Specific mutations in the enhancer II/core promoter/precore regions of hepatitis B virus subgenotype C2 in Korean patients with hepatocellular carcinoma

Abstract

Recently, hepatitis B virus (HBV) genotypes and mutations have been reported to be related to hepatocellular carcinoma (HCC). This cross-sectional case-control study examined the relationship between HCC and mutations in the enhancer II/core promoter and precore regions of HBV by comparing 135 Korean HCC patients infected with HBV genotype C2 (HBV/C2; HCC group) with 135 age-, sex-, and hepatitis B e antigen (HBeAg) status-matched patients without HCC (non- HCC group). Age and sex were also matched between HBeAg-positive and -negative patients. The prevalence of T1653, A1689, V1753, T1762/A1764, T1846, A1850, C1858, and A1896 mutations was evaluated in this population. The prevalence of the T1653 mutation in the box alpha region, the T1689 [corrected] mutation in between the box alpha and beta regions, and the T1762/A1764 mutations in the basal core promoter region was significantly higher in the HCC group compared to the non-HCC group (8.9% vs. 2.2%, P = 0.017; 19.3% vs. 4.4%, P < 0.001; and 60.7% vs. 22.2%; P < 0.001). Among HBeAg-negative patients, the frequency of the T1653 mutation was higher in the HCC group. Regardless of HBeAg status, the prevalence of the T1689, [corrected] and T1762/A1764 mutations was higher in the HCC group than in the non-HCC group. However, no association was observed between mutations in the precore region and HCC. Upon multivariate analysis, the presence of the T1653, T1689, [corrected] and T1762/A1764 mutations was an independent predictive factor for HCC. The addition of the T1653 or T1689 [corrected] mutation to T1762/A1764 increased the risk of HCC. In conclusion, the T1653, T1689, [corrected] and/or T1762/A1764 mutations were associated with the development of HCC in Korean patients infected with HBV/C2.

A case–control study on sequence variations in the enhancer II/core promoter/precore and X genes of hepatitis B virus in patients with hepatocellular carcinoma

“…To our knowledge, the current case-control study is the first to reveal the association between HBV mutations and the development of HCC among Thai patients. In this study, we found that double A1762T/G1764A mutations were an independent risk factor for the development of HCC, which was consistent with recent casecontrol studies conducted in China, Taiwan, and Korea [7,12,20,21]. Also, the magnitude of the OR of HCC associated with the presence of the BCP double mutants in this study was approximately 3 to 4-fold, which was similar with reports of other studies.…”

Comparison Study on the Complete Sequence of Hepatitis B Virus Identifies New Mutations in Core Gene Associated with Hepatocellular Carcinoma

“…Although the region nts 1613 to 1764 in the X gene and nts 1899 to 2203 in the pre-C/C gene constitute only 14.2% of the HBV genome, they contained 75.0% (9 of 12) of the mutations showing a significantly higher frequency in HCC patients from the full-length HBV sequence analysis (Table 2). Among the four HCC-related mutations in the X gene, C1653T, A1762T, and G1764A have been studied extensively (3,(12)(13)(14)(15)(16), whereas G1613A is less well defined. G1613A was first reported by Takahashi et al, who noted that, of 40 HCC tissue samples tested, 15 contained this type of mutation (13).…”

“…Recently, increasing evidence have shown that an HBV strain with a complex mutation pattern rather than a single mutation was associated with a higher risk for advanced liver disease. These combinations included C1653T plus A1762T/ G1764A (14), A1762T/G1764A plus C1766T and/or T1768A (12), pre-S deletion plus A1762T/G1764A (5), and deletions in BCP plus C and/or pre-S (32). Those cross-sectional studies provided little information on the evolution of the HBV sequence during HCC development.…”

Clinical utility of complex mutations in the core promoter and proximal precore regions of the hepatitis B virus genome

“…Thus, genotypes B and C are apparently aggressive with respect to the development of HCC. However, in South Korea, nearly all HBV cases are genotype C2 (Ce) [28][29][30][31][32][33] . Although highly prevalent in HCC (86%), the prevalence of the precore stop mutation does not differ significantly among chronic HBV carriers with or without HCC [32,34,35] .…”

“…However, in South Korea, nearly all HBV cases are genotype C2 (Ce) [28][29][30][31][32][33] . Although highly prevalent in HCC (86%), the prevalence of the precore stop mutation does not differ significantly among chronic HBV carriers with or without HCC [32,34,35] . Most isolates of HBV genotype C2 in South Korea carry the T1858 mutation [32,33] , which attenuates the stability of the secondary structure of the pregenome encapsidation signal (epsilon signal).…”