Published online Jul 14, 2019. doi: 10.3748/wjg.v25.i26.3392
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
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.
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.
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.
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.
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.”
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.
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.