| ObjectiveTo investigate the relationship between single nucleotide polymorphisms on mTOR complexes(mTORC1 and mTORC2)and genetic susceptibility to gastric malignancy.MethodsThe genome-wide association study(GWAS)database was used to assess the association of single nucleotide polymorphisms(SNPs)of nine candidate genes in the mTOR complex(mTORC1 and mTORC2)with gastric cancer risk,and the effect of SNP on gastric cancer susceptibility was calculated adopting a logistic regression model.Combined with expression quantitative trait loci(eQTL)analysis,the candidate SNP was selected.We used different models to analyze the stratified relationships between the candidate SNP and gastric cancer risk in different subgroups.Literatures on the correlation between candidate target gene and gastrointestinal tumors was searched In PubMed,WanFang data,CNKI(China National Knowledge Infrastructure),VIP database,and a Meta-analysis was conducted using STATA12.0 and other software to evaluate the correlation between the expression level of candidate target genes and the clinical and prognosis of gastrointestinal tumors.By downloading the data from the public database TCGA(The Cancer Genome Atlas),the expression level of candidate target gene in gastric cancer and its relationship with the clinical and prognosis of gastric cancer were analyzed,and the expression of target gene in gastric cancer was verified in the GEO(Gene Expression Omnibus)database.The detection of luciferase reporter gene was conducted to investigate the biological function of SNPs in target binding region.ResultsThe relationship between single nucleotide polymorphisms(SNPs)of nine candidate genes in the mTOR complexes and gastric cancer risk was evaluated using a genome-wide association study(GWAS)database,and the effect of SNPs on gastric cancer susceptibility was calculated using a logistic regression model.The results showed that the C allele in DEPTOR rs4871819 was closely associated with a lower risk of gastric cancer(OR = 0.89,95%CI =0.81-0.98,P=0.017),especially in the male subgroup(dominant mode: OR =0.38,95%CI =0.72-0.99 recessive model: OR = 0.71,95%CI =0.57-0.88)and in the age ≥50 subgroup(recessive model: OR = 0.77,95%CI =0.63-0.94,codominant model: OR = 0.78,95%CI =0.63-0.96;OR = 0.75,95%CI=0.61-0.94).In the meta-analysis,we found that the expression of DEPTOR in gastrointestinal tumors,lymphatic metastasis,clinical staging and prognosis were not statistically significant.Through data analysis in TCGA database,we found that the expression of DEPTOR in gastric tumor tissues was obviously lower than that in normal tissues(P=0.002).Similar results were observed in the GEO database(P<0.0001).We also found that patients with low-expression DEPTOR had a higher clinical staging(stage I + II + III vs IV)(P=0.003)and a poorer survival prognosis(HR = 0.69,95%CI =0.57-0.84,P= 0.00017).The genotype-tissue expression(GTEx)dataset also showed that the rs4871819 T allele had higher DEPTOR expression in gastric tissue than the C allele(P=0.03).In our further detection of luciferase reporter gene,the T allele of rs4871819 was higher than that of the C allele(P=0.026 and 0.018)in MGC-803 and SGC-7901 gastric cancer cells.ConclusionThe C allele in DEPTOR rs4871819 is strongly associated with a reduced risk of gastric cancer,especially in male and aged ≥50 years group.The rs4871819 T allele may predict a good prognosis in patients with gastric cancer.Our results suggest that rs4871819 determines susceptibility to gastric cancer to varying degrees.It provides important clues for the clinical diagnosis and treatment of gastric cancer in the future. |
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