Identification of genes expressed by immune cells of the colon that are regulated by colorectal cancer‐associated variants

Peltekova, Vanya; Lemire, Mathieu; Qazi, Aamer; Zaidi, Syed Hassan Ejaz; Trinh, Quang; Bielecki, Ryszard; Rogers, Marianne; Hodgson, Lyndsey; Wang, Mike; D'Souza, David J.A.; Zandi, Sasan; Chong, Taryne; Kwan, Jennifer; Kozak, Krystian; Borja, Richard de; Timms, Lee; Rangrej, Jagadish; Volar, Milica; Chan-Seng-Yue, Michelle; Beck, Timothy; Ash, Colleen; Lee, Shawna; Wang, Jianxin; Boutros, Paul C.; Stein, Lincoln; Dick, John E.; Gryfe, Robert; Mcpherson, John Douglas; Zanke, Brent W.; Pollett, Aaron; Gallinger, Steven; Hudson, Thomas J.

doi:10.1002/ijc.28557

Cited by 43 publications

(65 citation statements)

References 47 publications

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“…Fig 2 shows examples of putative shared regulatory sites at the COLCA1 and COLCA2 locus on chromosome 11. Of 4 eQTL variants independently associated with these genes, two are shared by both, consistent with previous studies demonstrating co-regulation between these genes [14]. …”

Section: Resultssupporting

confidence: 89%

Shared regulatory sites are abundant in the human genome and shed light on genome evolution and disease pleiotropy

2017

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Large-scale gene expression datasets are providing an increasing understanding of the location of cis-eQTLs in the human genome and their role in disease. However, little is currently known regarding the extent of regulatory site-sharing between genes. This is despite it having potentially wide-ranging implications, from the determination of the way in which genetic variants may shape multiple phenotypes to the understanding of the evolution of human gene order. By first identifying the location of non-redundant cis-eQTLs, we show that regulatory site-sharing is a relatively common phenomenon in the human genome, with over 10% of non-redundant regulatory variants linked to the expression of multiple nearby genes. We show that these shared, local regulatory sites are linked to high levels of chromatin looping between the regulatory sites and their associated genes. In addition, these co-regulated gene modules are found to be strongly conserved across mammalian species, suggesting that shared regulatory sites have played an important role in shaping human gene order. The association of these shared cis-eQTLs with multiple genes means they also appear to be unusually important in understanding the genetics of human phenotypes and pleiotropy, with shared regulatory sites more often linked to multiple human phenotypes than other regulatory variants. This study shows that regulatory site-sharing is likely an underappreciated aspect of gene regulation and has important implications for the understanding of various biological phenomena, including how the two and three dimensional structures of the genome have been shaped and the potential causes of disease pleiotropy outside coding regions.

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Section: Resultssupporting

confidence: 89%

Shared regulatory sites are abundant in the human genome and shed light on genome evolution and disease pleiotropy

2017

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“…This cis -eQTL has also been previously reported by several groups for normal colon tissue [17–20] and normal rectal tissue [19]. In addition, immunohistochemical evaluation of protein expression profiles were recently reported for COLCA 1 and COLCA2 in normal colon tissue [18]. COLCA1 protein was detected in the lamina propria, extracellularly between epithelial cells, and in immune cells (eosinophils, mast cells, neutrophils, macrophages, and dendritic cells).…”

Section: Discussionsupporting

confidence: 79%

In silico pathway analysis and tissue specific cis-eQTL for colorectal cancer GWAS risk variants

2017

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BackgroundGenome-wide association studies have identified 55 genetic variants associated with colorectal cancer risk to date. However, potential causal genes and pathways regulated by these risk variants remain to be characterized. Therefore, we performed gene ontology enrichment and pathway analyses to determine if there was an enrichment of genes in proximity to the colorectal cancer risk variants that could further elucidate the probable causal genes and pathways involved in colorectal cancer biology.ResultsFor the 65 unique genes that either contained, or were immediately neighboring up- and downstream, of these variants there was a significant enrichment for the KEGG pathway, Pathways in Cancer (p-value = 2.67 × 10−5) and an enrichment for multiple biological processes (FDR < 0.05), such as cell junction organization, tissue morphogenesis, regulation of SMAD protein phosphorylation, and odontogenesis identified through Gene Ontology analysis. To identify potential causal genes, we conducted a cis-expression quantitative trait loci (cis-eQTL) analysis using gene expression and genotype data from the Genotype-Tissue Expression (GTEx) Project portal in normal sigmoid (n = 124) and transverse (n = 169) colon tissue. In addition, we also did a cis-eQTL analysis on colorectal tumor tissue (n = 147) from The Cancer Genome Atlas (TCGA). We identified two risk alleles that were significant cis-eQTLs for FADS2 (rs1535) and COLCA1 and 2 (rs3802842) genes in the normal transverse colon tissue and two risk alleles that were significant cis-eQTLs for the CABLES2 (rs2427308) and LIPG (rs7229639) genes in the normal sigmoid colon tissue, but not tumor tissue.ConclusionsOur data reaffirm the potential to identify an enrichment for biological processes and candidate causal genes based on expression profiles correlated with genetic risk alleles of colorectal cancer, however, the identification of these significant cis-eQTLs is context and tissue specific.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3750-2) contains supplementary material, which is available to authorized users.

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“…21 Previous studies have indicated that COLCA1 plays a role in inflammation and cancer. 22 Moreover, COLCA1 has been implicated as a susceptibility locus for colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

Screening key genes and miRNAs in early-stage colon adenocarcinoma by RNA-sequencing

Liu

et al. 2017

Tumour Biol.

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Colon adenocarcinoma is the third leading cause of cancer-related deaths across the world, developing novel and non-invasive diagnostic and prognostic biomarkers for the early-stage colon adenocarcinoma at molecular level is essential. In our study, RNA-sequencing was performed to identify the differentially expressed genes and miRNAs (DEmiRNAs) in early-stage colon adenocarcinoma compared to tissues of precancerous lesions, colonic intraepithelial neoplasia. The DEmiRNA-target interaction network was constructed and functional annotation of targets of DEmiRNAs was performed. The Cancer Genome Atlas was used to verify the expression of selected differentially expressed genes. The receiver operating characteristic analyses of selected differentially expressed genes was performed. In total, 865 differentially expressed genes, 26 DEmiRNAs, and 329 DEmiRNA-target pairs were obtained. Based on the early-stage colon adenocarcinoma network, miR-548c-5p, miR-548i, and miR-548am-5p were the top three DEmiRNAs that covered most differentially expressed genes. NTRK2, DTNA, and BTG2 were the top three differentially expressed genes regulated by most DEmiRNAs. Cancer and colorectal cancer pathways were two significantly enriched pathways in early-stage colon adenocarcinoma. The common differentially expressed genes in both the pathways were AXIN2, Smad2, Smad4, PIK3R1, and BCL2. The expression levels of eight differentially expressed genes (NTRK2, DTNA, BTG2, COL11A1, Smad2, Smad4, PIK3R1, and BCL2) in The Cancer Genome Atlas database were compatible with our RNA-sequencing. All these eight differentially expressed genes and AXIN2 had the potential diagnosis value for Colon adenocarcinoma. In conclusion, a total of ten differentially expressed genes (NTRK2, DTNA, BTG2, COLCA1, COL11A1, AXIN2, Smad2, Smad4, PIK3R1, and BCL2) and four DEmiRNAs (miR-548c-5p, miR-548i, mir-424-5p, and miR-548am-5p) may be involved in the pathogenesis of early-stage colon adenocarcinoma which may make a contribution for developing new diagnostic and therapeutic strategies for early-stage colon adenocarcinoma.

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Identification of genes expressed by immune cells of the colon that are regulated by colorectal cancer‐associated variants

Cited by 43 publications

References 47 publications

Shared regulatory sites are abundant in the human genome and shed light on genome evolution and disease pleiotropy

Shared regulatory sites are abundant in the human genome and shed light on genome evolution and disease pleiotropy

In silico pathway analysis and tissue specific cis-eQTL for colorectal cancer GWAS risk variants

Screening key genes and miRNAs in early-stage colon adenocarcinoma by RNA-sequencing

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