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

Autor:	Varettoni M; Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy m.varettoni@smatteo.pv.it., Zibellini S; Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy., Defrancesco I; Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy., Ferretti VV; Department of Molecular Medicine, University of Pavia, Pavia, Italy., Rizzo E; enGenome srl, Pavia, Italy., Malcovati L; Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.; Department of Molecular Medicine, University of Pavia, Pavia, Italy., Gallì A; Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy., Porta MGD; Cancer Center, IRCCS Humanitas Research Hospital & Humanitas University, Milan, Italy., Boveri E; Anatomic Pathology Section, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy., Arcaini L; Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.; Department of Molecular Medicine, University of Pavia, Pavia, Italy., Candido C; Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy., Paulli M; Anatomic Pathology Section, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy., Cazzola M; Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.; Department of Molecular Medicine, University of Pavia, Pavia, Italy.
Jazyk:	angličtina
Zdroj:	Haematologica [Haematologica] 2017 Dec; Vol. 102 (12), pp. 2077-2085. Date of Electronic Publication: 2017 Oct 05.
DOI:	10.3324/haematol.2017.172718
Abstrakt:	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. (Copyright© 2017 Ferrata Storti Foundation.)
Databáze:	MEDLINE
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