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Integrated bioinformatics identifies the dysregulation induced by aberrant gene methylation in colorectal carcinoma.

ABSTRACT: Colorectal carcinoma (CRC) is one of the most common cancers, and is associated with a poor clinical outcome. The key genes and potential prognostic markers in colorectal carcinoma remain to be identified and explored for clinical application. DNA expression/methylation profiles were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed/methylated genes (DEGs and DEMs). A total of 255 genes and 372 genes were identified as being up-regulated and down-regulated, respectively, in GSE113513, GSE81558, and GSE89076. There were a total of 3350 hypermethylated genes and 443 hypomethylated genes identified in GSE48684. Twenty genes were found to be hypermethylated as well as down-regulated, and a functional enrichment analysis revealed that these genes were mainly involved in cancer-related pathways. Among these 20 genes, GPM6A, HAND2 and C2orf40 were related to poor outcomes in cancer patients based on a survival analysis. Concurrent decreases of GPM6A, HAND2 and C2orf40 protein expression were observed in highly-differentiated colorectal carcinoma tissues, and higher expression levels were found in undifferentiated or minimally-differentiated colorectal carcinoma tissues. In conclusion, 20 genes were found to be downregulated and hypermethylated in CRC, among which GPM6A, HAND2 and C2orf40 were explored for their potential prognostic value.

SUBMITTER: Ye Z

PROVIDER: S-EPMC8209361 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Integrated bioinformatics identifies the dysregulation induced by aberrant gene methylation in colorectal carcinoma.

Ye Zhenyu Z Li Yecheng Y Xie Jiaming J Feng Zhenyu Z Yang Xiaodong X Wu Yong Y Pu Yuwei Y Gao Jiawei J Xu Xiangrong X Zhu Zhaobi Z Li Wei W Chen Wei W Xing Chungen C

Genes & diseases 20200524 4

Colorectal carcinoma (CRC) is one of the most common cancers, and is associated with a poor clinical outcome. The key genes and potential prognostic markers in colorectal carcinoma remain to be identified and explored for clinical application. DNA expression/methylation profiles were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed/methylated genes (DEGs and DEMs). A total of 255 genes and 372 genes were identified as being up-regulated and down-reg ...[more]

PMID: 34179314

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Project description:BackgroundColorectal cancer (CRC) multiplicity has been mainly related to polyposis and non-polyposis hereditary syndromes. In sporadic CRC, aberrant gene promoter methylation has been shown to play a key role in carcinogenesis, although little is known about its involvement in multiplicity. To assess the effect of methylation in tumor multiplicity in sporadic CRC, hypermethylation of key tumor suppressor genes was evaluated in patients with both multiple and solitary tumors, as a proof-of-concept of an underlying epigenetic defect.Methodology/principal findingsWe examined a total of 47 synchronous/metachronous primary CRC from 41 patients, and 41 gender, age (5-year intervals) and tumor location-paired patients with solitary tumors. Exclusion criteria were polyposis syndromes, Lynch syndrome and inflammatory bowel disease. DNA methylation at the promoter region of the MGMT, CDKN2A, SFRP1, TMEFF2, HS3ST2 (3OST2), RASSF1A and GATA4 genes was evaluated by quantitative methylation specific PCR in both tumor and corresponding normal appearing colorectal mucosa samples. Overall, patients with multiple lesions exhibited a higher degree of methylation in tumor samples than those with solitary tumors regarding all evaluated genes. After adjusting for age and gender, binomial logistic regression analysis identified methylation of MGMT2 (OR, 1.48; 95% CI, 1.10 to 1.97; p = 0.008) and RASSF1A (OR, 2.04; 95% CI, 1.01 to 4.13; p = 0.047) as variables independently associated with tumor multiplicity, being the risk related to methylation of any of these two genes 4.57 (95% CI, 1.53 to 13.61; p = 0.006). Moreover, in six patients in whom both tumors were available, we found a correlation in the methylation levels of MGMT2 (r = 0.64, p = 0.17), SFRP1 (r = 0.83, 0.06), HPP1 (r = 0.64, p = 0.17), 3OST2 (r = 0.83, p = 0.06) and GATA4 (r = 0.6, p = 0.24). Methylation in normal appearing colorectal mucosa from patients with multiple and solitary CRC showed no relevant difference in any evaluated gene.ConclusionsThese results provide a proof-of-concept that gene promoter methylation is associated with tumor multiplicity. This underlying epigenetic defect may have noteworthy implications in the prevention of patients with sporadic CRC.

Project description:Malignant pheochromocytoma (PHEO) can only be fully diagnosed when metastatic foci develop. However, at this point in time, patients gain little benefit from traditional therapeutic methods. Methylation plays an important role in the pathogenesis of PHEO. The aim of this research was to use integrated bioinformatics analysis to identify differentially expressed genes (DEGs) showing aberrant methylation patterns in PHEO and therefore provide further understanding of the molecular mechanisms underlying this condition. Aberrantly methylated DEGs were first identified by using R software (version 3.6) to combine gene expression microarray data (GSE19422) with gene methylation microarray data (GSE43293). An online bioinformatics database (DAVID) was then used to identify all overlapping DEGs showing aberrant methylation; these were annotated and then functional enrichment was ascertained by gene ontology (GO) analysis. The online STRING tool was then used to analyze interactions between all overlapping DEGs showing aberrant methylation; these results were then visualized by Cytoscape (version 3.61). Next, using the cytoHubba plugin within Cytoscape, we identified the top 10 hub genes and found that these were predominantly enriched in pathways related to cancer. Reference to The Cancer Genome Atlas (TCGA) further confirmed our results and further identified an upregulated hypomethylated gene (SCN2A) and a downregulated hypermethylated gene (KCNQ1). Logistic regression analysis and receiver operating characteristic (ROC) curve analysis indicated that KCNQ1 and SCN2A represent promising differential diagnostic biomarkers between benign and malignant PHEO. Finally, clinical data showed that there were significant differences in the concentrations of potassium and sodium when compared between pre-surgery and post-surgery day 1. These suggest that KCNQ1 and SCN2A, genes that encode potassium and sodium channels, respectively, may serve as putative diagnostic targets for the diagnosis and prognosis of PHEO and therefore facilitate the clinical management of PHEO.

Project description:Colorectal cancer is one of the most common cancers of humans and the second highest in cancer-related death. Genes used as prognostic biomarkers play an imperative role in cancer detection and may direct the development of appropriate therapeutic strategies. Collagen type XI alpha 1 (COL11A1) is a minor fibrillary collagen that has an essential role in the regulation of cell division, differentiation, proliferation, migration, growth, and apoptosis of intestinal and colon cells. The present study seeks to evaluate the significance of the COL11A1 gene in the progression of colorectal cancer in humans across the various parameters using advanced bioinformatics approaches. The application of various databases and servers like ONCOMINE, UALCAN, and GEPIA were accessed for analyzing the differential expression of the COLL11A1 gene and its relative influence over the survival of the transformed subjects. In addition, oncogenomics of COL11A1 gene, mutations associated with this gene and interacting partners of the gene in the context of oncogenesis were studied using COSMIC, cBioPortal, GeneMANIA, and NetworkAnalyst. Our experimental data indicate that the COL11A1 gene is overexpressed in the transformed tissues across the various clinicopathological parameters reduces the probability of survival in both overall and disease-specific survival cases. Mutational studies imply that it can induce perturbations in various signaling pathways viz. RTK-RAS-PI3K, Wnt, TGF-β, and TP53 pathways influencing cancer development. Also, a positive association and correlation amongst the THBS2, COL10A1, COL5A2, and COL1A2 genes were observed, which most likely to contribute to the upregulation of carcinogenesis. Conclusively, this comprehensive study indicates the COL11A1 gene to be a significant contributor in the etiology of colorectal cancer, henceforth this gene can be considered as a prognostic biomarker for the conception of diagnostic and therapeutic strategies against colorectal cancer in the near future.

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Integrated bioinformatics identifies the dysregulation induced by aberrant gene methylation in colorectal carcinoma.

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Integrated bioinformatics identifies the dysregulation induced by aberrant gene methylation in colorectal carcinoma.

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