 2010, Haematologica.

[33]  M. Björkholm,et al.  Risk of lymphoproliferative disorders among first-degree relatives of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia patients: a population-based study in Sweden. , 2008, Blood.

[34]  C. Morton,et al.  Characterization of familial Waldenstrom's Macroglobulinemia. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  T. Therneau,et al.  Long-term follow-up of IgM monoclonal gammopathy of undetermined significance. , 2003, Seminars in oncology.

[36]  R. Gorlin,et al.  Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease , 2003, Nature Genetics.

[37]  M. Dimopoulos,et al.  Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. , 2003, Seminars in oncology.

[38]  J. Bernstein,et al.  Defects of B-cell terminal differentiation in patients with type-1 Kabuki syndrome. , 2016, The Journal of allergy and clinical immunology.

[39]  Claude-Alain H. Roten,et al.  Fast and accurate short read alignment with Burrows–Wheeler transform , 2009, Bioinform..