Polymorphisms of DNA Repair and Xenobiotic Genes Predispose to CpG Island Methylation in Non‐Neoplastic Gastric Mucosa

Abstract

Genetic factors, related to DNA repair or xenobiotic pathways might confer different degrees of susceptibility to gastric carcinogenesis. CpG island hyper methylation (CIHM) is a major event in gastric carcinogenesis. We evaluated the association between XRCC1, GSTP1, GSTT1 and GSTM1 polymorphisms with CIHM status in non-neoplastic gastric mucosa. XRCC1 Arg399Gln, and Arg194Trp, GSTP1 Ile104Val, and GSTT1, GSTM1 null polymorphisms were genotyped in 415 cancer free subjects, in relation to four candidate CpG (p14, p16, DAP-kinase and CDH1) loci, assessed by Methylation-Specific-Polymerase Chain Reaction (MSP). CIHM high was defined as two or more CpG islands methylated. Significant association between XRCC1 codon 399 Gln/Gln genotype and reduced susceptibility to CIHM of DAP-kinase (adjusted OR = 0.30, 95%CI = 0.13-0.71, p = .0055) and CIHM high (OR = 0.42, 95%CI = 0.19-0.97, p = .04). XRCC1 codon 399 Gin/Gln genotype also presented lower number of CIHM when compared with both Arg/Gln, and Arg/Arg + Arg/Gln genotypes (p = .02, .046, respectively) When subjects were divided according to age (>50 and <50), an association was found between GSTM1 null genotype and increased susceptibility to CIHM high in the 50 years and older generations (OR = 1.63, 95%CI = 1.01-2.62, p = .045). XRCC1 codon 399 Gln/Gln genotype is associated with reduced susceptibility to CIHM especially DAP-kinase. GSTM1 null genotype may increase the susceptibility to CIHM especially in older patients. Genetic factors, related to DNA repair or xenobiotic pathways may have a role in CIHM-related gastric carcinogenesis.