Genetic variants in Ras/Raf/MEK/ERK pathway are associated with gastric cancer risk in Chinese Han population
Genetic variants in Ras/Raf/MEK/ERK pathway are associated with gastric cancer risk in Chinese Han population
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Ras/Raf/MEK/ERK 通路基因变异与中国汉族人群胃癌风险相关
DOI：
10.1007/s00204-020-02771-w
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发表时间：
2020
影响因子：
6.1
通讯作者：
Zhang Zhengdong
中科院分区：
文献类型：
--
作者：
Wang Xiaowei;Wu Xu;Xin Junyi;Li Shuwei;Zheng Rui;Guan Dan;Gong Weida;Zhao Qinghong;Wang Meilin;Chu Haiyan;Du Mulong;Tao Guoquan;Zhang Haiyan;Zhang Zhengdong
Ras/Raf/MEK/ERK信号通路的异常调节控制着肿瘤的发生和发展。在以往的研究中，全基因组关联研究（GWAS）已经确定了多个与胃癌相关的基因位点。然而，由于GWAS的多重统计比较，许多遗传位点被遗漏。本研究应用多标记基因组注释分析（MAGMA）技术，对1625例胃癌患者和2100例正常对照的Ras/Raf/MEK/ERK通路基因及其单核苷酸多态性（SNPs）进行了分析。应用Logistic回归模型计算SNP对胃癌易感性的影响。基于基因型-组织表达（GTEx）计划进行表达数量性状位点（eQTL）分析。我们发现MAP2K1中的三个SNPs，rs4287513，rs76906202和rs11631448与胃癌风险显著相关（rs4287513：OR = 1.30，95%CI = 1.10 - 1.54，P = 1.92 × 10 - 3; rs76906202：OR = 0.87，95%CI = 0.79 - 0.96，P = 3.72 × 10 - 3; rs11631448：OR = 0.87，95%CI = 0.79 - 0.96，P = 3.72 × 10 - 3; rs11631448：OR = 0.87，95%CI = 0.79 - 0.96，P = 3.72 × 10 - 3; rs11631448：OR = 0.87，95%CI = 0.96，P = 3.72 × 10 - 3; rs11631448：OR = 0.87，95%CI = 0.96，P = OR = 1.21，95%CI = 1.05-1.39，P = 6.74 × 10 - 3）。在正常胃组织中，所有位点均为MAP2K1的eQTL。此外，MAP2K1的低表达与胃癌患者的不良生存率显著相关。因此，MAP2K1可能是Ras/Raf/MEK/ERK通路中与胃癌相关的关键基因，而MAP2K1的SNPs通过影响MAP2K1的表达而赋予胃癌易感性。
The dysregulation of Ras/Raf/MEK/ERK pathway governs occurrence and progression of cancers. In previous studies, genome-wide association studies (GWAS) have identified multiple gene loci related to gastric cancer. However, a great many genetic loci have been missed due to multiple statistical comparisons of GWAS. In this study, Multi-marker Analysis of GenoMic Annotation (MAGMA) was applied to analyze genes in Ras/Raf/MEK/ERK pathway and their single nucleotide polymorphisms (SNPs) based on Chinese GWAS including 1625 gastric cancer cases and 2100 controls. The SNP effects on gastric cancer susceptibility were calculated on the basis of a logistic regression model. Expression quantitative trait loci (eQTL) analysis was performed based on the genotype-tissue expression (GTEx) project. We identified that three SNPs inMAP2K1, rs4287513, rs76906202 and rs11631448 were markedly associated with gastric cancer risk (rs4287513: OR = 1.30, 95% CI = 1.10–1.54,P= 1.92 × 10–3; rs76906202: OR = 0.87, 95% CI = 0.79–0.96,P= 3.72 × 10–3; rs11631448: OR = 1.21, 95% CI = 1.05–1.39,P= 6.74 × 10–3). All the loci were eQTLs forMAP2K1in normal gastric samples. Moreover, the low expression ofMAP2K1was significantly associated with poor survival in gastric cancer patients. Thus,MAP2K1might represent a key gene related to gastric cancer in Ras/Raf/MEK/ERK pathway, whereas SNPs inMAP2K1confer gastric cancer susceptibility by having biological effects on theMAP2K1expression.