Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously identified several colorectal cancer (CRC)-associated polymorphisms using genome-wide association (GWA) analysis. We sought to fine-map the location of the functional variants for three of these regions at 8q23.3 (EIF3H), 16q22.1 (CDH1/CDH3) and 19q13.11 (RHPN2). We genotyped two case-control sets at high density in the selected regions and used existing data from four other case-control sets, comprising a total of 9328 CRC cases and 10 480 controls. To improve marker density, we imputed genotypes from the 1000 Genomes Project and Hapmap3 data sets. All three regions contained smaller areas in which a cluster of single nucleotide polymorphisms (SNPs) showed clearly stronger association signals than surrounding SNPs, allowing us to assign those areas as the most likely location of the disease-associated functional variant. Further fine-mapping within those areas was generally unhelpful in identifying the functional variation based on strengths of association. However, functional annotation suggested a relatively small number of functional SNPs, including some with potential regulatory function at 8q23.3 and 16q22.1 and a non-synonymous SNP in RPHN2. Interestingly, the expression quantitative trait locus browser showed a number of highly associated SNP alleles correlated with mRNA expression levels not of EIF3H and CDH1 or CDH3, but of UTP23 and ZFP90, respectively. In contrast, none of the top SNPs within these regions was associated with transcript levels at EIF3H, CDH1 or CDH3. Our post-GWA study highlights benefits of fine-mapping of common disease variants in combination with publicly available data sets. In addition, caution should be exercised when assigning functionality to candidate genes in regions discovered through GWA analysis.
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PMID:Fine-mapping of colorectal cancer susceptibility loci at 8q23.3, 16q22.1 and 19q13.11: refinement of association signals and use of in silico analysis to suggest functional variation and unexpected candidate target genes. 2153 88

Colorectal cancer (CRC) is the third most common cancer. Large-scale genome-wide association studies (GWAS) have been performed and reported some novel CRC susceptibility variants in European ancestry including the CDH1 rs9929218. Following GWAS and candidate studies evaluated the association between the CDH1 rs9929218 polymorphism and CRC in European, Asian and American populations. However, these studies reported inconsistent associations. Evidence shows that rs9929218 may regulate different gene expressions in different human tissues. Here, we reevaluated this association using large-scale samples from 16 studies (n=131768) using a meta-analysis method. In heterogeneity test, we did not identify significant heterogeneity among these studies. Meta-analysis using fixed effect model showed significant association between rs9929218 and CRC (P=6.16E-21, odds ratio (OR) =0.92, 95% confidence interval (CI) 0.91-0.94). In order to validate the effect of rs9929218 variant on CDH1 expression, we further performed a functional analysis using two large-scale expression datasets. We identified significant regulation relation between rs9929218 variant and the expression of CDH1, ZFP90, RP11-354M1.2 and MCOLN2 by both cis-effect and trans-effect. In summary, our analysis highlights significant association between rs9929218 polymorphism and CRC susceptibility.
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PMID:CDH1 rs9929218 variant at 16q22.1 contributes to colorectal cancer susceptibility. 2725 61

Genome-wide association studies (GWASs) implicate 16q22.1 locus in risk for colorectal cancer (CRC). However, the underlying oncogenic mechanisms remain unknown. Here, through comprehensive filtration, we prioritized rs7198799, a common SNP in the second intron of the CDH1, as the putative causal variant. In addition, we found an association of CRC-risk allele C of rs7198799 with elevated transcript level of biological plausible candidate gene ZFP90 via expression quantitative trait loci analysis. Mechanistically, causal variant rs7198799 resides in an enhancer element and remotely regulate ZFP90 expression by targeting the transcription factor NFATC2. Remarkably, CRISPR/Cas9-guided single-nucleotide editing demonstrated the direct effect of rs7198799 on ZFP90 expression and CRC cellular malignant phenotype. Furthermore, ZFP90 affects several oncogenic pathways, including BMP4, and promotes carcinogenesis in patients and in animal models with ZFP90 specific genetic manipulation. Taken together, these findings reveal a risk SNP-mediated long-range regulation on the NFATC2-ZFP90-BMP4 pathway underlying the initiation of CRC.
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PMID:A 16q22.1 variant confers susceptibility to colorectal cancer as a distal regulator of ZFP90. 3164 Dec 8