Association Of MiR-146a And MIF Polymorphisms With Susceptibility Of Gastric Cancer

Gastric cancer is a major cause of morbidity and mortality among malignant tumor of digestive tract. Although the incidence of gastric cancer has decreased since the 1930s, it remains the second most fatal malignancy in the world. Gastric cancer is a major public health issue in China where about half of the worldwide gastric cancer cases occur. It is a complex, multistep and multifactorial process, and is thought to result from an interaction between genetic backgrounds and environmental factors. Epidemiological studies show that the risk of gastric cancer was influenced by polymorphisms of many genes including microRNAs, immunoglobulin superfamily members, metabolic enzymes, other molecules involved in inflammatory response, DNA repair, oxidative damage, and et al. 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 single nucleotide polymorphisms (SNPs) of genes encoding microRNAs and immunoglobulin superfamily members.Recently, microRNA-146a (miRNA-146a) and Macrophage migration inhibitor factor (MIF) have been linked to tumorigenesis. SNPs of these genes including Pre-miR-146a C/G and MIF-173G/C have been confirmed to be associated with the expression of the genes and (or) the function of the proteins.However, to our knowledge, there is no study concerning association between these polymorphisms and susceptibility to gastric cancer. Thus, we conducted a hospital-based, case-control study to assess the association between the risk of gastric cancer and the Pre-miR-146a C/G and MIF-173G/C 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: A Study on the Association between Pre-miR-146a C/G Polymorphism and Susceptibility to Gastric CancerTo investigate the association between Pre-miR-146a C/G polymorphism and gastric cancer risk, we conducted a hospital-based case-control study of 304 gastric cancer cases and 304 controls matched on age and gender. The genotypes were identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We found that the genotype frequencies were significantly different (P=0.037) between cases and controls. Compared with the CC homozygotes, the variant genotypes (CG + GG) were associated with a 58% increased risk of gastric cancer (adjusted OR=1.58, 95% CI=1.12-2.22). Further stratification analyses indicated that the increased risk was especially noteworthy in young subjects (age≤58) (adjusted OR=1.76, 95% CI=1.08-2.87), males (adjusted OR=1.53, 95% CI=1.04-2.27) and non-smokers (adjusted OR=1.55, 95% CI=1.06-2.28). We also evaluated the correlations of the variant genotypes with clinicopathologic features of gastric cancer, including tumor differentiation, depth of tumor infiltration, lymph node status and tumor location. However, no statistically significant association was observed. Our results suggest that the Pre-miR-146a C/G polymorphism may be associated with increased risk of gastric cancer. PartⅡ: A Study on the Association between MIF-173G/C Polymorphism and Susceptibility to Gastric CancerMacrophage migration inhibitory factor (MIF) is a T cell-derived cytokine that inhibits the migration of macrophages and play an important pathogenetic role in proinflammatory, enzymatic and hormonal activities. The MIF gene maps to chromosome 22q11.2, and its -173G/C (rs755622) polymorphism has been shown to influence susceptibility to several diseases. To investigate the association between MIF-173G/C polymorphism and gastric cancer risk, we conducted a hospital-based case-control study of 283 gastric cancer cases and 283 controls matched on age and gender. The genotype and allele frequencies were significantly different (P=0.008 and 0.015, respectively) between cases and controls. Further analysis showed that the variant CC genotype had a 3.49-fold increased risk of gastric cancer when compared with GG genotype (adjusted OR=3.49, 95% CI=1.53-7.97). The elevated gastric cancer risk associated with the variant genotypes ( GC + CC) was observed only in male subjects (adjusted OR=1.52, 95% CI=1.03-2.25), but not in females. Further analyses revealed that the variant genotypes (GC+CC) were associated with depth of tumor infiltration. These findings suggest that the MIF-173G/C 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.