Associations Between Hepatitis B Virus Mutations and the Risk of Hepatocellular Carcinoma: A Meta-Analysis (original) (raw)
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Worldwide genetic diversity of HBV genotypes and risk of hepatocellular carcinoma
Cancer Letters, 2009
Hepatitis B viruses (HBV) are responsible for over 50% of the worldwide attributable risk of hepatocellular carcinoma (HCC) and this figure increases even further in regions of high endemicity. Systematic sequencing of HBV genomes has identified that this common virus existed as eight distinct genotypes (denoted A-H), each regrouping variants with less than 8% divergence in their DNA sequence. These genotypes differ by their geographic distribution in populations around the globe. There is evidence that HBV genotypes also differ by their pathogenic properties, including their risk of persistence as chronic infection and their capacity to induce precursor disease or cancer. On the other hand, HBV genes may undergo mutations that become selected during the course of chronic infection and progressive liver disease. The most significant of these mutations in the context of HCC are those occurring in the pre-core (Pre-C) and basal core promoter (BCP) regions. These mutations may upregulate HBV expression and increase its virulence. These mutations may occur in all HBV genotypes but are more common in genotypes associated with more severe disease and cancer, in particular genotype C. Understanding the molecular basis of pathological variations between HBV variants is critical for prediction of disease severity. It will also be important to determine whether differences among genotypes may have an impact on the long-term protective efficacy of universal HBV vaccination.
Cancer Science, 2007
Hepatitis B virus (HBV) genotype C and the basic core promoter (BCP) mutations were reported to be associated with the development of hepatocellular carcinoma (HCC). In this study the full sequences of HBV genomes were analyzed in order to find the other predictors of HCC development. We determined the full sequences of HBV genomes in 24 genotype C carriers who developed HCC (HCC group) at the beginning of follow-up and at the time of HCC diagnosis, and 20 patients who did not develop HCC (non-HCC group) served as a control. The number of nucleotide and amino acid substitutions in most regions was higher in the HCC group than in the non-HCC group, and the following substitutions and deletions were found more frequently in the HCC group than in the non-HCC group: G1317A and T1341C/A/G in the X promoter region were detected in 13 and six of the HCC cases, four and none of the non-HCC cases, respectively; and pre-S2 deletion was detected in eight HCC and none of the non-HCC cases. Compared with the wild type X promoter, the mutant type X promoters, M1 (G1317A), M2 (T1341C), and M4 (T1341G) showed increases in activity of 2.3, 3.8, and 1.4 times, respectively, in HepG2 cells. Substitutions and deletion of nucleotides of the HBV genome, especially the pre-S2 deletion and G1317A and T1341C/A/G mutations may be useful markers for predicting the development of HCC.
Carcinogenesis, 2004
The role of hepatitis B virus (HBV) genotypes, core promoter (CP) and precore mutants on hepatocellular carcinoma (HCC) is still controversial. We aimed to determine their role on the development and clinical features of HCC. HBV genotypes and CP/precore mutations were determined in 90 HCC patients and 180 matched control patients. In the 90 HCC patients, 22 (24.4%) and 68 (75.6%) had subtype Ba and genotype C, respectively. The prevalence of genotype C and CP mutations was significantly higher in HCC patients compared with controls (75.6 versus 57.8%, P 0.004; 90.9 versus 74.8%, respectively, P 0.007). Among carriers of genotype C, 91.8% of the HCC patients and 88.8% of controls had CP mutations. Among carriers of subtype Ba, HCC patients had a higher prevalence of CP mutations compared with controls (88.2 versus 54.5%, respectively, P 0.02). By logistic regression analysis, the only factor associated with HCC was a mutation of the CP region (P 0.032). There were no differences in the clinical features on presentation, the chance of receiving treatment and the cumulative survival rate for chemoembolization-treated patients between patients with subtype Ba and genotype C. There was too small a number of CP wild-type to do a similar comparison with CP mutants. In conclusion, there was a significantly higher prevalence of both genotype C and CP mutations in patients with HCC. The association between HBV genotype C and HCC was probably not genuine but was due to the high percentage of CP mutations in patients with genotype C.
Clinical relevance and public health significance of hepatitis B virus genomic variations
World Journal of Gastroenterology, 2009
Ten hepatitis B virus (HBV) genotypes (A-J) and 34 HBV subgenotypes have been identified so far. HBV genotypes and subgenotypes have distinct geographical distributions, and have been shown to differ with regard to clinical outcome, prognosis, and response to interferon treatment. Infection with subgenotype A2 is frequently associated with high viral load, resulting in acute infection via horizontal transmission. Genotypes A and B are more sensitive to interferon treatment than genotypes D and C, respectively. Genotype B is more frequent in acute hepatitis than genotype C, whereas genotype C (C2) is more frequently associated with an increased risk of hepatocellular carcinoma (HCC), mostly cirrhotic, as compared with genotype B (B2). Genotype mixture is associated with high viral load and worse outcome of HBV infection. HBV mutations in the S genes, especially amino acids substitution at position 145 (G145R), are associated with immune escape, whereas mutations in the PreS or S genes which impair HBsAg secretion could present a risk to blood safety. HBV variants harboring mutations in the viral polymerase gene that confer resistance to nucleoside analogs may be selected during antiviral therapy. Different genotypes have distinct mutation patterns in the PreS and EnhⅡ/BCP/Precore regions. PreS deletions, C1653T, T1753V, and A1762T/G1764A are associated with an increased risk of HCC. HCCassociated HBV mutants may not transmit via motherto-child transmission, and are likely generated during HBV-induced pathogenesis. Examination of HBV mutations alone or in combination and host genetic susceptibility will be helpful in classifying the HBV-infected subjects who will develop HCC and need active antiviral treatments.
Frontiers of Medicine in China, 2010
The association of viral mutations and haplotypic carriages with mutations in the preS region of hepatitis B virus (HBV) genotypes B and C with hepatocellular carcinoma (HCC) is of great significance for the prediction of this malignancy, but it remains obscure. We analyzed the preS sequences of HBV genotypes B and C from 1172 HBV-infected subjects including 231 patients with HCC. As compared with the HBV-infected subjects without HCC, C2875T, G2946C, A3054C, C3060A, T3066C, C3116T, A3120C, G3191A, A1C, C7A, C10A, A31C, C76T, G105C, and G147C in both genotypes were significantly associated with increased risks of HCC. C2875A, G2950A, G2951A, A3054T, C3060T, T3066A, T3069G, A3120T, and G3191C were significantly associated with increased risks of HCC in genotype C, whereas these mutations were inversely associated with HCC in genotype B. Multivariate regression analyses showed that C76A/T was a novel factor independently associated with an increased risk of HCC, as compared with those without HCC. The frequencies of haplotypes 2964A-3116T-preS2 start codon wild-type-7C, 2964C-3116T-7A-76C, and 2964A-3116T-7C-76A/T were significantly higher in the patients with HCC (P<0.001), whereas a haplotypic carriage with a single mutation and another three wildtypes were inversely associated with HCC. Conclusively, the association of HBV mutations in the preS region with HCC depends on HBV genotype and haplotypic carriage with two or more mutations that are each associated with an increased risk of HCC independently.
Malaysian Journal of …
The influences of hepatitis B virus (HBV) genotypes and core promoter mutations (A 1762 G 1764 →T 1762 A 1764 ) on HBV DNA levels in HBV-infected serum were investigated. The correlations between the titers of HBV e antigen (HBeAg) and its corresponding antibody with HBV DNA levels were also studied. Seventy HBV-infected serum samples were utilized for the study. Genotyping, core promoter mutations and precore stop codon mutations were analyzed using polymerase chain reaction (PCR) and restriction fragments length polymorphism (RFLP). Serological markers were quantified using enzyme-linked immunosorbent assays. HBV DNA levels were determined with real-time PCR. Our data did not yield significant correlation between HBV DNA with the genotypes B and C (median: 1.68 x 10 7 vs. 2.98 x 10 8 copies/mL; P=0.69) as well as with the core promoter mutations (median: 3.85 x 10 5 vs. 7.02 x 10 5 copies/mL; P=0.37). No precore stop codon mutant was detected in our study. HBeAg titers were positively correlated to HBV DNA levels (R 2 =0.2549; P=0.001) but this was not observed for its corresponding antibody (R 2 =0.0034; P=0.24). Our data suggest that viral genotypes and the core promoter mutations may not have a direct influence on HBV DNA levels.
Hepatitis monthly, 2011
Chronic infection with hepatitis B virus (HBV) is the major risk factor for hepatocellular carcinoma (HCC) worldwide. Ten HBV genotypes (A-J) have been discovered so far. Genotypes B and C are endemic in East and Southeast Asia. Genotype C HBV is associated with increased risks of cirrhosis and HCC. Genotype B (B2) is associated with the development of HCC in non-cirrhotic patients younger than 50 years and with relapse of HCC after surgical treatment. It is also associated with earlier hepatitis B e antigen seroconversion than genotype C. High HBV load is independently associated with the occurrence and post-treatment recurrence of HCC. Different genotypes have distinct patterns of mutations. Viral mutations in the core promoter region and in the preS region are frequently found to be significantly associated with an increased risk of HCC. These mutations often occur before the onset of HCC and accumulate during the progression of chronic HBV infection. Multiple such mutations are ...
Hepatitis B virus preS2Δ38–55 variants: A newly identified risk factor for hepatocellular carcinoma
JHEP Reports, 2020
Background & Aims: Although HBV is a major cause of death in Africa, its genetic variability has been poorly documented. This study aimed to address whether HBV genotype and surface gene variants are associated with HBV-related liver disease in The Gambia. Methods: We conducted a case-control study nested in the Prevention of Liver Fibrosis and Cancer in Africa programme. Consecutive treatment-naive patients with chronic HBV infection and detectable viral load were recruited: 211 controls with no significant liver disease and 91 cases (56 cirrhosis and 35 HCC cases). HBV genotypes and surface gene variants were determined by Sanger sequencing or next-generation sequencing (NGS) in serum DNA. Aflatoxin B1 (AFB1)-specific codon 249 TP53 mutation was determined by NGS in circulating cell-free plasma DNA. Results: In phylogenetic analysis, 85% of individuals carried HBV genotype E, 14% genotype A, and 1% A/E recombinant viruses. Surface gene variants were more frequently observed in cases (43% and 57% in cirrhosis and HCC cases, respectively) than controls (25%; p <0.001), with preS2 deletions between nucleotides 38-55 (preS2D38-55) being the main genetic variant detected. In multivariable analysis, HBeAg seropositivity, low HBsAg levels, and HDV seropositivity were significantly associated with cirrhosis and HCC, whilst older age, higher viral load, genotype A, preS2D38-55, and AFB1 exposure were only associated with HCC. There was a multiplicative joint effect of preS2D38-55 variants with HBeAg seropositivity (odds ratio [OR] 43.1 [10.4-177.7]), high viral load >2,000 IU/ml (OR 22.7 [8.0-64.9]), HBsAg levels <10,000 IU/ml (OR 19.0 [5.5-65.3]), and AFB1 exposure (OR 29.3 [3.7-230.4]) on HCC risk. Conclusions: This study identified a hotspot for HBV preS2 deletions as a strong independent factor for HCC in The Gambia, with HBV genotypes and AFB1 exposure contributing to the high liver cancer risk.