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

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

Marzia Varettoni  1 , Silvia Zibellini  2 , Irene Defrancesco  2 , Virginia Valeria Ferretti  3 , Ettore Rizzo  4 , Luca Malcovati  2   3 , Anna Gallì  2 , Matteo Giovanni Della Porta  5 , Emanuela Boveri  6 , Luca Arcaini  2   3 , Chiara Candido  2 , Marco Paulli  6 , Mario Cazzola  2   3
Affiliations

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

Marzia Varettoni et al. Haematologica. 2017 Dec.

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.

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Figures

Figure 1.
Figure 1.
MYD88 allele burden in patients with IgM monoclonal gammopathy of undetermined significance, asymptomatic and symptomatic Waldenström macroglobulinemia.
Figure 2.
Figure 2.
Correlation of MYD88 allele burden with disease phenotype in patients with Waldenström macroglobulinemia.
Figure 3.
Figure 3.
Treatment-free survival of asymptomatic patients with Waldenström macroglobulinemia according to CXCR4 mutation status.
Figure 4.
Figure 4.
Treatment-free survival of asymptomatic patients with Waldenström macroglobulinemia according to MYD88 and CXCR4 mutational status.
Figure 5.
Figure 5.
Pattern of mutations observed in patients with (A) IgM monoclonal gammopathy of undetermined significance or (B) Waldenström macroglobulinemia.
Figure 6.
Figure 6.
Variant allele frequency of MYD88 and CXCR4 mutations as determined by next-generation sequencing.
Figure 7.
Figure 7.
Variant allele frequency of MYD88 and KMT2D mutations as determined by next-generation sequencing.
See this image and copyright information in PMC

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