Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Jan 27, 2018; 10(1): 155-165
Published online Jan 27, 2018. doi: 10.4254/wjh.v10.i1.155
Epigenetic basis of hepatocellular carcinoma: A network-based integrative meta-analysis
Venkat Bhat, Sujitha Srinathan, Elisa Pasini, Marc Angeli, Emily Chen, Cristina Baciu, Mamatha Bhat
Venkat Bhat, Department of Psychiatry, University Health Network and University of Toronto, Toronto M5G2N2, Canada
Sujitha Srinathan, Elisa Pasini, Marc Angeli, Emily Chen, Cristina Baciu, Mamatha Bhat, Multi Organ Transplant Program, University Health Network, Toronto M5G2N2, Canada
Mamatha Bhat, Division of Gastroenterology, Department of Medicine, University Health Network and University of Toronto, Toronto M5G2N2, Canada
Author contributions: Bhat V, Pasini E, Baciu C and Bhat M contributed to study design and writing of manuscript; Srinathan S, Pasini E and Angeli M contributed to data collection; Baciu C and Pasini E contributed to data analysis and interpretation of data; all authors critically reviewed final manuscript.
Conflict-of-interest statement: The authors deny any conflict of interest.
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:
Correspondence to: Mamatha Bhat, FRCP(C), MD, MSc, Lecturer, Staff Physician, Multi Organ Transplant Program, University Health Network, 585 University Avenue, Toronto M5G2N2, Ontario, Canada.
Telephone: +1-416-3404800 Fax: +1-416-3404043
Received: November 5, 2017
Peer-review started: November 5, 2017
First decision: November 15, 2017
Revised: November 17, 2017
Accepted: December 5, 2017
Article in press: December 7, 2017
Published online: January 27, 2018

To identify the key epigenetically modulated genes and pathways in HCC by performing an integrative meta-analysis of all major, well-annotated and publicly available methylation datasets using tools of network analysis.


PubMed and Gene Expression Omnibus were searched for genome-wide DNA methylation datasets. Patient clinical and demographic characteristics were obtained. DNA methylation data were integrated using the Ingenuity Pathway Analysis, a software package for visualizing and analyzing biological networks. Pathway enrichment analysis was performed using IPA, which also provides literature-driven and computationally-predicted annotations for significant association of genes to curated molecular pathways.


From an initial 928 potential abstracts, we identified and analyzed 11 eligible high-throughput methylation datasets representing 354 patients. A significant proportion of studies did not provide concomitant clinical data. In the promoter region, HIST1H2AJ and SPDYA were the most commonly methylated, whereas HRNBP3 gene was the most commonly hypomethylated. ESR1 and ERK were central genes in the principal networks. The pathways most associated with the frequently methylated genes were G-protein coupled receptor and cAMP-mediated signalling.


Using an integrative network-based analysis approach of genome-wide DNA methylation data of both the promoter and body of genes, we identified G-protein coupled receptor signalling as the most highly associated with HCC. This encompasses a diverse range of cancer pathways, such as the PI3K/Akt/mTOR and Ras/Raf/MAPK pathways, and is therefore supportive of previous literature on gene expression in HCC. However, there are novel targetable genes such as HIST1H2AJ that are epigenetically modified, suggesting their potential as biomarkers and for therapeutic targeting of the HCC epigenome.

Keywords: Network analysis, Hepatocellular carcinoma, Methylation

Core tip: Hepatocellular carcinoma (HCC) is a high-fatality cancer with limited screening biomarkers and therapeutic options. It arises in the context of chronic liver disease, having accumulated epigenetic changes over time. The goal of this study was to perform an integrative network-based meta-analysis of all genome-wide DNA methylation data in HCC. Using bioinformatics tools, we identified the most important aberrantly methylated genes and associated pathways. G-protein receptor signaling was the most significantly associated with HCC based on differential methylation of involved genes, which is consistent with the implication of the Ras/Raf/MAPK and mTOR pathways. The identification of novel epigenetically modified genes such as HIST1H2AJ within known pathways suggests targeting of the epigenome as a potential therapeutic avenue for HCC.