Dataset Information

Novel genetic variants in the P38MAPK pathway gene ZAK and susceptibility to lung cancer.

ABSTRACT: The P38MAPK pathway participates in regulating cell cycle, inflammation, development, cell death, cell differentiation, and tumorigenesis. Genetic variants of some genes in the P38MAPK pathway are reportedly associated with lung cancer risk. To substantiate this finding, we used six genome-wide association studies (GWASs) to comprehensively investigate the associations of 14?904 single nucleotide polymorphisms (SNPs) in 108 genes of this pathway with lung cancer risk. We identified six significant lung cancer risk-associated SNPs in two genes (CSNK2B and ZAK) after correction for multiple comparisons by a false discovery rate (FDR)?<0.20. After removal of three CSNK2B SNPs that are located in the same locus previously reported by GWAS, we performed the LD analysis and found that rs3769201 and rs7604288 were in high LD. We then chose two independent representative SNPs of rs3769201 and rs722864 in ZAK for further analysis. We also expanded the analysis by including these two SNPs from additional GWAS datasets of Harvard University (984 cases and 970 controls) and deCODE (1319 cases and 26?380 controls). The overall effects of these two SNPs were assessed using all eight GWAS datasets (OR?=?0.92, 95%CI?=?0.89-0.95, and P?=?1.03?×?10-5 for rs3769201; OR?=?0.91, 95%CI?=?0.88-0.95, and P?=?2.03?×?10-6 for rs722864). Finally, we performed an expression quantitative trait loci (eQTL) analysis and found that these two SNPs were significantly associated with ZAK mRNA expression levels in lymphoblastoid cell lines. In conclusion, the ZAK rs3769201 and rs722864 may be functional susceptibility loci for lung cancer risk.

SUBMITTER: Feng Y

PROVIDER: S-EPMC6128286 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Novel genetic variants in the P38MAPK pathway gene ZAK and susceptibility to lung cancer.

Feng Yun Y Wang Yanru Y Liu Hongliang H Liu Zhensheng Z Mills Coleman C Owzar Kouros K Xie Jichun J Han Younghun Y Qian David C DC Hung Rj Rayjean J RJ Brhane Yonathan Y McLaughlin John J Brennan Paul P Bickeböller Heike H Rosenberger Albert A Houlston Richard S RS Caporaso Neil N Landi Maria Teresa MT Brüske Irene I Risch Angela A Ye Yuanqing Y Wu Xifeng X Christiani David C DC Amos Christopher I CI Wei Qingyi Q

Molecular carcinogenesis 20171031 2

The P38MAPK pathway participates in regulating cell cycle, inflammation, development, cell death, cell differentiation, and tumorigenesis. Genetic variants of some genes in the P38MAPK pathway are reportedly associated with lung cancer risk. To substantiate this finding, we used six genome-wide association studies (GWASs) to comprehensively investigate the associations of 14 904 single nucleotide polymorphisms (SNPs) in 108 genes of this pathway with lung cancer risk. We identified six significa ...[more]

PMID: 29071797

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Project description:BackgroundBoth antibody-dependent cellular cytotoxicity and phagocytosis activate innate immunity, and the Fc gamma receptor (FCGR)-mediated phagocytosis is an integral part of the process. We assessed associations between single-nucleotide polymorphisms (SNPs) in FCGR-related genes and survival of patients with non-small cell lung cancer (NSCLC).MethodsWe evaluated associations between 24,734 (SNPs) in 97 FCGR-related genes and survival of 1,185 patients with NSCLC using a published genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the results in another independent dataset of 894 NSCLC patients.ResultsIn the single-locus analysis with Bayesian false discovery probability (BFDP) for multiple testing correction, we found 1,084 SNPs to be significantly associated overall survival (OS) (P<0.050 and BFDP ≤0.80), of which two independent SNPs (PLCG2 rs9673682 T>G and PLPP1 rs115613985 T>A) were further validated in another GWAS dataset of 894 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study, with combined allelic hazards ratios for OS of 0.87 [95% confidence interval (CI): 0.81-0.94 and P=5.90×10-4] and 1.18 (95% CI: 1.08-1.29 and 1.32×10-4, respectively). Expression quantitative trait loci analysis showed that the rs9673682 G allele was significantly correlated with increased mRNA expression levels of PLCG2 in 373 transformed lymphoblastoid cell-lines (P=7.20×10-5). Additional evidence from differential expression analysis further supported a tumor-suppressive effect of PLCG2 on OS of patients with lung cancer, with lower mRNA expression levels in both lung squamous carcinoma and adenocarcinoma than in adjacent normal tissues.ConclusionsGenetic variants in PLCG2 of the FCGR-mediated phagocytosis pathway may be promising predictors of NSCLC survival, possibly through modulating gene expression, but additional investigation of the molecular mechanisms of PLPP1 rs115613985 is warranted.

Dataset Information

Novel genetic variants in the P38MAPK pathway gene ZAK and susceptibility to lung cancer.

Publications

Novel genetic variants in the P38MAPK pathway gene ZAK and susceptibility to lung cancer.

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