Mutations within the hepatitis B virus genome among chronic hepatitis B patients with hepatocellular carcinoma

Abstract

Chronic hepatitis B infection is a major cause of hepatocellular cancer (HCC). The pathogenesis of the carcinogenesis is not fully understood. Viral proteins such as the X protein and the truncated middle S protein have been implicated to be transactivators. In order to investigate whether any mutations within relevant parts of the hepatitis B virus (HBV) genome could be associated with the development of HCC, the genomes of 16 HBV strains from chronic HBV carriers with HCC were studied. Serum samples were subjected to PCR and the HBV DNA sequenced subsequently. Genotypes A-D were represented. The sequence analysis showed that an especially high proportion, 50% (CI 95%, 25-75%), of the patients with HCC carried HBV mutants with deletions or insertions in the N-terminal half of the pre-S2 region or had a point mutation in the start codon of pre-S2 compared with controls with chronic HBV infection, 21% (CI 95%, 3-39%). A high proportion (69%) also had mutations at position 1762 (A --> T) and/or 1764 (G --> A) in the core promoter region, but the proportion of core promoter mutations was no different from what was found in a control group of HBV carriers without HCC (68%). The pre-S2 variants, which involve deletions of immunogenic regions, may have a survival advantage as they are mostly found in long-standing HBV infection. There were no other mutations found frequently within the region coding for the X protein.

Influence of Hepatitis B Virus X and Core Promoter Mutations on Hepatocellular Carcinoma among Patients Infected with Subgenotype C2

“…Table 3 compares ALT levels and HBV DNA levels, as well as mutations in the X region, box ␣ (enhancer II), the core promoter, and the precore region, among 60 HBeAg-positive patients (29 non-HCC and 31 HCC) matched for age and sex in a case-control study. Among HBeAg-positive patients, the platelet count was significantly lower for the HCC group than for the non-HCC group (10.6 ϫ 3 ; P ϭ 0.0062). The frequency of the T1653 mutation in the box ␣ region was significantly higher for the HCC group than for the non-HCC group (52% versus 24%; P ϭ 0.036) ( Table 3).…”

“…In the multivariate analysis among all 160 patients, the presence of T1653, the presence of V1753, and a platelet count of Յ10 ϫ 10 4 /mm 3 Table 5). The presence of H1499 was identified as a significant negative factor for HCC (odds ratio, 0.243 [95% confidence interval, 0.078 to 0.76]).…”

“…Mutations in the basal core promoter (BCP) region at nucleotides (nt) 1762 and 1764 (T1762/A1764) and in the precore region at nt 1896 (A1896) are associated with HBV e antigen (HBeAg) seroconversion and persistent viral replication. It is noteworthy that both BCP and precore mutations are often found in patients with advanced liver disease (e.g., HCC) (2,3,16,19,23,25,38). The T1762/A1764 mutations alter HBeAg production at the transcriptional level, and the A1896 mutation in the precore region terminates the translation of precursor protein, abrogates HBeAg production, and results in seroconversion.…”

Hepatitis B virus pre‐S2 mutant upregulates cyclin A expression and induces nodular proliferation of hepatocytes†

“…Recently, the prevalence of pre-S mutants has been correlated to the risk of hepatocellular carcinoma in patients with chronic HBV infection. [36][37][38] The data we presented in this study will provide valuable information on the potential function of pre-S mutants in HBV-related hepatocarcinogenesis.…”

Repeated Passage of Wild-Type Woodchuck Hepatitis Virus in Lymphoid Cells Does Not Generate Cell Type-Specific Variants or Alter Virus Infectivity

“…The main focus of the previous studies was on the mutations potentially associated with the development of fulminant hepatitis or HCC and on those located in the areas of the X gene encoding the basic core promoter and the core upstream regulatory sequences. Overall, the HBV X gene appears to be well conserved during chronic hepatitis B, and conservation of the X protein seems to be essential for the virus' ability to actively replicate (2,19). On the other hand, mutations in the HBV X gene sequence have been documented in HCC (5,20).…”