Mutations in the Hepatitis C Virus core Gene Are Associated with Advanced Liver Disease and Hepatocellular Carcinoma

Abstract

Purpose Hepatitis C virus (HCV) infection can promote the development of hepatocellular carcinoma (HCC). Published data implicate the HCV core gene in oncogenesis. We tested the hypothesis that core gene sequences from HCC patients differ from those of patients without cirrhosis/HCC. Experimental Design Full-length HCV sequences from HCC patients and controls were obtained from the investigators and GenBank and compared to each other. A logistic regression model was developed to predict the HCC risk of individual point mutations and other sequence features. Mutations in partial sequences (bases 36–288) from HCC patients and controls were also analyzed. The first base of the AUG start codon was designated position 1. Results A logistic regression model developed through analysis of full-length core gene sequences identified seven polymorphisms significantly associated with increased HCC risk (36G/C, 209A, 271U/C, 309A/C, 435A/C, 481A, 546A/C) and an interaction term (for 209A-271U/C) that had an odds ratio < 1.0. Three of these polymorphisms could be analyzed in the partial sequences. Two of them, 36G/C and 209A, were again associated with increased HCC risk, but 271U/C, was not. The odds ratio of 209A-271U/C was not significant. Conclusions HCV core genes from patients with and without HCC differ at several positions. Of interest, 209A has been associated with interferon resistance and HCC in previous studies. Our findings suggest that HCV core gene sequence data might provide useful information about HCC risk. Prospective investigation is needed to establish the temporal relationship between the appearance of the viral mutations and development of HCC.

Analysis of Interferon Signaling by Infectious Hepatitis C Virus Clones with Substitutions of Core Amino Acids 70 and 91

“…In addition to the poor virological responses of HCV core amino acid 70/91 mutants to peg-IFN-plus-RBV treatment (4,6,12), patients infected with the core mutants showed increased incidence of hepatocellular malignancies (2,15,49). It has been reported that the HCV core R70 but not L91 mutant frequently causes steatosis and increased hepatic oxidative stress (52).…”

Deep-Sequencing Analysis of the Association between the Quasispecies Nature of the Hepatitis C Virus Core Region and Disease Progression

“…With regard to viral factors, the relationship between the viral core region and disease progression in HCV genotype 1b infection has attracted clinical attention. Specifically, it has been reported that the core amino acid (aa) 70 residue, identified as a variable related to the outcome of interferon (IFN) therapy (3), is closely associated with the progression of hepatitis and hepatocarcinogenesis in Japan and North America (4)(5)(6)(7). Those previous studies and our own have reported that core aa 70 variation is strongly linked to carcinogenesis and that substitutions in the core aa 70 region aggravate hepatitis and heighten the risk of hepatocarcinogenesis during the clinical course, corroborating the relationship between the status of the core region and disease progression (8,9).…”

Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets

“…Mutations in the hepatitis C virus core gene are associated with advanced liver disease and hepatocellular carcinoma [42] . And there has been found an association between mutations in the core region of hepatitis C virus genotype 1 and hepatocellular carcinoma development [43] .…”