title: The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis.
abstract: The genetic basis for Waldenström macroglobulinemia (WM) remains to be clarified. Although 6q losses are commonly present, recurring gene losses in this region remain to be defined. We therefore performed whole genome sequencing (WGS) in 30 WM patients, which included germline/tumor sequencing for 10 patients. Validated somatic mutations occurring in >10% of patients included MYD88, CXCR4, and ARID1A that were present in 90%, 27%, and 17% of patients, respectively, and included the activating mutation L265P in MYD88 and warts, hypogammaglobulinemia, infection, and myelokathexis-syndrome-like mutations in CXCR4 that previously have only been described in the germline. WGS also delineated copy number alterations (CNAs) and structural variants in the 10 paired patients. The CXCR4 and CNA findings were validated in independent expansion cohorts of 147 and 30 WM patients, respectively. Validated gene losses due to CNAs involved PRDM2 (93%), BTG1 (87%), HIVEP2 (77%), MKLN1 (77%), PLEKHG1 (70%), LYN (60%), ARID1B (50%), and FOXP1 (37%). Losses in PLEKHG1, HIVEP2, ARID1B, and BCLAF1 constituted the most common deletions within chromosome 6. Although no recurrent translocations were observed, in 2 patients deletions in 6q corresponded with translocation events. These studies evidence highly recurring somatic events, and provide a genomic basis for understanding the pathogenesis of WM.
authors.affiliation: Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Hunter
authors.forename: Lian
authors.initials: L
authors.lastname: Xu
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Yangsheng
authors.initials: Y
authors.lastname: Zhou
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Manning
authors.forename: Christina
authors.initials: C
authors.lastname: Tripsas
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Patterson
authors.forename: Patricia
authors.initials: P
authors.lastname: Sheehy
authors.forename: Steven P
authors.initials: SP
authors.lastname: Treon
mesh_terms: D000595:Amino Acid Sequence; D001853:Bone Marrow / Q000473:pathology; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics; D004268:DNA-Binding Proteins; D017353:Gene Deletion; D023281:Genomics; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D000081207:Primary Immunodeficiency Diseases; D019718:Receptors, CXCR4 / Q000235:genetics*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics; D014178:Translocation, Genetic; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics* / Q000473:pathology; D014860:Warts / Q000235:genetics*
chemical_list: C112476:ARID1A protein, human; C527276:CXCR4 protein, human; D004268:DNA-Binding Proteins; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D009687:Nuclear Proteins; D019718:Receptors, CXCR4; D014157:Transcription Factors