Genetic variants in PI3K/Akt/mTOR pathway genes contribute to gastric cancer risk.

PI3K/Akt/mTOR pathway is involved in tumor initiation and progression, including gastric cancer (GC). However, the single nucleotide polymorphisms (SNPs) in this pathway and underlying molecular mechanism remain largely unexplored. A case-control study of 1275 GC patients and 1436 controls was performed to explore the associations of potentially functional SNPs in PI3K/Akt/mTOR pathway genes with the risk of GC. In the logistic regression analyses, one SNP rs7536272 out of the four candidate SNPs showed a significant association with GC risk (additive model: OR = 1.16, 95% CI = 1.03-1.30; co-dominant model: AG vs. AA, OR = 1.30, 95% CI = 1.11-1.53; dominant model: AG/GG vs. AA, OR = 1.28, 95% CI = 1.10-1.49).The luciferase assay indicated that rs7536272 G allele significantly enhanced the transcriptional activity, compared with A allele. Further expression quantitative trait loci (eQTL) analysis showed that GC patients with rs7536272 AG/GG genotypes had remarkably higher PIK3R3 levels than those with AA genotype, suggesting that rs7536272 polymorphism influenced the expression of PIK3R3. Additionally, we observed that GC patients with high expression of PIK3R3 had significant poorer outcome than those with low expression (HR = 1.29, 95% CI = 1.09-1.53). Our result demonstrated that SNP rs7536272, a functional risk variant located in the promoter region of PIK3R3, showed association with increased transcriptional activity and upregulation of PIK3R3 expression, thus involved in GC development.