Polymorphism in the P2X7 receptor gene and survival in chronic lymphocytic leukaemia

Background The P2X7 receptor is a ligand-gated cation channel that mediates ATP-induced apoptotic death in haemopoietic and chronic lymphocytic leukaemia (CLL) cells. We aimed to investigate the clinical effect of a single nucleotide polymorphism in the P2X7 receptor gene (1513A-->C) and correlate findings with the immunoglobulin heavy chain variable (V-H) gene mutation status, a prognostic marker in CLL. Methods We investigated tumour DNA in 170 patients with CLL using PCR-RFLP analysis with Hhal restriction enzyme cleavage to screen for the polymorphism in the P2X7 receptor gene. The V gene mutation status was assessed in 165 patients by PCR amplification and nucleotide sequencing. We correlated the findings of the P2X7 receptor genotype with the V-H gene mutation data and overall survival and screened for the P2X7 receptor polymorphism in 200 healthy controls. Findings Of the 170 patients, 35 (21%) were heterozygous and one (1%) homozygous for the 1513C allele; whereas 134 (79%) had the 1513A/A genotype of the P2X7 receptor gene. Overall survival was significantly longer for patients with CLL heterozygous for the 1513C allele than those with the 1513A/A genotype. Median survival for heterozygous patients was 104 months (range 33-467) and 72 months (1-190) for homozygous patients (p=0.009). Of the 165 patients with CLL in whom we assessed the V-H gene mutation status, the V-H genes were mutated in 71 (43%) patients and unmutated in 94; 18 (25%) of the 71 patients with mutated genes had 1513C allele compared with 17 (18%) of 94 who had unmutated genes. In patients with mutated V-H genes, those with CLL who were 1513C positive had 53 months' longer median survival than did those with the 1513A/A genotype (151 vs 98 months, p=0.011). Interpretation The P2X7 polymorphism could affect clinical outcome in CLL, especially in patients with mutated V-H genes. Studies are necessary to elucidate the biological role of the P2X7 polymorphism in CLL in vivo.