Genetic variants in Ras/Raf/MEK/ERK pathway are associated with gastric cancer risk in Chinese Han population

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 x 10(-3); rs76906202: OR = 0.87, 95% CI = 0.79-0.96,P = 3.72 x 10(-3); rs11631448: OR = 1.21, 95% CI = 1.05-1.39,P = 6.74 x 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.