Genetic variants in Hippo signalling pathway-related genes affect the risk of colorectal cancer
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GENOTOXICITY AND CARCINOGENICITY
Genetic variants in Hippo signalling pathway‑related genes affect the risk of colorectal cancer Hengyang Shen1,2 · Yixuan Meng3,4 · Tao Hu1,2 · Shuwei Li3,4 · Mulong Du3,4 · Junyi Xin3,4 · Dongying Gu5 · Meilin Wang3,4 · Zan Fu1,2 Received: 16 December 2019 / Accepted: 10 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract The Hippo signalling pathway plays a crucial role in carcinogenesis. Therefore, we hypothesized that genetic variants in genes related to this pathway are associated with the colorectal cancer risk. A case–control study including 1150 patients and 1342 controls was performed to assess the association of genetic variants of genes involved in the Hippo signalling pathway with the risk of colorectal cancer. The results were corrected for multiple comparisons using the false discovery rate (FDR). We used a regression model to determine the effects of single-nucleotide polymorphisms (SNPs) on the survival of patients with colorectal cancer in The Cancer Genome Atlas (TCGA) datasets. An expression quantitative trait loci (eQTL) analysis was performed using TCGA datasets and the Genotype-Tissue Expression (GTEx) project. Gene Expression Omnibus (GEO) datasets were used to provide additional data on the expression of genes in colorectal cancer. The SCRIB rs13251492 G allele was associated with a significantly decreased risk of colorectal cancer (odds ratio (OR) = 0.79, 95% confidence interval (CI) = 0.70–0.89, P = 7.76 × 10–5, P(FDR) = 6.98 × 10–4). Patients with the rs13251492 AG/GG allele experienced a longer recurrence-free survival (RFS) time (hazard ratio (HR) = 0.64, 95% CI = 0.42–0.99, P = 0.049) than patients with the rs13251492 A allele. The eQTL analysis revealed a significant association between rs13251492 and the expression of the SCRIB mRNA in colorectal tumors. Dual-luciferase reporter assays in DLD-1 and HCT116 cells revealed a lower enhancer activity of the rs13251492 G allele than the A allele. In addition, the SCRIB mRNA was expressed at markedly higher levels in colorectal cancer tissues than in normal tissues. Therefore, we identified the SCRIB rs13251492 variant as a novel colorectal cancer susceptibility locus and provided evidence of its functional relevance. Keywords Hippo signalling pathway · SCRIB · Colorectal cancer risk · Survival · Genetic variants
Hengyang Shen, Yixuan Meng and Tao Hu contributed equally to this study. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02910-3) contains supplementary material, which is available to authorized users.
Abbreviations CI Confidence interval eQTL Expression quantitative trait loci FDR False discovery rate HR Hazards ratio HWE Hardy–Weinberg equilibrium
* Meilin Wang [email protected] * Zan Fu [email protected] 1
The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 30
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