Genetic variants in Hippo signalling pathway-related genes affect the risk of colorectal cancer
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 associatio...
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Veröffentlicht in: | Archives of toxicology 2021, Vol.95 (1), p.271-281 |
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Sprache: | eng |
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Zusammenfassung: | 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. |
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ISSN: | 0340-5761 1432-0738 |
DOI: | 10.1007/s00204-020-02910-3 |