Helicobacter pylori infection, interleukin 1 beta polymorphism and predisposition to gastric cancer through the CpG island methylation pathway

Abstract

BACKGROUND: The association of HP infection and IL-1β polymorphism increases the risk of developing gastric cancer. Gastric mucosa of patients with Helicobacter pylori (HP) infection have CpG island methylation at tumor suppressor genes. Interleukin 1beta (IL-1β) increases gene methylation at CpG islands. We postulate that HP infection and IL-1β polymorphism predispose to gastric cancer through CpG island methylation pathway. Aim: To investigate if an association exists between IL-1β polymorphism, HP infection and methylation and in patients with gastric cancer. METHODS: We determined IL-1B-511/-31 and IL-1RN genotypes in 98 patients with gastric cancer. Methylation of MGMT, E-cadherin, DAPK and p16 were assessed in these patients using methylation-specific PCR and confirmed by sequencing. HP status was confirmed by histology and serology. RESULTS: HP infection was present in 65.3% (64) patients. The T and C alleles at the -511 locus of the IL-1B gene were in near total linkage disequilibrium with the C and T alleles at the -31 locus. Hence only -511 locus was assessed. The allele frequencies at IL-1B-511 were 16% (16), 59% (58), and 25% (24) for C/C, C/T, and T/T genotypes, respectively. Allele 2 of the IL-1RN locus was not detected in any patients. Methylation of MGMT, E-cadherin, DAPK and p16 were present in 30% (29), 59% (58), 43% (42) and 45% (44) of patients, respectively. Methylation of two or more genes was present in 84% (20) of patients with the IL-1B-511 T/T genotype, 44% (7) with C/C genotype, and 74% (43) with T/C genotype (p = 0.02). This association was present in patients with HP infection: 88% (15) with T/T genotype, 38% (3) with C/C genotype, and 77% (30) with T/C genotype (p = 0.02), but not present in patients without HP infection (p = 0.6). CONCLUSION: We postulate that the patients with HP infection and IL-1B-511 T/T genotype may be predisposed to gastric cancer through the CpG island methylation pathway.