Genomic landscape of CXCR4 mutations in Waldenstrom's Macroglobulinemia
Résumé
Purpose: Whole-genome sequencing has revealed MYD88 L265P and CXCR4 mutations (CXCR4mut) as the most prevalent somatic mutations in Waldenstrom's macroglobulinemia (WM). CXCR4 mutation has proved to be of critical importance in WM, 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 WM. Experimental Design. We have scanned the 2 coding exons of CXCR4 in WM using deep next generation sequencing and Sanger sequencing in 98 WM patients, and correlated with SNP array landscape and mutational spectrum of 8 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 WM. 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 CXCR4mut WM 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 WM, and identified a specific signature associated to CXCR4mut, characterized with complex genomic aberrations among MYD88L265P WM. Our results suggest the existence of various genomic subgroups in WM.