@article{Marzia Varettoni_Silvia Zibellini_Irene Defrancesco_Virginia Valeria Ferretti_Ettore Rizzo_Luca Malcovati_Anna Gallì_Matteo Giovanni Della Porta_Emanuela Boveri_Luca Arcaini_Chiara Candido_Marco Paulli_Mario Cazzola_2017, place={Pavia, Italy}, title={Pattern of somatic mutations in patients with Waldenström macroglobulinemia or IgM monoclonal gammopathy of undetermined significance}, volume={102}, url={https://haematologica.org/article/view/8286}, DOI={10.3324/haematol.2017.172718}, abstractNote={We analyzed <em>MYD88</em> 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 (<em>MYD88</em>, <em>CXCR4</em>, <em>ARID1A</em>, <em>KMT2D</em>, <em>NOTCH2</em>, <em>TP53</em>, <em>PRDM1</em>, <em>CD79B</em>, <em>TRAF3</em>, <em>MYBBP1A</em>, and <em>TNFAIP3</em>). <em>MYD88</em> (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. <em>MYD88</em> 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 <em>MYD88</em> had a distinct clinical phenotype characterized by less bone marrow infiltration (<em>P</em>=0.01) and more frequent extramedullary involvement (<em>P</em>=0.001) compared to patients with mutated <em>MYD88</em>. Patients with wild-type <em>MYD88</em> did not show additional mutations in the other target genes. <em>CXCR4</em> mutations were found by Sanger sequencing in 22% of patients with Waldenström macroglobulinemia. With next-generation sequencing, a <em>CXCR4</em> 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 <em>CXCR4</em> mutation had a shorter treatment-free survival (51 months) than that of patients with wild-type <em>CXCR4</em> (median not reached) (<em>P</em>=0.007). Analysis of variant allele frequencies indicated that <em>CXCR4</em> mutations were present in the dominant clone in the majority of cases. Recurrent somatic mutations of <em>KMT2D</em&gt; were found in 24% of patients with Waldenström macroglobulinemia and 5% of patients with IgM monoclonal gammopathy of undetermined significance and were primarily subclonal.}, number={12}, journal={Haematologica}, author={Marzia Varettoni and Silvia Zibellini and Irene Defrancesco and Virginia Valeria Ferretti and Ettore Rizzo and Luca Malcovati and Anna Gallì and Matteo Giovanni Della Porta and Emanuela Boveri and Luca Arcaini and Chiara Candido and Marco Paulli and Mario Cazzola}, year={2017}, month={Nov.}, pages={2077-2085} }