HBV core promoter mutations prevail in patients with hepatocellular carcinoma from Guangxi, China

Abstract

The development of primary liver cancer frequently is associated with persistent HBV infection, and tumours may arise in individuals who are anti-HBe positive. However, it is unclear whether viruses with an HBeAg-negative phenotype are associated with tumour development or are selected, during seroconversion, after chromosomal integration of wild-type viral DNA. In order to investigate the temporal evolution of the HBV genome in such individuals, the polymerase chain reaction was used to amplify HBV DNA from tumour tissue and serum of 14 patients from Guangxi, China with hepatocellular carcinoma. Comparison of nucleotide and amino acid sequences of the precore and proximal core region of HBV from the two sites in each patient produced evidence of divergence following integration in the tumour, but in most cases, HBeAg-negativity could not be explained by precore mutations. Sequences from the core promoter region were therefore examined and mutations were found in the majority, which are believed to upregulate transcription of the core (and pregenomic) RNA but to downregulate precore mRNA. To determine whether this finding merely reflected sequence variation among geographical isolates of HBV, the same region of HBV DNA from asymptomatic controls was sequenced and these mutations were found to be rare. We hypothesise that HBV with the core promoter mutations replicates at higher levels than the wild type, with the consequence that more integrations occur into the hepatocyte chromosomes during the early stages of infection. These hepatocytes may expand clonally and be targets for further mutagenic events leading to tumour development.

Risk for hepatocellular carcinoma with respect to hepatitis B virus genotypes B/C, specific mutations of enhancer II/core promoter/precore regions and HBV DNA levels

“…Viral replication can also be further enhanced by a second mechanism in which the transcription of the pregenomic RNA will be increased through the removal of the nuclear receptor binding site and creation of a hepatocytes nuclear binding factor 30. These changes increase the core RNA transcription with enhanced core protein, DNA polymerase, pre-genomic RNA synthesis, but suppress the precore RNA transcription whose normal function is to decrease pregenomic RNA packaging 31 32. This is in complete concordance with the finding of the present study and of Chauhan and colleagues 33.…”

HBx M130K and V131I (T-A) mutations in HBV genotype F during a follow-up study in chronic carriers

“…However this result was not statistically significant based on the Fisher exact test, 1 tail, p = 0.05, probably due to the small sample size in the groups. Other studies have shown a better correlation between the presence of T-A mutations and patients with fulminant hepatitis, severe exacerbation [20] or liver cirrhosis [22] especially with genotypes A or C when compared with asymptomatic carriers [12-14]. In agreement with the literature T-A mutations seem to appear more frequently in genotypes C [23,24] and A [13] than D [25,26] or B [27].…”

“…A double point mutation with a transversion nucleotide from adenine to thymine at nucleotide 1762, K130M with a transition from adenine to guanine at position 1764 V131I (T-A mutations), has been found more frequently in patients with hepatic tumors than in asymptomatic chronic patients from China [11,12] and Africa [13]. In East Asia where genotype C is the most common genotype, it has been reported that the T-A mutation occurs more frequently in relation to this genotype [14].…”

Update of research and management of hepatitis B

“…Several studies have demonstrated that these mutations were found more frequently in patients with HCC than in those with chronic hepatitis B. [61][62][63][64] Because these core promoter variants may result from a long-lasting immune response and may be associated with more severe liver disease, it is unclear if the core promoter mutations or X protein alterations are directly involved in hepatocarcinogenesis. However, a recent report suggested that they could at least be viewed as a predictor of the development of HCC.…”