Polymorphic DNA repair and metabolic genes: a multigenic study on gastric cancer.

Risk factors for gastric cancer (GC) include inter-individual variability in the inflammatory response to Helicobacter pylori infection, in the ability of detoxifying DNA reactive species and repairing DNA damage generated by oxidative stress and dietary carcinogens. To evaluate the association between polymorphic DNA repair genes and GC risk, a case-control study including 314 histologically confirmed GC patients and 548 healthy controls was conducted in a GC high-risk area in Tuscany, Italy. Polymorphic variants of base excision repair (APE1-D148E, XRCC1-R194W, XRCC1-R399Q and OGG1-S326C), nucleotide excision repair (XPC-PAT, XPA-23G>A, ERCC1-19007T>C and XPD-L751Q), recombination (XRCC3-T241M) and alkylation damage reversal (MGMT-L84F) were tested for their potential role in the development of GC by using logistic regression models. The same population was also characterised for GSTT1 and GSTM1 variant alleles to search for possible functional interactions between metabolic and DNA repair genotypes by two-way interactions using multivariate logistic models. No significant association between any single DNA repair genotype and GC risk was detected with a borderline association with the XPC-PAT homozygous genotype [odds ratio (OR) =1.42; 95% confidence interval (CI) 0.94-2.17]. Gene-gene interaction analysis revealed combinations of unfavourable genotypes involving either multiple DNA repair polymorphisms or DNA repair and GST-specific genotypes. The combination of the XPC-PAT and the XPA variant alleles significantly increased GC risk (OR=2.15; 95% CI 1.17-3.93, P=0.0092). A significant interaction was also found between the APE1 wild-type genotype and either the single GSTT1 (OR=4.90; 95% CI 2.38-10.11, P=0.0079) or double GSTM1-GSTT1 null (OR=7.84; 95% CI 3.19-19.22, P=0.0169) genotypes or the XPA-mutant allele (OR=3.56; 95% CI 1.53-8.25, P=0.0012). These findings indicate that a complex interaction between host factors such as oxidative stress, antioxidant capacity and efficiency of multiple DNA repair pathways underlies the inter-individual variability in GC risk.

Classification of gastritis in first-degree relatives of patients with gastric cancer in a high cancer-risk area in Italy.

BACKGROUND: Screening gastroscopic examinations were performed in a cohort of individuals at high risk for developing gastric carcinoma (GC). PATIENTS AND METHODS: Five gastric biopsies were obtained following the Houston schema. Five histological parameters of gastritis were investigated: acute gastritis, chronic gastritis, and its sequelae; mucosal atrophy, intestinal metaplasia and pseudopyloric metaplasia. RESULTS: Out of 134 patients, 50% (n=67) had Helicobacter pylori (HP) infection. The sum of scores for the first four parameters was significantly higher in HP-positive cases than in HP-negative ones (p<0.0001). The frequency of these histological parameters was similar to other series from Northern and Central Italy. Hence, none of the histological parameters of gastritis explain the high GC risk in this borough of Florence, considering that the incidence rate of GC is higher in Central than in Northern Italy. CONCLUSION: Similarities in the frequency of chronic gastritis and sequelae in Northern and Central Italy substantiate the conviction that the difference in GC risk in these regions might be the result of local environmental or lifestyle factors, rather than HP infection. This knowledge is crucial, considering that environmentally related diseases are theoretically preventable.