title: Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia.
abstract: Whole genome sequencing has revealed activating somatic mutations in MYD88 (L265P) and CXCR4 in Waldenström macroglobulinemia (WM). CXCR4 somatic mutations in WM are the first ever reported in human cancer and are similar to nonsense (NS) and frameshift (FS) germline mutations found in warts, hypogammaglobulinemia, infections and myelokathexis (WHIM) syndrome. We genotyped lymphoplasmacytic cells from 175 WM patients and observed significantly higher bone marrow (BM) disease involvement, serum immunoglobulin-M levels, and symptomatic disease requiring therapy, including hyperviscosity syndrome in those patients with MYD88(L265P)CXCR4(WHIM/NS) mutations (P < .03). Patients with MYD88(L265P)CXCR4(WHIM/FS) or MYD88(L265P)CXCR4(WILDTYPE (WT)) had intermediate BM and serum immunoglobulin-M levels; those with MYD88(WT)CXCR4(WT) showed lowest BM disease burden. Fewer patients with MYD88(L265P) and CXCR4(WHIM/FS or NS) vs MYD88(L265P)CXCR4(WT) presented with adenopathy (P < .01), further delineating differences in disease tropism based on CXCR4 status. Neither MYD88 nor CXCR4 mutations correlated with SDF-1a (RS1801157) polymorphisms in 54 patients who were genotyped for these variants. Unexpectedly, risk of death was not impacted by CXCR4 mutation status, but by MYD88(WT) status (hazard ratio 10.54; 95% confidence interval 2.4-46.2, P = .0018). Somatic mutations in MYD88 and CXCR4 are important determinants of clinical presentation and impact overall survival in WM. Targeted therapies directed against MYD88 and/or CXCR4 signaling may provide a personalized treatment approach to WM.
authors.affiliation: Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Steven P
authors.initials: SP
authors.lastname: Treon
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.forename: Lian
authors.initials: L
authors.lastname: Xu
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Hunter
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001853:Bone Marrow / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D019718:Receptors, CXCR4 / Q000235:genetics*; D016896:Treatment Outcome; D008258:Waldenstrom Macroglobulinemia / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality
chemical_list: D053594:Myeloid Differentiation Factor 88; D019718:Receptors, CXCR4