Genetic Polymorphisms Of Rage, ECE-1b And TIMP2 And Susceptibility To Gastric Cancer

Although the incidence of gastric cancer has been decreasing in the world over the past few decades, it is the second most fatal malignancy in the world. Gastric cancer remains a major public health issue in China where about half of the worldwide gastric cancer cases occur. Gastric carcinogenesis is a complex, multistep and multifactorial process. Like many malignancies, gastric cancer is the result of interactions between environmental factors and genetic factors of the host. Epidemiological studies have also provided evidence that the risk of gastric cancer was influenced by polymorphisms of many genes including inflammatory response, DNA repair, metabolic enzymes, oxidative damage, immunoglobulin superfamily and microRNAs. Our group explored the molecular markers with potential to predict occurrence and progression of gastric cancer, based on the hypothesis that there might be a similar genetic background that makes some individuals more susceptible to gastric cancer and liable to metastases in cancer progression. In the present study, we are particularly focusing on the polymorphisms of immunoglobulin superfamily, endothelin axis and matrix metalloproteinase axis.Recently, the receptor for advanced glycation endproducts (RAGE), endothelin-converting enzyme-1b (ECE-1b) and tissue inhibitor of metalloproteinase-2 (TIMP-2) has been linked to the pathogenesis of gastric cancer. Single nucleotide polymorphisms of these genes including RAGE Gly82Ser,ECE-1b C-338A and TIMP2 G-418C have been confirmed to influence the expression of the genes and the function of the proteins.However, to our knowledge, there is no study concerning association between the functional polymorphisms and susceptibility to gastric cancer. In the hospital-based, case-control study, we assessed the association between the risk of gastric cancer and the RAGE Gly82Ser,ECE-1b C-338A and TIMP2 G-418C polymorphism by univariate and multivariate analysis.It is important to find the polymorphisms which could be used as the marker for genetic susceptibility to gastric cancer. Identification of genetic factors that are responsible for susceptibility to gastric cancer is indispensable for establishing novel and efficient ways of preventing the disease.PartⅠ: Gly82Ser polymorphism of the receptor for advanced glycation end products is associated with an increased risk of gastric cancerIt has been shown that the expression of RAGE is closely associated with invasion and metastasis in gastric cancer. A Gly82Ser polymorphism in exon 3 of RAGE gene was identified and thought to have an effect on the functions of its protein. Therefore, the goal of the present study was to investigate whether the polymorphism is involved in the development or progression of gastric cancer. In the hospital-based case-control study, the RAGE genotypes were determined using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) in 566 individuals (283 gastric cancer patients and 283 age, sex matched controls). The distribution of genotype was significantly different between cases and controls (P=0.038). Compared with the wild-type 82Gly/Gly carriers, subjects with the variant genotypes (82Gly/Ser and 82Ser/Ser) had a significantly higher risk of gastric cancer [adjusted odds ratio (OR)=1.47; 95% confidence interval (CI)=1.05 - 2.06]. Moreover, the elevated gastric cancer risk was especially evident in younger individuals (age≤58), non-smokers and rural subjects (adjusted OR=2.49, 1.70 and 1.75;95% CI=1.53-4.05, 1.16-2.49 and 1.06-2.88, respectively). Further analyses revealed that the variant genotypes were associated with adjacent organ invasion in the subanalysis of gastric cancer patients. Our findings indicate that the RAGE Gly82Ser polymorphism may not only confer an increased risk of gastric cancer, but also with invasion of gastric cancer in the Chinese population.PartⅡ: Association of endothelin-converting enzyme-1b C-338A polymorphism with gastric cancer risk: a case-control studyTo investigate the association between ECE-1b C-338A polymorphism and gastric cancer risk, we conducted a hospital-based case-control study of 256 gastric cancer cases and 256 controls matched on age and gender. The genotypes were identified by polymerase chain reaction-restriction fragment length polymorphism. We found that the genotype frequencies were significantly different (P=0.005) between cases and controls. Compared with the wild genotype CC, the variant genotypes (CA + AA) were associated with a 64% increased risk of gastric cancer (adjusted OR=1.64, 95% CI=1.15-2.33). Further stratification analyses indicated that the increased risk was especially noteworthy in older subjects (age≥58) (adjusted OR=1.91, 95% CI=1.18-3.09), women (adjusted OR=2.30, 95% CI=1.11-4.79) and non-smokers (adjusted OR=1.79, 95% CI=1.19-2.67). However, no correlation of the polymorphism with gastric cancer progression was observed. Our results suggest that the ECE-1b C-338A polymorphism may be associated with increased risk of gastric cancer.PartⅢ: Tissue inhibitor of metalloproteinase-2 G-418C polymorphism is associated with an increased risk of gastric cancerTo examine the effect of TIMP2 G-418C polymorphism on gastric cancer risk. We conducted a hospital-based case-control study using PCR-RFLP method in 412 individuals (206 gastric cancer patients and 206 age, sex matched cancer-free controls). The genotype and allele frequencies were significantly different (P=0.007 and 0.005, respectively) between cases and controls. Further analysis showed that the variant TIMP2 genotypes (CC + GC) had a 51% increased risk of gastric cancer compared with GG (adjusted OR=1.51, 95% CI=1.00-2.26, P=0.049). The elevated gastric cancer risk was especially evident in younger individuals (age <58) (adjusted OR=2.21, 95% CI=1.18-4.16) and smokers (adjusted OR=2.61, 95% CI=1.01-6.72). However, no significant association was observed between the variant genotypes and clinicopathological features of gastric cancer. These findings suggest that the TIMP2 G-418C polymorphism is a genetic predisposing factor for gastric cancer.In summary, we have suggested the polymorphisms of genes involved in different pathogenic pathways in gastric carcinogenesis. Further investigations of the combined effects of polymorphisms within these genes and risk factors may help to clarify the influence of genetic variation in the carcinogenic process.