A Kramvis1, M C Kew, S Bukofzer. 1. Medical Research Council, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa.
Abstract
BACKGROUND/AIM: The aim of this study was to sequence the precore region of HBV isolated from serum and tumorous and non-tumorous liver tissue from patients with hepatocellular carcinoma to identify mutations that might play a role in malignant transformation. METHODS: HBV DNA was extracted from 62 sera, 14 tumorous and 12 non-tumorous liver tissue samples of patients with hepatocellular carcinoma, amplified by the polymerase chain reaction and sequenced directly. RESULTS: Thirty-nine patients were HBeAg-negative and 23 HBeAg-positive. Missense mutations were present predominantly in HBeAg-negative sera. The most common missense mutation, a guanine to thymine transversion, occurred at nucleotide 1862 in the bulge of the encapsidation signal; it was more prevalent in HBeAg-negative (10/39) than in HBeAg-positive patients (1/23) (p = 0.03). Mutations known to prevent HBeAg synthesis were detected in seven sera; five with an 1896 stop-codon mutation, one with an 1817 nonsense mutation, and one with a frameshift mutation caused by an insertion between 1838 and 1839. Missense mutations and deletions were present more often in tumorous tissue derived from HBsAg-negative patients. In the tumours missense mutations occurred at position 1862 and 1899, and the deletions affected direct repeat 1 and/or the encapsidation signal and included the x gene stop-codon. CONCLUSIONS: The 1862 mutation, and other missense mutations and deletions detected in the precore gene, may disrupt HBV DNA replication and/or signal peptide cleavage leading to HBeAg-negativity. Disruption of viral replication may promote integration of unencapsidated replicative intermediates and hence contribute to hepatocarcinogenesis.
BACKGROUND/AIM: The aim of this study was to sequence the precore region of HBV isolated from serum and tumorous and non-tumorous liver tissue from patients with hepatocellular carcinoma to identify mutations that might play a role in malignant transformation. METHODS: HBV DNA was extracted from 62 sera, 14 tumorous and 12 non-tumorous liver tissue samples of patients with hepatocellular carcinoma, amplified by the polymerase chain reaction and sequenced directly. RESULTS: Thirty-nine patients were HBeAg-negative and 23 HBeAg-positive. Missense mutations were present predominantly in HBeAg-negative sera. The most common missense mutation, a guanine to thymine transversion, occurred at nucleotide 1862 in the bulge of the encapsidation signal; it was more prevalent in HBeAg-negative (10/39) than in HBeAg-positive patients (1/23) (p = 0.03). Mutations known to prevent HBeAg synthesis were detected in seven sera; five with an 1896 stop-codon mutation, one with an 1817 nonsense mutation, and one with a frameshift mutation caused by an insertion between 1838 and 1839. Missense mutations and deletions were present more often in tumorous tissue derived from HBsAg-negative patients. In the tumours missense mutations occurred at position 1862 and 1899, and the deletions affected direct repeat 1 and/or the encapsidation signal and included the x gene stop-codon. CONCLUSIONS: The 1862 mutation, and other missense mutations and deletions detected in the precore gene, may disrupt HBV DNA replication and/or signal peptide cleavage leading to HBeAg-negativity. Disruption of viral replication may promote integration of unencapsidated replicative intermediates and hence contribute to hepatocarcinogenesis.
Authors: Jennifer Grant; Oche Agbaji; Anna Kramvis; Mukhlid Yousif; Mu'azu Auwal; Sudhir Penugonda; Placid Ugoagwu; Robert Murphy; Claudia Hawkins Journal: Trop Med Int Health Date: 2017-05-22 Impact factor: 2.622