Integrative Analysis of DNA Methylation and microRNA Expression Reveals Mechanisms of Racial Heterogeneity in Hepatocellular Carcinoma.

Rency S Varghese,Habtom W Ressom,Amber Alley,Alexander H Kroemer,Mahlet G Tadesse,Yunxi Zhang,Megan E Barefoot,Sidharth Jain,Yifan Chen,Deepak Kumar,Zaki A Sherif

doi:10.3389/fgene.2021.708326

Abstract

Pathologic alterations in epigenetic regulation have long been considered a hallmark of many cancers, including hepatocellular carcinoma (HCC). In a healthy individual, the relationship between DNA methylation and microRNA (miRNA) expression maintains a fine balance; however, disruptions in this harmony can aid in the genesis of cancer or the propagation of existing cancers. The balance between DNA methylation and microRNA expression and its potential disturbance in HCC can vary by race. There is emerging evidence linking epigenetic events including DNA methylation and miRNA expression to cancer disparities. In this paper, we evaluate the epigenetic mechanisms of racial heterogenity in HCC through an integrated analysis of DNA methylation, miRNA, and combined regulation of gene expression. Specifically, we generated DNA methylation, mRNA-seq, and miRNA-seq data through the analysis of tumor and adjacent non-tumor liver tissues from African Americans (AA) and European Americans (EA) with HCC. Using mixed ANOVA, we identified cytosine-phosphate-guanine (CpG) sites, mRNAs, and miRNAs that are significantly altered in HCC vs. adjacent non-tumor tissue in a race-specific manner. We observed that the methylome was drastically changed in EA with a significantly larger number of differentially methylated and differentially expressed genes than in AA. On the other hand, the miRNA expression was altered to a larger extent in AA than in EA. Pathway analysis functionally linked epigenetic regulation in EA to processes involved in immune cell maturation, inflammation, and vascular remodeling. In contrast, cellular proliferation, metabolism, and growth pathways are found to predominate in AA as a result of this epigenetic analysis. Furthermore, through integrative analysis, we identified significantly differentially expressed genes in HCC with disparate epigenetic regulation, associated with changes in miRNA expression for AA and DNA methylation for EA.

Highlights

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide
The patients for this study were recruited at MedStar Georgetown University Hospital (MGUH) through an inclusion protocol approved by the Georgetown University institutional review board (IRB)
We investigated whether the differentially expressed (DE) mRNA targets of DE miRNAs in AA overlap with genes that are differentially methylated and differentially expressed (DMDE) in European Americans (EA), suggesting differential epigenetic regulation at play in dysregulation of common genes involved in hepatocellular carcinoma (HCC) pathogenesis

Summary

Introduction

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. The incidence is higher in African-Americans (AA) and is associated with more advanced tumor stage at diagnosis and lower survival rate compared to other racial groups including European-Americans (EA) (Ryerson et al, 2016; Islami et al, 2017; American Cancer Society [ACS], 2018). Racial health inequalities are mostly attributed to socioeconomic differences, there is a growing realization that genetic and epigenetic events can contribute to cancer incidence and clinical outcomes (Wallace et al, 2011; Daly and Olopade, 2015). There is emerging evidence linking epigenetic events including DNA methylation and microRNA (miRNA) expression to cancer disparities in breast, prostate, endometrial and colon cancers (Mehrotra et al, 2004; Kwabi-Addo et al, 2010; Wang et al, 2012, 2016; Long et al, 2013; Nwaneri et al, 2016; Hashimoto et al, 2017; Shiina et al, 2017)

Objectives

Methods

Results

Conclusion