Nucleotide changes related to hepatocellular carcinoma in the enhancer 1/x‐promoter of hepatitis B virus subgenotype C2 in cirrhotic patients

Cho, Eunyoung; Kim, Haak-Cheoul; Choi, Chang-Soo; Shin, Sae Ron; Park, Channy; So, Hong-Seob; Kim, Hyung Jin; Park, Raekil; Cho, Ji Hyun; Moon, Hyung Bae

doi:10.1111/j.1349-7006.2010.01612.x

Cited by 6 publications

(5 citation statements)

References 57 publications

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“…The role of HBV enhancer-I region/HBx promoter in HCC has been studied very infrequently, except in one study [41] and almost never in HBV genotype D. However, we observed several sequence heterogeneities in this region. Previously, the G1053A mutation at the p53 factor like binding site was shown to enhance the expression of HBx and it was correlated well with the high replication efficiency of the HBV-genotype C virus [41] . But the clinical relevance of the high prevalence of A1053G and T1050G/A mutation in HBV-genotype D and its association with HCC is not clear ( Table 3 ).…”

Section: Discussionmentioning

confidence: 61%

Novel Point and Combo-Mutations in the Genome of Hepatitis B Virus-Genotype D: Characterization and Impact on Liver Disease Progression to Hepatocellular Carcinoma

et al. 2014

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BackgroundThe contribution of chronic hepatitis B virus (HBV) infection in the pathogenesis of hepatocellular carcinoma (HCC) through progressive stages of liver fibrosis is exacerbated by the acquisition of naturally occurring mutations in its genome. This study has investigated the prevalence of single and combo mutations in the genome of HBV-genotype D from treatment naïve Indian patients of progressive liver disease stages and assessed their impact on the disease progression to HCC.MethodsThe mutation profile was determined from the sequence analysis of the full-length HBV genome and compared with the reference HBV sequences. SPSS 16.0 and R software were used to delineate their statistical significance in predicting HCC occurrence.ResultsAge was identified as associated risk factor for HCC development in chronic hepatitis B (CHB) patients (p≤0.01). Beyond the classical mutations in basal core promoter (BCP) (A1762T/G1764A) and precore (G1862T), persistence of progressively accumulated mutations in enhancer-I, surface, HBx and core were showed significant association to liver disease progression. BCP_T1753C, core_T147C, surface_L213I had contributed significantly in the disease progression to HCC (p<0.05) in HBeAg positive patients whereas precore_T1858C, core_I116L, core_P130Q and preS1_S98T in HBeAg negative patients. Furthermore, the effect of individual mutation was magnified by the combination with A1762T/G1764A in HCC pathogenesis. Multivariate risk analysis had confirmed that core_P130Q [OR 20.71, 95% CI (1.64–261.77), p = 0.019] in B cell epitope and core_T147C [OR 14.58, 95% CI (1.17–181.76), p = 0.037] in CTL epitope were two independent predictors of HCC in HBeAg positive and negative patients respectively.ConclusionsThus distinct pattern of mutations distributed across the entire HBV genome may be useful in predicting HCC in high-risk CHB patients and pattern of mutational combinations may exert greater impact on HCC risk prediction more accurately than point mutations and hence these predictors may support the existing surveillance strategies in proper management of the patients.

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Section: Discussionmentioning

confidence: 61%

Novel Point and Combo-Mutations in the Genome of Hepatitis B Virus-Genotype D: Characterization and Impact on Liver Disease Progression to Hepatocellular Carcinoma

et al. 2014

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“…Mutated nucleotides of the enhancer and X promoter, especially G1053A and G1229A mutations in the HBV subgenotype C2 of patients with cirrhosis could be risk factors for HCC; this might be due to an increase in the HBx levels through the transactivation of the enhancer/X promoter [69].…”

Section: Hbv Genotype C and Disease Outcomementioning

confidence: 99%

Is There Any Value to Hepatitis B Virus Genotype Analysis?

Tanwar

Dusheiko

2011

Curr Gastroenterol Rep

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Hepatitis B may cause a varying spectrum of diseases ranging from an asymptomatic or mild anicteric acute illness, to severe or fulminant hepatitis. Similarly, the outcome of chronic hepatitis B is variable. Viral factors associated with outcome of chronic hepatitis B virus (HBV) infection include hepatitis B e antigen status, HBV DNA, genotype, and HBV variants. HBV genotypes and subgenotypes have been associated with differences in clinical and virological characteristics, indicating that they may play a role in the virus-host relationship. A total of ten hepatitis B virus genotypes have been defined with a distinct geographical distribution. Hitherto, genotypes A, B, C and D have been studied most extensively. The HBV genotype appears to influence not only the natural history of HBV related liver disease but also the response to HBV treatment. HBV genotypes are also linked with both core promoter and BCP mutations. Progression to chronic infection appears to occur more frequently following acute infection with genotypes A and D than with the other studied genotypes. Genotypes A and B appear to have higher rates of spontaneous HBeAg seroconversion. More advanced liver disease and progression to HCC is more often seen in chronic infection with genotypes C and D in contrast to genotypes A and B. More specifically, genotypes A1, C, B2-B5 and H appear to be associated with more serious complications than genotypes A2, B1 and B6. These observations suggest important pathogenic differences between HBV genotypes. Genotypes A and B have higher response rates to interferon based therapy than genotypes C and D. Knowledge of HBV genotype enables clinicians to identify those patients at increased risk of disease progression whilst aiding the selection of appropriate antiviral therapy. Genotyping and monoclonal subtyping can provide useful information for epidemiological studies. In conclusion, genotyping of chronic HBV infections can help practicing physicians identify those at risk of disease progression and determine optimal anti-viral therapy.

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“…To validate these 60 NGS‐defined HCC‐associated HBV SNVs, a systematic literature review of 2270 potentially relevant articles was conducted, and 109 of these were assessed as being appropriate for final analysis (supplementary material, Figure S3 and Table S6). The articles discussed 167 HBV variants, which were categorized into four levels of supporting evidence that they are associated with HCC.…”

Section: Resultsmentioning

confidence: 99%

Hepatocellular carcinoma‐associated single‐nucleotide variants and deletions identified by the use of genome‐wide high‐throughput analysis of hepatitis B virus

Liu

Lee

et al. 2017

The Journal of Pathology

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This study investigated hepatitis B virus (HBV) single-nucleotide variants (SNVs) and deletion mutations linked with hepatocellular carcinoma (HCC). Ninety-three HCC patients and 108 non-HCC patients were enrolled for HBV genome-wide next-generation sequencing (NGS) analysis. A systematic literature review and a meta-analysis were performed to validate NGS-defined HCC-associated SNVs and deletions. The experimental results identified 60 NGS-defined HCC-associated SNVs, including 41 novel SNVs, and their pathogenic frequencies. Each SNV was specific for either genotype B (n = 24) or genotype C (n = 34), except for nt53C, which was present in both genotypes. The pathogenic frequencies of these HCC-associated SNVs showed a distinct U-shaped distribution pattern. According to the meta-analysis and literature review, 167 HBV variants from 109 publications were categorized into four levels (A-D) of supporting evidence that they are associated with HCC. The proportion of NGS-defined HCC-associated SNVs among these HBV variants declined significantly from 75% of 12 HCC-associated variants by meta-analysis (Level A) to 0% of 10 HCC-unassociated variants by meta-analysis (Level D) (P < 0.0001). PreS deletions were significantly associated with HCC, in terms of deletion index, for both genotypes B (P = 0.030) and C (P = 0.049). For genotype C, preS deletions involving a specific fragment (nt2977-3013) were significantly associated with HCC (HCC versus non-HCC, 6/34 versus 0/32, P = 0.025). Meta-analysis of preS deletions showed significant association with HCC (summary odds ratio 3.0; 95% confidence interval 2.3-3.9). Transfection of Huh7 cells showed that all of the five novel NGS-defined HCC-associated SNVs in the small surface region influenced hepatocarcinogenesis pathways, including endoplasmic reticulum-stress and DNA repair systems, as shown by microarray, real-time polymerase chain reaction and western blot analysis. Their carcinogenic mechanisms are worthy of further research. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Nucleotide changes related to hepatocellular carcinoma in the enhancer 1/x‐promoter of hepatitis B virus subgenotype C2 in cirrhotic patients

Cited by 6 publications

References 57 publications

Novel Point and Combo-Mutations in the Genome of Hepatitis B Virus-Genotype D: Characterization and Impact on Liver Disease Progression to Hepatocellular Carcinoma

Novel Point and Combo-Mutations in the Genome of Hepatitis B Virus-Genotype D: Characterization and Impact on Liver Disease Progression to Hepatocellular Carcinoma

Is There Any Value to Hepatitis B Virus Genotype Analysis?

Hepatocellular carcinoma‐associated single‐nucleotide variants and deletions identified by the use of genome‐wide high‐throughput analysis of hepatitis B virus

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