Genetic variants in Ras/Raf/MEK/ERK pathway are associated with gastric cancer risk in Chinese Han population
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TOXICOGENOMICS AND OMICS TECHNOLOGIES
Genetic variants in Ras/Raf/MEK/ERK pathway are associated with gastric cancer risk in Chinese Han population Xiaowei Wang1,2 · Xu Wu3 · Junyi Xin1,2 · Shuwei Li1,2 · Rui Zheng1,2 · Dan Guan1,2 · Weida Gong4 · Qinghong Zhao5 · Meilin Wang1,2,6 · Haiyan Chu1,2 · Mulong Du1,7 · Guoquan Tao3 · Haiyan Zhang8 · Zhengdong Zhang1,2,6 Received: 16 December 2019 / Accepted: 4 May 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract 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 in MAP2K1, 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 for MAP2K1 in normal gastric samples. Moreover, the low expression of MAP2K1 was significantly associated with poor survival in gastric cancer patients. Thus, MAP2K1 might represent a key gene related to gastric cancer in Ras/Raf/MEK/ERK pathway, whereas SNPs in MAP2K1 confer gastric cancer susceptibility by having biological effects on the MAP2K1 expression. Keywords Gastric cancer · Ras/Raf/MEK/ERK pathway · SNP · MAP2K1 · Susceptibility
Introduction Gastric cancer is confirmed to be the fifth most common cancer and the third leading cause of cancer-related mortality in the world (Torre et al. 2015). In China, the indicate number of new cases of gastric cancer and deaths in 2015 Xiaowei Wang, Xu Wu and Junyi Xin contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02771-w) contains supplementary material, which is available to authorized users. * Guoquan Tao [email protected] * Haiyan Zhang [email protected] * Zhengdong Zhang [email protected] Extended author information available on the last page of the article
are 679,100 and 498,000, respectively (Chen et al. 2016). Gastric cancer is an urgent social problem and studies on the pathogenesis of gastric cancer are crucial. Chronic infection with Helicobacter pylori (H. pylori) is the most common risk factor for gastric cancer (Plummer et al. 2015; Wang et al. 2014). Althou
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