| BackgroundGastric cancer is one of the most common cancers worldwide.The definite etiology and pathogenesis are not clear yet.Bacterial virulence,environmental and genetic factors are believed to play essential roles and among them,genetic factors gain growing concerns.Evidences for susceptibility to gastric cancer mainly rest in epidemiology and case reports from families of gastric cancer.Case-control study and cohort study demonstrate that first-degree relatives of gastric cancer patients have a two-to-three-fold increased risk for developing such disease.Therefore, cancer genetics is one of the strategies to explore cancer in terms of molecular biology mechanisms that give cells a selective growth advantage allowing tumor progression to occur,especially the studies of the genes that can affect the immune system,DNA repair,inflammatory response and level of expression or the function of some protein(including enzyme).Cytotoxic T lymphocyte antigen-4(CTLA-4) is widely considered as a pivotal molecule in down-regulating T-cell mediated immune responses,thus leading to suppressed antitumor effects.Several polymorphisms in CTLA-4 gene have been discovered and documented to impact CTLA-4 protein expression and function,and subsequently confirmed to be closely associated with a number of diseases including several cancers and autoimmune disorders.ObjectivesThe case-control study was to explore the possible association between the polymorphisms of CTLA-4 and susceptibility to gastric cancer in Shandong and Beijing regions.MethodsTwo hundred and five patients with gastric cancer and 262 ethic-,age- and gender-matched healthy controls were included in this study.Polymerase chain reaction(PCR) and restriction fragment length polymorphism(RFLP) methods were performed for genotyping exonl +49A/G and promoter -1661A/G polymorphisms,and a PCR amplification refractory mutation system(ARMS) technique was used for promoter -1772T/C.Results1.The alleles of the three SNPs in CTLA-4 gene of the subjects shows polymorphism(+49A→G,-1661A→G and-1772T→C,respectively).2.Significantly higher frequencies of the AG and GG mutant genotypes of exon 1 +49A/G were determined in GC patients compared with those of controls (P＜0.001,OR=3.215,95%CI=1.914-5.401;P=0.001,OR=2.146,95%CI = 1.346-3.421).3.The frequency of promoter -1661AG mutant genotype was significantly higher in the GC patients than that in the controls(P=0.004,OR=1.882,95% CI=1.219-2.907).4.No statistically significant differences were observed for the genotype frequencies of-1772T/C SNP between GC patients and noncancer controls.5.Haplotype analysis demonstrated that the mutant haplotypes GAT (+49A-1661A-1772C) and AGT frequencies were significantly increased in GC patients in comparison with the control group(P＜0.001,OR=2.002, 95%CI=1.372-2.922;P=0.043,OR=1.616,95%CI=1.016-2.564).On the contrary,the wild haplotype AAT and mutant haplotype GGT were significantly lower in cases than in controls(P=008,P=0.026,respectively)Conclusions1.The obtained data illustrated that +49A/G and -1661A/G polymorphisms in CTLA-4 gene may be critical risk factors of genetic susceptibility to gastric cancer. 2.The mutant haplotypes GAT and AGT likely confer a susceptibility to gastric cancer in Chinese population.3.The wild haplotype AAT and mutant haplotype GGT are like protective factors for gastric cancer.Our data indicate that polymorphisms of CTLA-4 gene is one of the susceptible genes of gastric cancer and the finding may provide an important genetic marker for the screening high risk individual among the population.This will benefit more specific intervention,prevention,and early diagnosis and following procedures for human gastric cancer.
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