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He Z, Tang D. Perioperative predictors of outcome of hepatectomy for HBV-related hepatocellular carcinoma. Front Oncol 2023; 13:1230164. [PMID: 37519791 PMCID: PMC10373594 DOI: 10.3389/fonc.2023.1230164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Accepted: 06/28/2023] [Indexed: 08/01/2023] Open
Abstract
Hepatitis B virus (HBV) is identified as a major risk factor for hepatocellular carcinoma (HCC), resulting in so-called hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC). Hepatectomy for HCC is acknowledged as an efficient treatment strategy, especially for early HCC. Furthermore, patients with advanced HCC can still obtain survival benefits through surgical treatment combined with neoadjuvant therapy, adjuvant therapy, transcatheter arterial chemoembolization, and radiofrequency ablation. Therefore, preoperative and postoperative predictors of HBV-related HCC have crucial indicative functions for the follow-up treatment of patients with feasible hepatectomy. This review covers a variety of research results on preoperative and postoperative predictors of hepatectomy for HBV-related HCC over the past decade and in previous landmark studies. The relevant contents of Hepatitis C virus-related HCC, non-HBV non-HCV HCC, and the artificial intelligence application in this field are briefly addressed in the extended content. Through the integration of this review, a large number of preoperative and postoperative factors can predict the prognosis of HBV-related HCC, while most of the predictors have no standardized thresholds. According to the characteristics, detection methods, and application of predictors, the predictors can be divided into the following categories: 1. serological and hematological predictors, 2. genetic, pathological predictors, 3. imaging predictors, 4. other predictors, 5. analysis models and indexes. Similar results appear in HCV-related HCC, non-HBV non-HCV HCC. Predictions based on AI and big biological data are actively being applied. A reasonable prediction model should be established based on the economic, health, and other levels in specific countries and regions.
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Affiliation(s)
| | - Di Tang
- Department of General Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
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2
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Kumar R. Review on hepatitis B virus precore/core promoter mutations and their correlation with genotypes and liver disease severity. World J Hepatol 2022; 14:708-718. [PMID: 35646275 PMCID: PMC9099108 DOI: 10.4254/wjh.v14.i4.708] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/04/2021] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
Of 350 million people worldwide are chronically infected with hepatitis B virus (HBV) and are at risk of developing cirrhosis and hepatocellular carcinoma (HCC) later in life. HBV is the most diverse DNA virus, and its genome is composed of four open reading frames: Presurface antigen/surface antigen gene (preS/S), precore/core gene (preC/C), polymerase gene (P), and the X gene (X). HBV produces quasispecies naturally or in response to antiviral agents because of the absence of proofreading activity amid reverse transcription and a high replication rate. The virus has 10 genotypes (A to J) with different geographical distributions. There are various HBV mutations in the HBV genome, including preC/C mutations, preS/S mutations, P gene mutations, and X gene mutations. The core promoter region plays a vital part in the replication, morphogenesis and pathogenesis of the virus. The precore region also plays a crucial role in viral replication. Both core promoter and precore mutations rescue the virus from host immune surveillance and result in the formation of mutated strains that may have altered pathogenicity. preC/C mutations are associated with liver disease progression. Precore mutations stop hepatitis B e antigen (HBeAg) production and basal core promoter mutations downregulate HBeAg production. Mutations in the basal core promoter are also associated with increased HBV replication and an increased incidence of advanced liver diseases such as cirrhosis and HCC. The emergence of antiviral-resistant mutations is the main reason for treatment failure. This review focuses mainly on preC/C promoter mutations and their correlation with genotypes and liver disease severity. Thorough perception and knowledge of HBV genetic variety and mutants could be vital to discover techniques for the prognosis and control of HBV infection.
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Affiliation(s)
- Rajesh Kumar
- Department of School Education, Haryana Government, Panchkula 134109, Haryana, India
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3
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Jeong H, Kim DH, Choi YM, Choi H, Kim D, Kim BJ. rt269I Type of Hepatitis B Virus (HBV) Polymerase versus rt269L Is More Prone to Mutations within HBV Genome in Chronic Patients Infected with Genotype C2: Evidence from Analysis of Full HBV Genotype C2 Genome. Microorganisms 2021; 9:601. [PMID: 33803998 PMCID: PMC7999911 DOI: 10.3390/microorganisms9030601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/08/2021] [Accepted: 03/10/2021] [Indexed: 12/03/2022] Open
Abstract
Recently, it has been reported that the rt269I type of hepatitis B virus (HBV) polymerase (Pol) versus the rt269L type is more significantly related to lower viral replication and HBeAg negative infections in chronic hepatitis B (CHB) patients of genotype C2. In this study, we compared mutation rates within HBV genomes between rt269L and rt269I using a total of 234 HBV genotype C2 full genome sequences randomly selected from the HBV database (115 of rt269L and 119 of rt269I type). When we applied the Benjamini and Hochberg procedure for multiple comparisons, two parameters, dN and d, at the amino acids level in the Pol region were significantly higher in the rt269I type than in the rt269L type. Although it could not reach statistical significance from the Benjamini and Hochberg procedure, nonsynonymous (NS) mutations in the major hydrophilic region (MHR) or "a" determinant in the surface antigens (HBsAg ORF) related to host immune escape or vaccine escape are more frequently generated in rt269I strains than in rt269L. We also found that there are a total of 19 signature single nucleotide polymorphisms (SNPs), of which 2 and 17 nonsynonymous mutation types were specific to rt269L and rt269I, respectively: Of these, most are HBeAg negative infections (preC-W28*, X-V5M and V131I), lowered HBV DNA or virion production (C-I97F/L, rtM204I/V) or preexisting nucleot(s)ide analog resistance (NAr) (rtN139K/H, rtM204I/V and rtI224V) or disease severity (preC-W28*, C-I97F/L, C-Q182K/*, preS2-F141L, S-L213I/S, V/L5M, T36P/S/A, V131I, rtN139K/H, rtM204I/V and rtI224V). In conclusion, our data showed that rt269I types versus rt269L types are more prone to overall genome mutations, particularly in the Pol region and in the MHR or "a" determinant in genotype C2 infections and are more prevalent in signature NS mutations related to lowered HBV DNA replication, HBsAg and HBeAg secretion and potential NAr variants and hepatocellular carcinoma (HCC), possibly via type I interferon (IFN-I)-mediated enhanced inflammation. Our data suggest that rt269L types could contribute to liver disease progression via the generation of immune escape or enhanced persistent infection in chronic patients of genotype C2.
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Affiliation(s)
- Hyein Jeong
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Institute, College of Medicine, Seoul National University, Seoul 03080, Korea; (H.J.); (D.H.K.); (Y.-M.C.)
| | - Dong Hyun Kim
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Institute, College of Medicine, Seoul National University, Seoul 03080, Korea; (H.J.); (D.H.K.); (Y.-M.C.)
| | - Yu-Min Choi
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Institute, College of Medicine, Seoul National University, Seoul 03080, Korea; (H.J.); (D.H.K.); (Y.-M.C.)
| | - HyeLim Choi
- Department of Biomedical Sciences, and Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 03080, Korea; (H.C.); (D.K.)
| | - Donghyun Kim
- Department of Biomedical Sciences, and Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 03080, Korea; (H.C.); (D.K.)
| | - Bum-Joon Kim
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Institute, College of Medicine, Seoul National University, Seoul 03080, Korea; (H.J.); (D.H.K.); (Y.-M.C.)
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4
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In silico Analysis of Genetic Diversity of Human Hepatitis B Virus in Southeast Asia, Australia and New Zealand. Viruses 2020; 12:v12040427. [PMID: 32283837 PMCID: PMC7232418 DOI: 10.3390/v12040427] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 04/06/2020] [Accepted: 04/08/2020] [Indexed: 02/08/2023] Open
Abstract
The extent of whole genome diversity amongst hepatitis B virus (HBV) genotypes is not well described. This study aimed to update the current distribution of HBV types and to investigate mutation rates and nucleotide diversity between genotypes in Southeast Asia, Australia and New Zealand. We retrieved 930 human HBV complete genomes from these regions from the NCBI nucleotide database for genotyping, detection of potential recombination, serotype prediction, mutation identification and comparative genome analyses. Overall, HBV genotypes B (44.1%) and C (46.2%) together with predicted serotypes adr (36%), adw2 (29%) and ayw1 (19.9%) were the most commonly circulating HBV types in the studied region. The three HBV variants identified most frequently were p.V5L, c.1896G>A and double mutation c.1762A>T/c.1764G>A, while genotypes B and C had the widest range of mutation types. The study also highlighted the distinct nucleotide diversity of HBV genotypes for whole genome and along the genome length. Therefore, this study provided a robust update to HBV currently circulating in Southeast Asia, Australia and New Zealand as well as an insight into the association of HBV genetic hypervariability and prevalence of well reported mutations.
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CDK1, CCNB1, CDC20, BUB1, MAD2L1, MCM3, BUB1B, MCM2, and RFC4 May Be Potential Therapeutic Targets for Hepatocellular Carcinoma Using Integrated Bioinformatic Analysis. BIOMED RESEARCH INTERNATIONAL 2019; 2019:1245072. [PMID: 31737652 PMCID: PMC6815605 DOI: 10.1155/2019/1245072] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 07/07/2019] [Accepted: 08/01/2019] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is a malignant tumor with high mortality. The abnormal expression of genes is significantly related to the occurrence of HCC. The aim of this study was to explore the differentially expressed genes (DEGs) of HCC and to provide bioinformatics basis for the occurrence, prevention and treatment of HCC. The DEGs of HCC and normal tissues in GSE102079, GSE121248, GSE84402 and GSE60502 were obtained using R language. The GO function analysis and KEGG pathway enrichment analysis of DEGs were carried out using the DAVID database. Then, the protein–protein interaction (PPI) network was constructed using the STRING database. Hub genes were screened using Cytoscape software and verified using the GEPIA, UALCAN, and Oncomine database. We used HPA database to exhibit the differences in protein level of hub genes and used LinkedOmics to reveal the relationship between candidate genes and tumor clinical features. Finally, we obtained transcription factor (TF) of hub genes using NetworkAnalyst online tool. A total of 591 overlapping up-regulated genes were identified. These genes were related to cell cycle, DNA replication, pyrimidine metabolism, and p53 signaling pathway. Additionally, the GEPIA database showed that the CDK1, CCNB1, CDC20, BUB1, MAD2L1, MCM3, BUB1B, MCM2, and RFC4 were associated with the poor survival of HCC patients. UALCAN, Oncomine, and HPA databases and qRT-PCR confirmed that these genes were highly expressed in HCC tissues. LinkedOmics database indicated these genes were correlated with overall survival, pathologic stage, pathology T stage, race, and the age of onset. TF analysis showed that MYBL2, KDM5B, MYC, SOX2, and E2F4 were regulators to these nine hub genes. Overexpression of CDK1, CCNB1, CDC20, BUB1, MAD2L1, MCM3, BUB1B, MCM2, and RFC4 in tumor tissues predicted poor survival in HCC. They may be potential therapeutic targets for HCC.
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6
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Ge Z, Tian T, Meng L, Song C, Yu C, Xu X, Liu J, Dai J, Hu Z. HBV mutations in EnhII/BCP/PC region contribute to the prognosis of hepatocellular carcinoma. Cancer Med 2019; 8:3086-3093. [PMID: 31033235 PMCID: PMC6558498 DOI: 10.1002/cam4.2169] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 03/29/2019] [Accepted: 03/29/2019] [Indexed: 12/14/2022] Open
Abstract
Background Accompanied by HBV infection, HBV mutations gradually occur because HBV polymerase appears proofread deficiencies. In our previous study, we have identified that EnhII/BCP/PC mutations and genotype C of HBV DNA were associated with hepatocellular carcinoma (HCC) risk. In this study, we extend our research to explore HCC prognosis associated genotype and mutations in EnhII/BCP/PC regions. Methods We designed a case‐cohort study of 331 HCC patients to evaluate the effects of the HBV genotypes and mutations on HCC survival. Log‐rank test and Cox proportional hazard models were used for the analyses. Results Results showed that genotype C, which was more frequent in HBV‐related HCC (77.4%), presented a negative signal with HCC survival. Interestingly, we detected a significant association between EnhII/BCP/PC mutation nt1753 and HCC prognosis (Log‐rank P = 0.034). Subgroup analysis revealed that this risk effect was more pronounced in non‐B genotype (P = 0.090 for heterogeneity test). We also detected a borderline multiplicative interaction between genotypes of nt1753 and HBV genotype on HCC survival (P for interaction = 0.069). Conclusions These findings indicated that, in Chinese population, nt1753 in EnhII/BCP/PC region might be a novel marker for HCC prognosis.
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Affiliation(s)
- Zijun Ge
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Ting Tian
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Lijuan Meng
- Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Ci Song
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Chengxiao Yu
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Xin Xu
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Jibin Liu
- Department of Hepatobiliary Surgery, Nantong Tumor Hospital, Nantong, China
| | - Juncheng Dai
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Zhibin Hu
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.,Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China
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7
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Al-Qahtani AA, Al-Anazi MR, Nazir N, Abdo AA, Sanai FM, Al-Hamoudi WK, Alswat KA, Al-Ashgar HI, Khan MQ, Albenmousa A, El-Shamy A, Alanazi SK, Dela Cruz D, Bohol MFF, Al-Ahdal MN. The Correlation Between Hepatitis B Virus Precore/Core Mutations and the Progression of Severe Liver Disease. Front Cell Infect Microbiol 2018; 8:355. [PMID: 30406036 PMCID: PMC6204459 DOI: 10.3389/fcimb.2018.00355] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Accepted: 09/18/2018] [Indexed: 12/13/2022] Open
Abstract
Viral mutations acquired during the course of chronic hepatitis B virus (HBV) infection are known to be associated with the progression and severity of HBV-related liver disease. This study of HBV-infected Saudi Arabian patients aimed to identify amino acid substitutions within the precore/core (preC/C) region of HBV, and investigate their impact on disease progression toward hepatocellular carcinoma (HCC). Patients were categorized according to the severity of their disease, and were divided into the following groups: inactive HBV carriers, active HBV carriers, liver cirrhosis patients, and HCC patients. Two precore mutations, W28* and G29D, and six core mutations, F24Y, E64D, E77Q, A80I/T/V, L116I, and E180A were significantly associated with the development of cirrhosis and HCC. Six of the seven significant core mutations that were identified in this study were located within immuno-active epitopes; E77Q, A80I/T/V, and L116I were located within B-cell epitopes, and F24Y, E64D, and V91S/T were located within T-cell epitopes. Multivariate risk analysis confirmed that the core mutations A80V and L116I were both independent predictors of HBV-associated liver disease progression. In conclusion, our data show that mutations within the preC/C region, particularly within the immuno-active epitopes, may contribute to the severity of liver disease in patients with chronic hepatitis. Furthermore, we have identified several distinct preC/C mutations within the study population that affect the clinical manifestation and progression of HBV-related disease. The specific identity of HBV mutations that are associated with severe disease varies between different ethnic populations, and so the specific preC/C mutations identified here will be useful for predicting clinical outcomes and identifying the HBV-infected patients within the Saudi population that are at high risk of developing HCC.
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Affiliation(s)
- Ahmed A Al-Qahtani
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,Department of Microbiology and Immunology, Alfaisal University School of Medicine, Riyadh, Saudi Arabia
| | - Mashael R Al-Anazi
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Nyla Nazir
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Ayman A Abdo
- Section of Gastroenterology, Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,Liver Disease Research Center, King Saud University, Riyadh, Saudi Arabia
| | - Faisal M Sanai
- Liver Disease Research Center, King Saud University, Riyadh, Saudi Arabia.,Gastroenterology Unit, Department of Medicine, King Abdulaziz Medical City, Jeddah, Saudi Arabia
| | - Waleed K Al-Hamoudi
- Section of Gastroenterology, Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,Liver Disease Research Center, King Saud University, Riyadh, Saudi Arabia
| | - Khalid A Alswat
- Section of Gastroenterology, Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,Liver Disease Research Center, King Saud University, Riyadh, Saudi Arabia
| | - Hamad I Al-Ashgar
- Gastroenterology Unit, Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Mohammed Q Khan
- Gastroenterology Unit, Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Ali Albenmousa
- Department of Gastroenterology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Ahmed El-Shamy
- Department of Pharmaceutical and Biomedical Sciences, California Northstate University, Elk Grove, CA, United States
| | - Salah K Alanazi
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Damian Dela Cruz
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Marie Fe F Bohol
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Mohammed N Al-Ahdal
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,Department of Microbiology and Immunology, Alfaisal University School of Medicine, Riyadh, Saudi Arabia
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8
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Zhang Y, Huang J, Chen J, Yang K, Chen J, Xu L, Zhou Z, Chen M. The mutation of hepatitis B virus and the prognosis of hepatocellular carcinoma after surgery: a pilot study. Cancer Manag Res 2018; 10:599-611. [PMID: 29628773 PMCID: PMC5877868 DOI: 10.2147/cmar.s160047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background Although hepatitis B virus (HBV) is still one of the most common etiological factors for hepatocellular carcinoma (HCC), the association between the HBV mutations and the clinical characteristics and prognosis of HBV-related HCC patients (HBV-HCC) after surgical resection remains largely unknown. Materials and methods A cohort of 131 consecutive patients who received hepatectomy for HBV-HCC were retrospectively enrolled. The HBV genotype and 14 genomic mutations, which have been reported to relate to HCC in liver samples, were sequenced. The associations between the genomic mutations and clinical characteristics and outcomes were analyzed. Results Both A1762T/G1764A mutation and Pre S deletion related to worse overall survival (OS, p=0.040 and p<0.001, respectively) and disease-free survival (DFS, p=0.040 and p<0.001, respectively), G1899A mutation related to worse OS (p=0.030), A1762T/G1764A mutation correlated with tumor size (r=0.204, p=0.019), G1899A mutation correlated with vascular invasion (r=0.332, p<0.001), and Pre S deletion correlated with alpha-fetoprotein (AFP; r=0.254, p=0.003) positively. Multivariate analysis with Cox proportional hazards model revealed that both A1762T/G1764A mutation and Pre S deletion were independent prognostic factors for OS (hazard ratio [HR]=3.701, 95% CI=1.390–9.855, p=0.009, and HR=4.816, 95% CI=2.311–10.032, p<0.001, respectively) and DFS (HR=3.245, 95% CI=1.400–7.521, p=0.006, and HR=2.437, 95% CI=1.311–4.530, p<0.001, respectively), and patients with dual mutations were found to have the worst OS and DFS (p<0.001 and p<0.001, respectively). Patients with A1762T/G1764A mutation or Pre S deletion were more likely to have early recurrence (p=0.042 and p=0.019, respectively). Conclusion HBV DNA genomic mutations in A1762T/G1764A and Pre S deletion were associated with worse prognoses and early recurrence for HBV-HCC patients after surgery.
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Affiliation(s)
- Yaojun Zhang
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Junting Huang
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Jinbin Chen
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Keli Yang
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Jiancong Chen
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Li Xu
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Zhongguo Zhou
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Minshan Chen
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
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9
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Yin F, Xie Y, Fan H, Zhang J, Guo Z. Mutations in hepatitis B virus polymerase are associated with the postoperative survival of hepatocellular carcinoma patients. PLoS One 2017; 12:e0189730. [PMID: 29287068 PMCID: PMC5747429 DOI: 10.1371/journal.pone.0189730] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2017] [Accepted: 11/30/2017] [Indexed: 12/15/2022] Open
Abstract
Proofreading deficiencies of hepatitis B virus polymerase result in frequent DNA mutations in the hepatitis B virus genome. Here, we performed sequencing analysis of the hepatitis B virus polymerase gene to assess its association with the postoperative survival in 92 patients with HBV-related hepatocellular carcinoma by using the Kaplan–Meier method. The 2525, 2733, 2738, 2768, 2946, 3063, 3066, 3109, 31, 529, 735, 939, 1078, 1137, 1383, 1461, 1485, 1544, and 1613 mutation sites were identified as being associated with HCC outcomes by the log-rank test. After adjusting for clinical characteristics by using the Cox hazard model, site 31 (relative risk, 8.929; 95% confidence interval, 3.433–23.22; P = 0.000) in the spacer domain and sites 529 (relative risk, 5.656; 95% confidence interval, 1.599–19.999; P = 0.007) and 1078 (relative risk, 3.442; 95% confidence interval, 1.070–11.068; P = 0.038) in the reverse transcriptase domain of hepatitis B virus polymerase were identified as independent predictors of postoperative survival in hepatitis B virus related hepatocellular carcinoma. The mutations at the 31 (Ser314Pro), 529 (Asp480Asn), and 1078 (Ser663Ala) sites all resulted in amino acid changes in hepatitis B virus polymerase and were associated with shortened life-span. The 31 and 529 sites were located in the overlapping region for the PreS and S genes but did not induce amino acid substitution in these two regions. Our finding of the correlation between hepatitis B virus DNA polymerase mutations and hepatocellular carcinoma survival will help identify the patients subgroup with poor prognosis, and help the clinicians to refine the therapeutic decision individualized.
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Affiliation(s)
- Fei Yin
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Ying Xie
- Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, Shijiazhuang, P.R. China
| | - Haiyan Fan
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Jingjing Zhang
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Zhanjun Guo
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China
- * E-mail:
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Khemlina G, Ikeda S, Kurzrock R. The biology of Hepatocellular carcinoma: implications for genomic and immune therapies. Mol Cancer 2017; 16:149. [PMID: 28854942 PMCID: PMC5577674 DOI: 10.1186/s12943-017-0712-x] [Citation(s) in RCA: 310] [Impact Index Per Article: 38.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 08/15/2017] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is a leading cause of cancer-related death worldwide. It is highly refractory to most systemic therapies. Recently, significant progress has been made in uncovering genomic alterations in HCC, including potentially targetable aberrations. The most common molecular anomalies in this malignancy are mutations in the TERT promoter, TP53, CTNNB1, AXIN1, ARID1A, CDKN2A and CCND1 genes. PTEN loss at the protein level is also frequent. Genomic portfolios stratify by risk factors as follows: (i) CTNNB1 with alcoholic cirrhosis; and (ii) TP53 with hepatitis B virus-induced cirrhosis. Activating mutations in CTNNB1 and inactivating mutations in AXIN1 both activate WNT signaling. Alterations in this pathway, as well as in TP53 and the cell cycle machinery, and in the PI3K/Akt/mTor axis (the latter activated in the presence of PTEN loss), as well as aberrant angiogenesis and epigenetic anomalies, appear to be major events in HCC. Many of these abnormalities may be pharmacologically tractable. Immunotherapy with checkpoint inhibitors is also emerging as an important treatment option. Indeed, 82% of patients express PD-L1 (immunohistochemistry) and response rates to anti-PD-1 treatment are about 19%, and include about 5% complete remissions as well as durable benefit in some patients. Biomarker-matched trials are still limited in this disease, and many of the genomic alterations in HCC remain challenging to target. Future studies may require combination regimens that include both immunotherapies and molecularly matched targeted treatments.
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Affiliation(s)
- Galina Khemlina
- Department of Geriatrics, University of California, UC San Diego, 9500 Gilman Drive, #9111, La Jolla, CA, 92093-9111, USA. .,Kaiser Permanente Southern California, San Diego, USA.
| | - Sadakatsu Ikeda
- Department of Medicine, Division of Hematology/Oncology, and Center for Personalized Cancer Therapy, University of California, Moores Cancer Center, San Diego, USA.,Tokyo Medical and Dental University, Tokyo, Japan
| | - Razelle Kurzrock
- Department of Medicine, Division of Hematology/Oncology, and Center for Personalized Cancer Therapy, University of California, Moores Cancer Center, San Diego, USA
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11
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Almeida RWD, Mello FCDA, Menegoy IV, Santo MPDE, Ginuíno CF, Sousa PSFD, Villar LM, Lampe E, Lewis-Ximenez LL. Detection and molecular characterisation of a diagnosis escape variant associated with occult hepatitis B virus in Brazil. Mem Inst Oswaldo Cruz 2017; 112:485-491. [PMID: 28591309 PMCID: PMC5452485 DOI: 10.1590/0074-02760160477] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 03/21/2017] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Many studies have identified mutations in the hepatitis B surface antigen (HBsAg) as important factors limiting the ability of commercial serological assays to detect this viral antigen. However, an association between mutations in the HBsAg gene and the occurrence of occult HBV infection (OBI) in patients has not been established. OBJECTIVES To detect hepatitis B virus (HBV) DNA in patients with anti-HBc as a unique serological marker, a previously published, cost-effective TaqMan-based real-time polymerase chain reaction (PCR) test with minor groove binding probes was adapted for use in this study. The current study also aimed to investigate HBsAg mutations and genotypes of HBV in OBI at the Viral Hepatitis Ambulatory Clinic in Rio de Janeiro to determine any possible association. METHODS Intra-assay and inter-assay reproducibility were determined, and the mean coefficient of variation values obtained were 2.07 and 3.5, respectively. Probit analysis indicated that the 95% detection level was 25 IU/mL. The prevalence of OBI was investigated in 35 serum samples with an ‘anti-HBc alone’ profile from individuals who attended our clinic between 2011 and 2013. FINDINGS HBV DNA was detected in only one sample, resulting in an OBI rate of 2.9%. Nucleotide sequencing of the pre-S/S region was performed to genotype and analyse mutations within the HBsAg gene of this HBV DNA. The HBV in the OBI case was classified as sub-genotype A1, and a sequence analysis of the small S gene revealed 12 mutations in the major hydrophilic region compared to the consensus A1 sequence. Most of these mutations occurred in amino acid residues that have been reported as clinically relevant because they have been implicated in vaccine escape and/or inability to detect HBsAg by commercial serological assays. MAIN CONCLUSIONS Our study suggests the importance of specific HBsAg mutations, different from those in D, B, and C genotypes, in sub-genotype A1 HBV associated with OBI.
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Affiliation(s)
- Ricardo Wagner de Almeida
- Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Hepatites Virais, Rio de Janeiro, RJ, Brasil
| | | | - Isabelle Vasconcelos Menegoy
- Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Hepatites Virais, Rio de Janeiro, RJ, Brasil
| | | | - Cléber Ferreira Ginuíno
- Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Hepatites Virais, Rio de Janeiro, RJ, Brasil
| | | | - Livia Melo Villar
- Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Hepatites Virais, Rio de Janeiro, RJ, Brasil
| | - Elisabeth Lampe
- Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Hepatites Virais, Rio de Janeiro, RJ, Brasil
| | - Lia Laura Lewis-Ximenez
- Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Hepatites Virais, Rio de Janeiro, RJ, Brasil
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12
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Jia J, Li H, Wang H, Chen S, Wang M, Feng H, Gao Y, Wang Y, Fang M, Gao C. Hepatitis B virus core antigen mutations predict post-operative prognosis of patients with primary hepatocellular carcinoma. J Gen Virol 2017; 98:1399-1409. [PMID: 28640739 PMCID: PMC5656792 DOI: 10.1099/jgv.0.000790] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 03/26/2017] [Indexed: 12/11/2022] Open
Abstract
The aim of this study was to explore the relationship between hepatitis B virus (HBV) core antigen (HBc) mutations and the post-operative prognosis of HBV-related hepatocellular carcinoma (HCC). In total, 98 patients suffering from HBV-related HCC and treated with surgery were enrolled, with a 48 month follow-up. The preCore/Core region of the HBV genome from tumour tissue (TT) and paired adjacent non-tumour tissue (ANTT) of these patients was sequenced, and a phylogenetic tree was reconstructed. The correlations between the viral features and evolutionary divergence of preCore/Core amino acid sequences from 67 paired TTs and ANTTs were analysed. Cox proportional hazard model analysis was applied for post-operative hazard risk evaluation. Phylogenetic analysis revealed that all of the sequences were ascribed to genotype C. The evolutionary divergence of amino acid sequences from matched TTs and ANTTs was significantly negatively correlated with serum and intrahepatic HBV DNA levels. Multivariate analysis showed that the HBc E77 mutation was associated with shorter overall survival, and HBc S87 and P156 mutations were independent risk factors for relapse. Furthermore, in contrast to with patients without the S87 mutation, no correlation was observed between serum HBV DNA and intrahepatic HBV DNA in HCC patients with the S87 mutation. Analysis of the intrahepatic sequence may advance our understanding of viral status; thus, it is useful for prognosis prediction for HBV-related HCC.
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Affiliation(s)
- Jian’an Jia
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China
- Department of Laboratory Medicine, 105th Hospital of PLA, Hefei 230031, PR China
| | - Huiming Li
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China
| | - Hui Wang
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China
- Department of Clinical Laboratory, First Affiliated Hospital of Chinese PLA’s General Hospital, Beijing 100048, PR China
| | - Shipeng Chen
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China
| | - Mengmeng Wang
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China
| | - Huijuan Feng
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China
| | - Yuzhen Gao
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China
| | - Yunjiu Wang
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China
| | - Meng Fang
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China
| | - Chunfang Gao
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China
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13
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Peng L, Yang G, Wu C, Wang W, Wu J, Guo Z. Mutations in hepatitis B virus small S genes predict postoperative survival in hepatocellular carcinoma. Onco Targets Ther 2016; 9:7367-7372. [PMID: 27980426 PMCID: PMC5144890 DOI: 10.2147/ott.s121785] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Hepatitis B virus (HBV) DNA is prone to mutations due to proofreading deficiencies of HBV polymerase. We have previously identified hepatocellular carcinoma (HCC) survival-associated HBV mutations in the X, precore, and core regions. In the present study, we extended our research to assess HCC survival-associated HBV mutations in the small S gene of HBV genome in 115 HCC patients including 60 patients with HBV B genotype, 52 patients with HBV C genotype, and 3 patients with other genotypes. The overfrequencies of mutations at nucleotides 529 and 735 are 8.5% and 91.5%, respectively, but the distribution frequencies of these mutations are not different between HBV genotypes B and C. Mutational sites 529 (relative risk: 3.611, 95% confidence interval [CI]: 1.414-9.221, P=0.007) and 735 (relative risk: 1.905, 95% CI: 1.101-3.297, P=0.021) were identified as statistically significant independent predictors for HCC survival by multivariate survival analysis using a Cox proportional hazards model. Moreover, the mutated 529A and 735T were associated with both short survival time and high HBV DNA load score in HCC patients. The analysis of DNA mutations in the HBV S gene may help identify HCC subgroups with poor prognosis and may provide reference for therapeutic decisions.
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Affiliation(s)
- Li Peng
- Department of Hepatobiliary Surgery
| | | | - Chensi Wu
- Department of Gastroenterology and Hepatology
| | | | - Jianhua Wu
- Animal Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Zhanjun Guo
- Department of Gastroenterology and Hepatology
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14
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Chen L, Gu L, Gu Y, Wang H, Deng M, Stamataki Z, Oo YH, Huang Y. HBV core promoter mutations and AKT upregulate S-phase kinase-associated protein 2 to promote postoperative hepatocellular carcinoma progression. Sci Rep 2016; 6:35917. [PMID: 27779207 PMCID: PMC5078796 DOI: 10.1038/srep35917] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 10/05/2016] [Indexed: 12/31/2022] Open
Abstract
Mutations in the hepatitis B virus (HBV) core promoter (CP) have been shown to be associated with hepatocellular carcinoma (HCC). The CP region overlaps HBV X gene, which activates AKT to regulate hepatocyte survival. However, the cooperation between these two cascades in HCC progression remains poorly understood. Here, we assayed virological factors and AKT expression in liver tissues from 56 HCC patients with better prognoses (BHCC, ≥5-year survival) and 58 with poor prognoses (PHCC, <5-year survival) after partial liver resection. Results showed double mutation A1762T/G1764A (TA) combined with other mutation(s) (TACO) in HBV genome and phosphorylated AKT (pAKT) were more common in PHCC than BHCC. TACO and pAKT levels correlated with proliferation and microvascularization but inversely correlated with apoptosis in HCC samples. These were more pronounced when TACO and pAKT co-expressed. Levels of p21 and p27 were decreased in TACO or pAKT overexpressing HCC due to SKP2 upregulation. Levels of E2F1 and both mRNA and protein of SKP2 were increased in TACO expressing HCC. Levels of 4EBP1/2 decreased and SKP2 mRNA level remained constant in pAKT-overexpressing HCC. Therefore, TACO and AKT are two independent predictors of postoperative survival in HCC. Their co-target, SKP2 may be a diagnostic or therapeutic marker.
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Affiliation(s)
- Lubiao Chen
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Lin Gu
- Guangdong Provincial Key Laboratory of Liver Diseases Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yurong Gu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hongbo Wang
- Guangdong Provincial Key Laboratory of Liver Diseases Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Meihai Deng
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zania Stamataki
- Institute of Biomedical Research and NIHR Center for Liver Disease, University of Birmingham, Birmingham, United Kingdom
| | - Ye Htun Oo
- Institute of Biomedical Research and NIHR Center for Liver Disease, University of Birmingham, Birmingham, United Kingdom
| | - Yuehua Huang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Liver Diseases Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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15
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Kim H, Lee SA, Do SY, Kim BJ. Precore/core region mutations of hepatitis B virus related to clinical severity. World J Gastroenterol 2016; 22:4287-4296. [PMID: 27158197 PMCID: PMC4853686 DOI: 10.3748/wjg.v22.i17.4287] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 03/10/2016] [Accepted: 04/07/2016] [Indexed: 02/06/2023] Open
Abstract
Despite the availability of an effective vaccine, hepatitis B virus (HBV) infection remains a major health problem, with more than 350 million chronically infected people worldwide and over 1 million annual deaths due to cirrhosis and liver cancer. HBV mutations are primarily generated due both to a lack of proofreading capacity by HBV polymerase and to host immune pressure, which is a very important factor for predicting disease progression and therapeutic outcomes. Several types of HBV precore/core (preC/C) mutations have been described to date. The host immune response against T cells drives mutation in the preC/C region. Specifically, preC/C mutations in the MHC class II restricted region are more common than in other regions and are significantly related to hepatocellular carcinoma. Certain mutations, including preC G1896A, are also significantly related to HBeAg-negative chronic infection. This review article mainly focuses on the HBV preC/C mutations that are related to disease severity and on the HBeAg serostatus of chronically infected patients.
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