Genetic variants in PI3K/Akt/mTOR pathway genes contribute to gastric cancer risk
Genetic variants in PI3K/Akt/mTOR pathway genes contribute to gastric cancer risk
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PI3K/Akt/mTOR 通路基因的遗传变异会增加胃癌风险
DOI：
10.1016/j.gene.2018.05.093
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发表时间：
2018-09-05
期刊：
影响因子：
3.5
通讯作者：
Zhang, Zhengdong
中科院分区：
文献类型：
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作者：
Ge, Yuqiu;Liu, Hanting;Zhang, Zhengdong
PI3K/Akt/mTOR 通路参与肿瘤的发生和进展，包括胃癌 (GC)。然而，该途径中的单核苷酸多态性（SNP）和潜在的分子机制在很大程度上仍未被探索。对 1275 名 GC 患者和 1436 名对照进行了病例对照研究，以探讨 PI3K/Akt/mTOR 通路基因中潜在功能性 SNP 与 GC 风险的关联。在逻辑回归分析中，4 个候选 SNP 中的 1 个 SNP rs7536272 显示与 GC 风险显着相关（加法模型：OR = 1.16，95% CI = 1.03-1.30；共同显性模型：AG 与 AA，OR = 1.30，95% CI = 1.11-1.53；显性模型：AG/GG 与 AA，OR = 1.28, 95% CI = 1.10-1.49)。荧光素酶检测表明，与A等位基因相比，rs7536272 G等位基因显着增强了转录活性。进一步的表达数量性状位点（eQTL）分析显示，rs7536272 AG/GG基因型的胃癌患者PIK3R3水平显着高于AA基因型的胃癌患者，提示rs7536272多态性影响PIK3R3的表达。此外，我们观察到 PIK3R3 高表达的 GC 患者的预后明显较差于低表达的患者（HR = 1.29，95% CI = 1.09-1.53）。我们的结果表明，SNP rs7536272（位于 PIK3R3 启动子区域的功能性风险变异）与转录活性增加和 PIK3R3 表达上调相关，从而参与 GC 发育。
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.