The Association Study Of Polymorphisms In PI3K/AKT/mTOR Pathway And Gastric Cancer Susceptibility

Background:Gastric cancer (GC) is the fifth common and third leading cause of death worldwide. Although there was a steady decline in GC incidence and mortality rates in recent years in China, GC has risen to the second common and mortal tumors, only after lung cancer. GC is a kind of complex disease related to multiple factors, including environmental exposure factors and genetic factors. Familial aggregation and different reactions to the same environmental exposure suggested that individual diversity played an important role in risk of cancer. The study searching for potential biomarkers for gastric cancer may provide important clues for early detection and individualized treatment.Activating alterations of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB or AKT)/mammalian target of rapamycin (mTOR) signaling pathway are commonly observed in a variety of tumors, which are crucial to tumor initiation and progression. Single nucleotide polymorphisms (SNPs) in key genes of PI3K/AKT/mTOR pathway may alter gene expression and influence susceptibility. Our study aimed to identify whether SNPs in PI3K/AKT/mTOR pathway were associated with the susceptibility of GC, whether these SNPs altered the transcription of relevant genes, and whether they could serve as valid diagnostic biomarkers in the early stage of GC.Methods:We selected potential functional SNPs met the following criteria:1) located in promoter region,5’-untranslated regions (5’-UTR), exon region or 3’-untranslated regions (3’-UTR) of PIK3CA, PIK3CB, PIK3R1, PIK3R2, PIK3R3, AKT1, AKT2 or AKT3; 2) identified in a Chinese population with a minimal allele frequency (MAF)≥ 0.10, r2≥0.80. We performed a case-control study to validate the association between SNPs with susceptibility of GC in a Chinese population. TaqMan genotype method was taken to genotype these SNPs. Univariate and multivariate logistic regression model were applied for odd ratios (ORs) and 95%confidence interval (95%CI). We further investigated the relationship between the SNP rs2295080 and gastric cancer survival. Univariate and multivariate Cox regression model were applied for hazard ratios (HRs) and 95%CI. Besides, quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), luciferase assay and electrophoretic mobility shift assay (EMSA) were adopted to further investigate the potential functional effects of rs2295080 in mTOR promoter region.Results:Only rs7536272 and rs2295080 were significantly associated with the susceptibility of GC. For SNP rs7536272:compared with AA genotype, AG genotype was associated with an increasing risk of GC (adjusted OR= 1.34,95%CI= 1.09-1.65, P= 0.005). For SNP rs2295080:the G allele was associated with a decreased risk of GC (adjusted OR= 0.77,95%CI= 0.65-0.92, P= 0.003). No significant association was observed between the SNP rs2295080 and the survival of GC. The functional studies indicated that rs2295080 G allele in the promoter region of mTOR suppressed transcriptional activity of mTOR and downregulated the binding abilities to transcription factor, which resulted in decreased the expression of mTOR.Conclusion:The polymorphisms, rs7536272 and rs2295080 were associated with the susceptibility of GC in Chinese population, and could serve as diagnostic biomarkers for early detection of GC. And rs2295080 in the promoter region of mTOR suppressed transcriptional activity of mTOR and downregulated the binding abilities to transcription factor, which resulted in decreased expression of mTOR. This could provide new evidences for the investigation of pathology in GC.