Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia.

[waldenström macroglobulinemia]

Whole genome sequencing has revealed activating somatic mutations in MYD 88 (L 265 P ) and CXCR 4 in Waldenström macroglobulinemia (WM ). CXCR 4 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 MYD 88 (L 265 P )CXCR 4 (WHIM /NS ) mutations (P < .03 ). Patients with MYD 88 (L 265 P )CXCR 4 (WHIM /FS ) or MYD 88 (L 265 P )CXCR 4 (WILDTYPE (WT )) had intermediate BM and serum immunoglobulin-M levels ; those with MYD 88 (WT )CXCR 4 (WT ) showed lowest BM disease burden . Fewer patients with MYD 88 (L 265 P ) and CXCR 4 (WHIM /FS or NS ) vs MYD 88 (L 265 P )CXCR 4 (WT ) presented with adenopathy (P < .01 ), further delineating differences in disease tropism based on CXCR 4 status . Neither MYD 88 nor CXCR 4 mutations correlated with SDF-1 a (RS 1 801157 ) polymorphisms in 54 patients who were genotyped for these variants . Unexpectedly , risk of death was not impacted by CXCR 4 mutation status , but by MYD 88 (WT ) status (hazard ratio 10 .54 ; 95 % confidence interval 2 .4 -46 .2 , P = .0018 ). Somatic mutations in MYD 88 and CXCR 4 are important determinants of clinical presentation and impact overall survival in WM . Targeted therapies directed against MYD 88 and /or CXCR 4 signaling may provide a personalized treatment approach to WM .