Genomic Landscape of CXCR4 Mutations in Waldenstrom Macroglobulinemia

Purpose: Whole-genome sequencing has revealed MYD88 L265P and CXCR4 mutations (CXCR4(mut)) as the most prevalent somatic mutations in Waldenstrom macroglobulinemia. CXCR4 mutation has proved to be of critical importance in Waldenstrom macroglobulinemia, in part due to its role as a mechanism of resistance to several agents. We have therefore sought to unravel the different aspects of CXCR4 mutations in Waldenstrom macroglobulinemia. Experimental Design: We have scanned the two coding exons of CXCR4 in Waldenstrom macroglobulinemia using deep next-generation sequencing and Sanger sequencing in 98 patients with Waldenstrom macroglobulinemia and correlated with SNP array landscape and mutational spectrum of eight candidate genes involved in TLR, RAS, and BCR pathway in an integrative study. Results: We found all mutations to be heterozygous, somatic, and located in the C-terminal domain of CXCR4 in 25% of the Waldenstrom macroglobulinemia. CXCR4 mutations led to a truncated receptor protein associated with a higher expression of CXCR4. CXCR4 mutations pertain to the same clone as to MYD88 L265P mutations but were mutually exclusive to CD79A/CD79B mutations (BCR pathway). We identified a genomic signature in CXCR4(mut) Waldenstrom macroglobulinemia traducing a more complex genome. CXCR4 mutations were also associated with gain of chromosome 4, gain of Xq, and deletion 6q. Conclusions: Our study panned out new CXCR4 mutations in Waldenstrom macroglobulinemia and identified a specific signature associated to CXCR4(mut), characterized with complex genomic aberrations among MYD88L265P Waldenstrom macroglobulinemia. Our results suggest the existence of various genomic subgroups in Waldenstrom macroglobulinemia. (C) 2015 AACR.