Impact of Colon-Specific DNA Methylation-Regulated Gene Modules on Colorectal Cancer Patient Survival

Abstract

Background Colorectal cancer (CRC) is the second most commonly diagnosed cancer in females and the third in males worldwide. Although existing evidence explained some critical functions of the single genetic abnormality in the pathogenesis of CRC, the function of interactors involved in the colon-specific regulatory network, especially DNA methylation regulated network is still poorly understood. Material/Methods In this work, matched gene expression and DNA methylation samples of CRC patients were retrieved. Differential gene expression and methylation analyses were performed. In addition, gene expression and DNA methylation were integrated into a colon-specific regulatory gene network, detecting the epigenetically regulated gene modules which drive CRC through an underlying epigenetic mechanism. Finally, the colon-specific DNA methylation-regulated gene modules were validated using an independent set of CRC patients. Results Differential gene expression analysis demonstrated the upregulation of the cell cycle and DNA replication and downregulation of cGMP-PKG signaling pathway and calcium signaling pathway in CRC. Differentially methylated regions (DMRs) showed the different levels of methylation in promoters, CpG islands, and genes in CRC. In addition, gene expression and DNA methylation were integrated into a colon-specific regulatory gene network, detecting 8 epigenetically regulated gene modules which drive CRC through an underlying epigenetic mechanism. Interestingly, 2 of the colon-specific DNA methylation-regulated gene modules showed a significant predictive ability for the survival of an independent set of CRC patients. Conclusions The results of this study could open a new era and aid the development of novel therapeutic targets for the treatment of CRC patient.

A microRNA panel that regulates proinflammatory cytokines as diagnostic and prognosis biomarkers in colon cancer

“…In contrast the most downregulated pathways were cGMP-PKG and Cholinergic synapse ( Fig. 2 A), the downregulation of this pathways have been correlated to tumor growth, tumor location, and prognosis of CC [ 24 ]. Thus, these findings indicate that miRNA expression profile in colon cancer can regulate key signaling pathways involved in CC development and progression.…”

“…In an effort to expand the knowledge of miRNAs that regulate molecular events in inflammation and that could serve as diagnostic and prognostic indicators in colorectal cancer, in this study we focused on determining differentially expressed miRNA in CC tissues versus healthy colon and inflamed colon tissue samples. The identified miRNAs have an important role in the regulation of signaling pathways that lead to cancer development and progression as proinflammatory IL-17, Fanconi anemia pathway [ 27 ], homologous recombination DNA repair [ 28 ], cGMP-PKG, Cholinergic synapse and calcium signaling pathways [ 24 ]. In this regard, inflammation has been established as a main risk factor for developing CC [ 26 ].…”

Identification of epigenetic methylation-driven signature and risk loci associated with survival for colon cancer

“…Epigenetics focuses on the features and modification of the genome (8), including post-translational modifications of histones, cytosine modifications of DNA, nucleosome positioning and interactions of spatial conformation between genomic regions and accessible genomic loci2 (11,12). As a crucial part of epigenetics (13,14), DNA methylation was found to be involved in malignant progression (15).…”

Integrated Analysis of DNA methylation and transcriptome profile to identify key features of age-related macular degeneration

“…Functional epigenetic modules (FEM) analysis is a method for identification of interactome hotspots of differential methylation and differential expression [32]. FEM analysis was widely used to identify protein modules in integrative analysis of DNA methylation and transcriptome, such as Parkinson's disease, colorectal cancer and Pituitary Adenomas [33][34][35]. FEM analysis was performed to further explore association between DNA methylation and gene expression under protein interaction networks.…”