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

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.

IGHV segment utilization in immunoglobulin gene rearrangement differentiates patients with anti-myelin-associated glycoprotein neuropathy from others immunoglobulin M-gammopathies

“…The MYD88 mutational rate in anti-MAG neuropathy is closely related to the underlying B cell disorder. Indeed, the prevalence observed is comparable to our internal control groups and previous larger cohorts of WM or IgM-MGUS without anti-MAG 3,6,7 . With HTS, no CXCR4 mutation was detected for anti-MAG patients while 13.6%…”

“…MYD88 mutations is an early event in the pathogenesis of monoclonal gammopathy, promoting the emergence of a B-cell clone responsible for IgM paraprotein production 3,11 .…”

“…Management of anti-MAG neuropathy remains a challenge and no predictive factor has been described to identify patients with IgM monoclonal gammopathy at risk to develop anti-MAG neuropathy. Description of the mutational profile of MYD88, CXCR4, and TP53 genes have radically changed the diagnosis and prognostic evaluation of IgM monoclonal gammopathies 3,4,5 . Acting as a trigger for NFĸB signaling, MYD88 L265P is the most prevalent mutation in WM and IgM-MGUS 6,7 .…”

How Recent Advances in Biology of Waldenström’s Macroglobulinemia May Affect Therapy Strategy

“…TP53 alterations (mutation, deletion, or uniparental disomy) presented a greater frequency of genomic aberrations compared with TP53 WT. Low frequency of TP53 mutation at diagnosis was confirmed by other groups [45,46]. Patients with TP53 alterations had a shorter overall survival and a shorter time to progression to a symptomatic disease.…”

How I treat Waldenström macroglobulinemia

“…Absence of MYD88 L265P does not exclude WM: 5% to 10% of patients with WM do not have MYD88 L265P (they have other MYD88 mutations 14 or have wild-type MYD88). MYD88 L265P also is found in 30% to 80% of IgM MGUS cases 10, 13,15 (depending on method's sensitivity) and in other lymphomas, but at significantly lower rates. In 20% to 40% of patients, lymphoplasmacytes have somatic activating mutations in the C-terminal domain of the C-X-C chemokine receptor type 4 (CXCR4) gene, 10, 16 which are similar to germline mutations observed in WHIM syndrome (CXCR4 WHIM ).…”