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

Haematologica. 2017 Dec;102(12):2077-2085. doi: 10.3324/haematol.2017.172718. Epub 2017 Oct 5.

Abstract

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.

MeSH terms

  • DNA-Binding Proteins / genetics
  • Gene Frequency
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Monoclonal Gammopathy of Undetermined Significance / genetics*
  • Mutation*
  • Myeloid Differentiation Factor 88 / genetics
  • Neoplasm Proteins / genetics
  • Phenotype
  • Receptors, CXCR4 / genetics
  • Survival Analysis
  • Waldenstrom Macroglobulinemia / genetics*

Substances

  • CXCR4 protein, human
  • DNA-Binding Proteins
  • KMT2D protein, human
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • Neoplasm Proteins
  • Receptors, CXCR4