High Prevalence of 1762T 1764A Mutations in the Basic Core Promoter of Hepatitis B Virus Isolated From Black Africans With Hepatocellular Carcinoma Compared With Asymptomatic Carriers

Abstract

The purpose of this study was to identify mutations in the basic core promoter and enhancer II region of the hepatitis B virus (HBV) that might cause the HBV e antigen (HBeAg)-negative phenotype and contribute to hepatocarcinogenesis in black African carriers of the virus. The basic core promoter/enhancer II overlaps with the X gene. HBV DNA from serum of 47 asymptomatic carriers and 50 patients with hepatocellular carcinoma and from 28 tumor and 10 nontumor liver tissues was amplified and sequenced directly. That part of the enhancer II region not overlapping the basic core promoter was completely conserved in all samples. Missense mutations at nucleotides 1809 and 1812 in the basic core promoter were found in 80% of all sequences and may represent wild-type sequence in Southern African isolates. Nucleotide and amino acid divergences were higher in the basic core promoter of hepatocellular carcinoma patients when compared with asymptomatic carriers (P F .0001). This applied particularly to the paired 1762 adenine to thymine (1762 T ) and 1764 guanine to adenine (1764 A ) missense mutations, the prevalence of which was 66% in patients with hepatocellular carcinoma compared with 11% in asymptomatic carriers (P F .0001). Black Africans who are symptomless carriers of the hepatitis B virus (HBV) usually seroconvert from HBV e antigen (HBeAg) positivity to negativity after a relatively short time. 1 The carrier state is established in the first few years of life, 2 and by early adulthood between 1% and 14% only of black carriers remain HBeAg positive compared with 40% or more among ethnic Chinese, another population in which the virus is endemic. 1-4 Why black African carriers seroconvert earlier is not known. Nucleotide sequencing of the precore region of HBV isolates from a number of countries has shown the 1896 stop codon mutation to be a frequent cause of the HBeAgnegative phenotype, 5,6 with other nonsense or frame-shift mutations accounting for a small proportion (reviewed in Miyakawa et al. 7 ). However, these mutations are seldom present in black African carriers in Southern Africa 8,9 and our focus has shifted to the X open reading frame.The X open reading frame encodes the X protein that has transactivating activity (reviewed in Koike and Takada 10 ) and contains the basic core promoter (BCP)/enhancer II complex. The BCP, mapping between nucleotides 1742 and 1849, controls the transcription of both precore messenger RNA (mRNA), which codes for the protein that is the precursor of the e antigen, and pregenomic RNA (pgRNA), which controls HBV replication. 11 A pair of mutations in the BCP that is associated with a reduced level of HBeAg expression was first described in Japanese patients [12][13][14] : an adenine (A) to thymine (T) transversion at position 1762 together with a guanine (G) to A transition at 1764 in the second AT-rich region of the BCP are often present in patients with chronic hepatitis B [15][16][17][18][19][20] and fulminant hepatitis B, [14][15][16][21][22][23] and less often in asymptoma...

A Case–Control Study for Clinical and Molecular Biological Differences Between Hepatitis B Viruses of Genotypes B and C

“…13,18,25,26,36 Furthermore, hepatocellular carcinoma has been reported in association with BCP mutations. 26,37 Although the mechanism underlying the occurrence of BCP mutations is unclear, the patients with age greater than or equal to 35 years were at an increased risk for having them ( Table 3).…”

The hepatitis B virus HBx protein induces adherens junction disruption in a src-dependent manner

“…Although HBx expression is often detected in HBV-related HCCs (Feitelson and Duan, 1997), the prognosis and/or prevalence of metastasis of HBx-expressing tumors has not been studied so far. In addition, it has been shown that the X gene is often mutated in HCCs Baptista et al, 1999;Poussin et al, 1999). However, these mutations accumulate preferently within the transactivation domains of HBx, without a ecting HBx-mediated cell transformation (Gottlob et al, 1998b).…”

Specific mutations of hepatitis B virus in plasma predict liver cancer development

“…The HBV genome encodes its essential genes with overlapping ORFs; therefore, a mutation in the HBV genome can alter the expression of multiple proteins. In many cases of HCC in China and Africa, a double mutation in the HBV genome, an adenine-to-thymine transversion at nucleotide 1762 and a guanine-to-adenine transition at nucleotide 1764 (1762 T ͞ 1764 A ), has been found in tumors (5,10,11). This segment of the HBV genome contains an overlapping sequence for the base core promoter and the HBV X gene; therefore, the double mutation in codons 130 and 131 of the HBV X gene reported in human HCC is identical to the 1762 and 1764 nucleotide changes (12,13).…”

“…This segment of the HBV genome contains an overlapping sequence for the base core promoter and the HBV X gene; therefore, the double mutation in codons 130 and 131 of the HBV X gene reported in human HCC is identical to the 1762 and 1764 nucleotide changes (12,13). The onset of these mutations has been also associated with the increasing severity of the HBV infection and cirrhosis (10,11). Thus, the tracking of this polymorphism with disease outcomes makes it a candidate biomarker for early detection of HCC risk in individuals.…”