Haematologica
Haematologica
5 years ago

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

Malcovati, Defrancesco, Cazzola, Boveri, Candido, Arcaini, Della Porta, Zibellini, Rizzo, Varettoni, Paulli, Gallì, Ferretti
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 PCR and Sanger sequencing respectively. A subgroup of 119 patients was further studied with next-generation sequencing of 11 target genes (MYD88, CXCR4, ARID1-A, KMT2D, NOTCH2, TP53, PRDM1, CD79B, TRAF3, MYBBP1A, 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 PCR. MYD88 mutations other than classical L265P (V217F, S219C and M232T) were found in 4 cases with next-generation sequencing. MYD88 wild-type Waldenström macroglobulinemia patients had a distinct clinical phenotype characterized by lower bone marrow infiltration (P=0.01) and more frequent extramedullary involvement (P=0.001) as compared with mutated patients. MYD88 wild-type patients did not show additional mutations in the other target genes. CXCR4 mutations were found in 22% of Waldenström macroglobulinemia patients with Sanger. 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) as compared wild-type ones (median not reached) (P = 0.007). The analysis of variant allele frequencies indicates that CXCR4 mutations were present in the dominant clone in the majority of cases. Recurrent somatic mutations of KMT2D were found in 26% of patients with Waldenström macroglobulinemia and 5% of patients with IgM monoclonal gammopathy of undetermined significance and were primarily subclonal.

Publisher URL: http://doi.org/10.3324/haematol.2017.172718

DOI: 10.3324/haematol.2017.172718

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