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: http://creativecommons.org/licenses/by-nc/4.0/
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. daidq63@163.com
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
Processing time: 123 Days and 8.4 Hours
ARTICLE HIGHLIGHTS
Research background

Accumulating evidence has indicated that DNA methylation modification is a reversible process of gene regulation in epigenetics. However, studies of methylation in the individual genes and pathways are still insufficient. In the present research, we conducted a conjoint analysis of correlation between methylation and gene expression and patient prognosis in large cohorts based on the Illumina Methylation 450K BeadChip.

Research motivation

DNA methylation modification has been considered as a potential therapeutic target and biomarker that may improve the prognosis of colon cancer. Therefore, identification and analysis of methylation-regulated differentially expressed genes (MeDEGs) will be of great significant.

Research objectives

In our study, we aimed to conduct bioinformatics analysis to identify MeDEGs and prognosis-related MeDEGs in colon cancer. Functional enrichment analysis was performed to clarify the function of MeDEGs. Furthermore, our study elucidated the potential mechanisms of prognosis-related MeDEGs.

Research methods

We downloaded RNA expression profiles, Illumina Human Methylation 450K BeadChip data, and clinical data of colon cancer from The Cancer Genome Atlas project. Differentially expressed genes and differentially methylated genes were identified using with the “edgeR” package and the “limma” package in R software. Then, we performed Spearman’s correlation analysis to clarify the relationship between methylation and expression. The in silico function of MeDEGs was further analyzed in the DAVID database and Kyoto Encyclopedia of Genes and Genomes (KEGG) Orthology-Based Annotation System 3.0, respectively. The relationship between methylation and expression and overall survival was revealed through a Kaplan–Meier curve test. Gene set enrichment analysis (GSEA) and investigation of protein-protein interactions were performed to clarify the function of prognosis-related genes.

Research results

We identified a total of 5 up-regulated and 81 down-regulated MeDEGs that satisfied the conditions. Gene ontology analysis indicated that the enrichment terms are mainly associated with transcription regulation. According to KEGG pathway analysis, three cancer-related pathways were involved by MeDEGs. Hypermethylation of glial cell-derived neurotrophic factor (GDNF) and reelin (RELN) was negatively correlated with overall survival. Based on GSEA, hypermethylation of GDNF and RELN was both significantly associated with pathways including “RNA degradation,” “ribosome,” “mismatch repair,” “cell cycle”, and “base excision repair.”

Research conclusions

In conclusion, we provide a new and reliable pathway to identify MeDEGs based on Illumina Human Methylation 450K BeadChip. Methylation plays a critical role in regulating cancer-related gene expression, especially tumor-suppressor genes. Our study provides an in-depth understanding of methylation. Furthermore, the prognosis-related MeDEGs may be potential biomarkers and therapeutic targets in colon cancer.

Research perspectives

The application of high-throughput platform will provide great support for the precision medicine in cancer. We will conduct more studies to reveal the function of the prognosis-related MeDEGs and establish a valid and reliable high-throughput analysis system in the future.