Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 14, 2019; 25(26): 3392-3407
Published online Jul 14, 2019. doi: 10.3748/wjg.v25.i26.3392
Identification of differentially expressed genes regulated by methylation in colon cancer based on bioinformatics analysis
Yu Liang, Cheng Zhang, Dong-Qiu Dai
Yu Liang, Cheng Zhang, Dong-Qiu Dai, Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
Author contributions: Dai DQ conducted the study; Liang Y and Zhang C applied the experiments on TCGA project; Liang Y wrote the manuscript.
Institutional review board statement: The data of colon cancer we analyzed in this research are all from TCGA database. According to the guidelines released by TCGA, our research does not require the separate ethics committee approval.
Conflict-of-interest statement: The authors declare that there is no conflict of interest related to this study.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Dong-Qiu Dai, PhD, Chief Doctor, Professor, Surgical Oncologist, Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital of China Medical University, No. 4 Chongshan East Road, Shenyang 110032, Liaoning Province, China.
Telephone: +86-24-6204-3110 Fax: +86-24-6204-3110
Received: March 14, 2019
Peer-review started: March 14, 2019
First decision: April 30, 2019
Revised: May 9, 2019
Accepted: May 31, 2019
Article in press: June 1, 2019
Published online: July 14, 2019

DNA methylation, acknowledged as a key modification in the field of epigenetics, regulates gene expression at the transcriptional level. Aberrant methylation in DNA regulatory regions could upregulate oncogenes and downregulate tumor suppressor genes without changing the sequences. However, studies of methylation in the control of gene expression are still inadequate. In the present research, we performed bioinformatics analysis to clarify the function of methylation and supply candidate methylation-related biomarkers and drivers for colon cancer.


To identify and analyze methylation-regulated differentially expressed genes (MeDEGs) in colon cancer by bioinformatics analysis.


We downloaded RNA expression profiles, Illumina Human Methylation 450K BeadChip data, and clinical data of colon cancer from The Cancer Genome Atlas project. MeDEGs were identified by analyzing the gene expression and methylation levels using the edgeR and limma package in R software. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed in the DAVID database and KEGG Orthology-Based Annotation System 3.0, respectively. We then conducted Kaplan–Meier survival analysis to explore the relationship between methylation and expression and prognosis. Gene set enrichment analysis (GSEA) and investigation of protein-protein interactions (PPI) were performed to clarify the function of prognosis-related genes.


A total of 5 up-regulated and 81 down-regulated genes were identified as MeDEGs. GO and KEGG pathway analyses indicated that MeDEGs were enriched in multiple cancer-related terms. Furthermore, Kaplan–Meier survival analysis showed that the prognosis was negatively associated with the methylation status of glial cell-derived neurotrophic factor (GDNF) and reelin (RELN). In PPI networks, GDNF and RELN interact with neural cell adhesion molecule 1. Besides, GDNF can interact with GDNF family receptor alpha (GFRA1), GFRA2, GFRA3, and RET. RELN can interact with RAFAH1B1, disabled homolog 1, very low-density lipoprotein receptor, lipoprotein receptor-related protein 8, and NMDA 2B. Based on GSEA, hypermethylation of GDNF and RELN were both significantly associated with pathways including “RNA degradation,” “ribosome,” “mismatch repair,” “cell cycle” and “base excision repair.”


Aberrant DNA methylation plays an important role in colon cancer progression. MeDEGs that are associated with the overall survival of patients may be potential targets in tumor diagnosis and treatment.

Keywords: Colon cancer, Bioinformatics analysis, The Cancer Genome Atlas project, DNA methylation, Methylation-regulated differentially expressed genes, Overall survival

Core tip: We acquired high-throughput data from The Cancer Genome Atlas database and identified 5 up-regulated and 81 down-regulated methylation-regulated differentially expressed gene (MeDEGs). Then, we performed gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses to clarify the function of MeDEGs. Furthermore, methylation status and expression of glial cell-derived neurotrophic factor and reelin were found to be associated with overall survival. Our study revealed that methylation is critical in colon cancer development and the prognosis-related MeDEGs are worth exploring further.