Genomic variants link to hepatitis C racial disparities.

Matthew M Yeh,Benjamin Roberts,Sarag Boukhar,Sayed S Daoud,Nairanjana Dasgupta

doi:10.18632/oncotarget.19755

Abstract

Chronic liver diseases are one of the major public health issues in United States, and there are substantial racial disparities in liver cancer-related mortality. We previously identified racially distinct alterations in the expression of transcripts and proteins of hepatitis C (HCV)-induced hepatocellular carcinoma (HCC) between Caucasian (CA) and African American (AA) subgroups. Here, we performed a comparative genome-wide analysis of normal vs. HCV+ (cirrhotic state), and normal adjacent tissues (HCCN) vs. HCV+HCC (tumor state) of CA at the gene and alternative splicing levels using Affymetrix Human Transcriptome Array (HTA2.0). Many genes and splice variants were abnormally expressed in HCV+ more than in HCV+HCC state compared with normal tissues. Known biological pathways related to cell cycle regulations were altered in HCV+HCC, whereas acute phase reactants were deregulated in HCV+ state. We confirmed by quantitative RT-PCR that SAA1, PCNA-AS1, DAB2, and IFI30 are differentially deregulated, especially in AA compared with CA samples. Likewise, IHC staining analysis revealed altered expression patterns of SAA1 and HNF4α isoforms in HCV+ liver samples of AA compared with CA. These results demonstrate that several splice variants are primarily deregulated in normal vs. HCV+ stage, which is certainly in line with the recent observations showing that the pre-mRNA splicing machinery may be profoundly remodeled during disease progression, and may, therefore, play a major role in HCV racial disparity. The confirmation that certain genes are deregulated in AA compared to CA tissues also suggests that there is a biological basis for the observed racial disparities.

Highlights

Hepatocellular carcinoma (HCC) is one of the few malignancies in which the incidence is on the rise worldwide, especially in the US [1]
These results demonstrate that several splice variants are primarily deregulated in normal vs. Hepatitis C virus (HCV)+ stage, which is certainly in line with the recent observations showing that the premRNA splicing machinery may be profoundly remodeled during disease progression, and may, play a major role in HCV racial disparity
We describe our methods for expression microarray analysis at the genes and splice variants levels using Transcriptome Analysis Console (TAC2.0) software coupled by validation studies to confirm disease-specific splice variants of genes that could be involved in the racial disparity of HCV-induced hepatocellular carcinoma (HCC) by real-time quantitative RT-PCR (qRT-PCR) and immunohistochemistry using sixty liver and tumor tissue samples

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the few malignancies in which the incidence is on the rise worldwide, especially in the US [1]. The increasing incidence of HCC in the US is associated with the rise in Hepatitis C virus (HCV) infection [2]. It is estimated that 3.2 million people in the US are infected with HCV, a blood-borne disease linked to 12,000 US deaths a year [3]. Even with the availability of new oral direct acting antiviral drugs [4], it is anticipated that 320,000 patients will die from HCV, 157,000 will develop HCC, and 203,000 will develop cirrhosis in the 35 years [5]. There are disparities in the prevalence of HCV infection with African Americans (AA) being twice as likely to have been infected compared with Caucasian Americans (CA) [7]. There are significant racial/ ethnic disparities in access to HCV care [8].

Objectives

Methods

Results

Conclusion