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Hepatitis B virus (HBV) infection has been reported to be associated with non-Hodgkin lymphoma (NHL). However, the evidence is limited to the seroepidemiological study. There is a lack of evidence showing the HBV infection and integration in NHL cells. Here, we reported that in the Shanghai area, the positive rates of serum HBsAg (OR: 3.11; 95% CI: 2.20-4.41) and HBeAg (OR: 3.99; 95% CI: 1.73-9.91) were significantly higher in patients with NHL. HBsAg, HBcAg and HBV DNA were detected in 34.4%, 45.2% and 47.0% of the NHL tissues, respectively. Furthermore, by using a high-throughput viral integration detection approach (HIVID), integrated HBV DNA was identified from 50% (6/12) HBV-related NHL tissues. There were a total of 313 HBV integration sites isolated from the NHL tissues, among which four protein-coding genes (FAT2, SETX, ITGA10 and CD63) were interrupted by HBV DNA in their exons. Seven HBV preferential target genes (ANKS1B, HDAC4, EGFLAM, MAN1C1, XKR6, ZBTB38 and CCDC91) showed significantly altered expression levels in NHL, suggesting a potential role of these genes in NHL development. Taken together, HBV integration is a common phenomenon in NHL. This finding opens up a new direction of research into the mechanistic link between HBV infection and NHL., (© 2020 UICC.)

Most patients with hepatitis B virus (HBV) have no symptoms, and many are unaware of the infection. However, HBV can reactivate with immunosuppression; chemotherapy causes reactivation in 22 % of hepatitis B surface antigen-positive patients. HBV reactivation can be fatal. HBV reactivation can be prevented, provided that HBV is recognized prior to chemotherapy. The objective of this study is to estimate the health and economic effects of HBV screening strategies in patients receiving adjuvant chemotherapy for breast cancer. We developed a state-transition microsimulation model to examine the cost-effectiveness of three HBV screening strategies: (1) "No screening"; (2) "Screen-and-Treat to prevent reactivation" (screen-all) with either lamivudine/tenofovir (LAM/TDF) or entecavir (ETV); and (3) "Screen-and-Treat high-risk only" (screen-HR) and treat with either LAM/TDF or ETV. Model data were obtained from the published literature. We used a payer's perspective, a lifetime horizon, and a 5 % discount rate for the analysis. "Screen-all" would prevent at least 38 severe reactivations per 100,000 persons screened over the lifetime of the cohort. "Screen-all" was associated with an increase of 0.0034-0.0035 QALYs and an additional cost of C$164-C$266 per person, which translated into an incremental cost-effectiveness ratio of C$47,808/QALY-C$76,527/QALY gained compared with "No screening" depending on the antiviral therapy received. "Screen-all" was the most cost-effective strategy, while "Screen-HR" was inferior in all scenarios tested. HBV screening before adjuvant chemotherapy for breast cancer patients would prevent a significant number of reactivations, would likely be moderately cost-effective, and may extend the lives of breast cancer patients.

Background/aim: Hepatitis B Virus (HBV) mutations play a role in the development of hepatocellular carcinoma (HCC). However, the association between HBV polymerase gene mutations and HCC has not been reported. In this study, we conducted a multi-stage study to identify HCC-related mutations in the reverse transcriptase (RT) domain of the HBV polymerase gene., Methods: A total of 231 HCCs and 237 non-HCC controls from Qidong, China, were included in this study. The entire sequence of HBV RT was first compared between 29 HCC and 35 non-HCC cases, and candidate mutations were then evaluated in two independent validation sets., Results: There were 15 candidate mutations identified from the discovery set, with A799G and T1055A being consistently associated with HCC across all studies. A pooled analysis of samples revealed that A799G, A987G, and T1055A were independent risk factors for HCC, with adjusted odds ratios of 5.53 [95% confidence interval (CI), 1.69-18.10], 4.20 (95%CI, 1.15-15.35), and 3.78 (95%CI, 1.45-9.86), respectively. A longitudinal study showed that these mutations were detectable 4-5 years prior to HCC diagnosis., Conclusions: Our study provides evidence the first that HBV RT contains naturally occurring mutations that can be used as predictive markers for HCC.

Increasing evidence suggests that a link exists between hepatitis B virus (HBV) serum markers and pancreatic cancer (PC). In this study, HBsAg and HBcAg were expressed in 21.0% (34/162) of PC and 29.0% (47/162) of non-tumor pancreatic tissues, and they were significantly associated with chronic pancreatitis (P=0.000). The HBV S, C and X genes were identified in 20% (6/30) of PC and 26.9% (7/26) of non-tumor tissues by PCR. A serological survey revealed that the prevalence of HBV DNA and anti-HBc was significantly increased in PC patients compared with healthy controls. Our data suggest that HBV infection in the pancreas may play an etiologic role in PC., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objectives: To characterize the mutation pattern of a hepatitis B virus (HBV) core protein (HBcAg) derived from hepatocellular carcinoma (HCC) and adjacent nontumor tissues., Methods: HBV core gene fragments (nt. 1901-2365) were amplified from 98 HBV-related HCC tissues and 33 adjacent nontumor tissues. The deduced amino acids (AAs) of the core gene were aligned with the prototype sequences of HBV genotypes B and C., Results: In total, there were 54 positions that showed polymorphism at the deduced AA level. The mutations were predominantly located in three major (codons 83-87, 95-104 and 130-135) and three minor (codons 21-38, 59-63 and 151-155) mutation-clustering regions (MCRs). The substitution rate in MCRs was significantly higher than in mutation-devoid regions (p < 0.001). The most frequently occurring mutations in rank were codon P130T (38.8%), I97L (37.8%) and S87G (23.5%). In addition, there were 7 patients that showed internal deletions in the middle of HBcAg with sizes ranging from 34 to 59 AAs. Unexpectedly, the core genes isolated from tumor tissues had fewer mutations compared with those isolated from adjacent nontumor tissues from the same patients (p < 0.05)., Conclusions: Accumulation of naturally occurring mutations in certain restricted segments of HBcAg may be related to the development of HCC., (Copyright © 2011 S. Karger AG, Basel.)

Background: Mutations in the hepatitis B virus (HBV) genome may influence the activity of liver disease. The aim of this study was to identify new viral variations associated with hepatocellular carcinoma (HCC)., Methods: We carried out a comparison study on the complete sequence of HBV isolated from 20 HCC and 35 non-HCC patients in Qidong, China, an area with a high incidence of HCC. We compared the HBV sequences in a consecutive series of plasma samples from four HCC cases before and after the occurrence of HCC. In addition, we selected four mutations in the HBV core (C) gene to verify their relationships to HCC in an independent set of 103 HCC cases and 103 sex- and age-matched non-HCC controls., Results: The pre-S deletion and 12 point mutations, namely, the pre-S2 start codon mutation, T53C in the pre-S2 gene, T766A in the S gene, G1613A, C1653T, A1762T, G1764A in the X gene, and G1899A, C2002T, A2159G, A2189C, and G2203W (A or T) in the pre-C/C gene, showed close associations with HCC. In the validation study, A2159G, A2189C, and G2203W showed consistent associations with HCC by univariate analysis. Multivariate analysis showed that A2189C and G2203W were independent risk factors for HCC. The odds ratios (95% confidence interval) were 3.99 (1.61-9.92) and 9.70 (1.17-80.58), respectively, for A2189C and G2203W., Conclusions: These results implicate A2189C and G2203W as new predictive markers for HCC., Impact: The complete genome analysis of HBV provided pilot data for the identification of novel mutations that could serve as markers for HCC., (©2010 AACR.)

Objectives: To investigate the prevalence of hepatitis B virus (HBV) genotypes and the association with hepatocellular carcinoma (HCC) or basal core promoter (BCP) mutation in Qidong, China., Methods: The whole genome of HBV or X gene sequences were obtained from serum samples of HBV infected patients by using PCR and direct sequencing methods. Phylogenetic tree was constructed to determine the genotypes or subgenotypes of HBV., Results: According to the phylogenetic tree constructed from full-length sequence of HBV, genotype C2 was predominant in Qidong area. It was prevalent in 44 out of the 48 cases (91.7%), whereas genotype B2 only existed in 4 cases (8.3%). No other genotypes or recombinant types were found in Qidong patients. The result of genotyping based on X gene sequence confirmed the above observation. In a total of 182 samples, 169 (92.9%) showed genotype C2 and 10 (5.5%) showed genotype B2. There were 3 (1.6%) patients showed a coinfection with C2 and B2. The infection rate of genotype C in Qidong was significantly higher than that in neighboring city Shanghai (chi(2) = 12.252, P less than 0.01). There was no significant difference of genotype distribution between HCC and chronic hepatitis groups (P is more than 0.05). The frequency of T1762/A1764 double mutation in genotype C2 (70.3%) was significantly higher than that in genotype B2 (30.8%, P less than 0.05). The other two types of point mutation which also occurred in BCP, i.e. T1766 and A1768, were only seen in genotype C2., Conclusion: (1) Genotype C2 is the predominant genotype in Qidong, China. (2) There is no association between genotype C and HCC in Qidong. (3) Genotype C has a higher prevalence of BCP mutation than genotype B.

Background/aims: To investigate the mutations in hepatitis B virus (HBV) that might be related to hepatocellular carcinoma (HCC) in the high-risk area Qidong, China., Methods: DNA sequences of HBV basal core promoter (BCP) and the overlapping X gene were determined in 58 HCC and 71 chronic hepatitis (CH) patients. In addition, a consecutive series of plasma samples from 15 HCC cases were employed to compare the CP/X sequences before and after the occurrence of HCC., Results: T1762/A1764 double mutation was frequently found in Qidong patients, regardless of clinical status (65.5% in HCC and 73.2% in CH, P>0.05). Unexpectedly, the adjacent T1766/A1768 mutation significantly increased the risk of HCC (P<0.05). Moreover, the prevalence of triple mutations in BCP was significantly higher in patients with HCC than those with CH (P<0.05). The longitudinal study demonstrated that the mutations in BCP were gradually accumulated during the development of HCC. Colony formation assay showed while A1764 mutation alone did not alter the colony-inhibitory activity of HBx, double or triple mutations largely abrogated this effect., Conclusions: The complex mutation involving T1766/A1768 was closely related to HCC. The enhanced risk of HCC caused by BCP variants could be attributable partially to the aberrant activity of HBx.

We investigated the frequency and the clinical relevance of hepatitis B virus (HBV) pre-S mutations in Qidong, China. The results showed HBV pre-S mutants were detected in 48.4% (47/97) of patients with HBV infection. Both pre-S deletion and pre-S2 start codon mutations were more frequently found in HCC than in CH patients (51.1% vs. 18.0%, P < 0.01 and 21.2% vs. 8.0%, P = 0.06). In most cases, pre-S mutants coexisted with the wild-type HBV strain. Longitudinal observation clearly revealed that in four of five cases, HBV deletion mutants emerged during the course of HBV infection and eventually became the predominant or exclusive viral population at the stage of HCC. Thus, it was concluded that HBV pre-S mutations were highly prevalent and closely related to HCC in Qidong. Our results also provided direct evidence that pre-S deletion mutants were not acquired from the beginning of infection but arose de novo during the progression of liver disease.

Objective: Hepatitis B virus (HBV) integration into the host genome is frequently detected in HBV positive hepatocellular carcinoma (HCC) in China. The aim of this study is to carry out a large-scale screening for the HBV integrations sites in HCC samples from Chinese patients., Methods: Cellular DNA was extracted from 40 HBV-related HCC by proteinase K digestion/phenol extraction method. One primer specific to HBV sequence and another primer directed to human Alu repeat were used to amplify the virus/cellular DNA junction. To avoid undesirable amplifications between Alu sequences, primers were constructed with dUTPs and destroyed by uracil DNA glycosylase treatment after 15 initial cycles of amplification. Only desirable fragments were then further amplified with specific primers to the known region and to a tag sequence introduced in the Alu-Specific primer. The PCR product was purified and subject to direct sequencing by ABI 3700 Auto sequencer. NCBI (national center for biotechnology information) BLAST and MapViewer search were used for identification of HBV location on human genomes., Results: In 40 HBsAg positive HCC samples, 34 (85%) were showed to have at least one copy of HBV fragment in host genome, indicating HBV-Alu-PCR is a rapid way for identification of new cellular DNA sequences adjacent to HBV. Analysis from the 68 isolated viral-cellular junctions, X gene was found to be interrupted at any length, not specifically at DR1 and DR2 regions. Three-prime-deleted X gene was observed in 65 (96%) cases. HBV preferred to integrate into the intron and the up-stream regulatory region of the cellular genes. In no case HBV inserted into the exon. Our results also demonstrated that the cellular genes targeted by HBV are usually key regulators of cell proliferation and cell death. Three genes, myeloid/lymphoid or mixed-lineage leukemia 4, G protein alpha transducing activity polypeptide 1 and fibronectin, were found to be recurrently targeted by HBV., Conclusion: HBV-Alu-PCR is a powerful tool for the study of HBV integration sites. Truncated X is a major form existed in the HBV integrants. HBV integration is not distributed evenly throughout the host genome and viral insertional mutagenesis may play an important role in the development of HCC.

The role of the hepatitis B virus X protein (HBx) in the pathogenesis of hepatitis B virus (HBV) infection remains unclear. HBx exhibits pleiotropic biological effects, whose in vivo relevance is a matter for debate. In the present report, we have used a combination of HBx-expressing transgenic mice and liver cell transplantation to investigate the in vivo impact of HBx expression on liver cell proliferation and viability in a regenerative context. We show that moderate HBx expression inhibits liver regeneration after partial hepatectomy in HBx-expressing transgenic mice. We also demonstrate that the transplantation of HBx-expressing liver cells, isolated from HBx transgenic mice, is sufficient to inhibit overall recipient liver regeneration after partial hepatectomy. Moreover, the injection of serum samples drawn from HBx-expressing transgenic mice mimicked the inhibitory effect of HBx on liver regeneration. Finally, the incubation of primary rat hepatocytes with the supernatant of HBx-expressing liver cells inhibits cellular DNA synthesis. Taken together, our results demonstrate a paracrine inhibitory effect of HBx on liver cell proliferation and lead us to propose HBV as one of the few viruses implicated in human cancer which act, at least in part, through paracrine biological pathways.

Hepatitis B virus (HBV) infection has been reported to be associated with gastric cancer (GC). Nonetheless, no study has revealed the role of HBV infection in the survival of patients with GC, and the mutation profiles of HBV-infected patients with GC have never been documented. Here, we performed an updated meta-analysis and found a significantly increased risk of GC in HBV-infected individuals (sOR, 1.29; 95% CI, 1.22-1.37). Furthermore, we observed that in the Anhui area, the rate of serum HBsAg positivity (OR, 1.62; 95% CI, 1.03-2.55) was significantly higher in GC patients than in controls. Moreover, our results showed that HBV-positive patients had significantly worse disease-free survival (HR, 1.98; 95% CI, 1.39-2.82) and overall survival (HR, 1.84; 95% CI, 1.19-2.85) than HBV-negative patients. The results of Cox proportional hazards regression proved that HBV infection was an independent adverse prognostic factor in GC. Furthermore, by performing targeted-NGS, we found unique mutation profiles in HBV-infected GC samples, including five frequently mutated protein-coding genes (KMT2B , KMT2D , SOX1 , FGF12 , and TUBB2B). Expression and survival analyses of these genes identified three novel candidate genes that may have potential roles in GC development. Gene Ontology enrichment analysis showed that the recurrent mutations in HBV-positive GC samples were related to cell proliferation, cell migration, and transcription. Taking together, our study proved that HBV infection is an independent prognostic factor in GC patients. The unique mutation profiles of HBV-infected patients with GC open a new research direction toward the underling mechanism between HBV infection and GC. [ABSTRACT FROM AUTHOR]

Aim: Hepatitis B virus (HBV) integration is one of the mechanisms contributing to hepatocellular carcinoma (HCC) development. However, the status of HBV integration in intrahepatic cholangiocarcinoma (ICC) is poorly understood. This study aims to characterize the viral integration in HBV‐related ICC. Methods: The presence of HBV S and C gene in ICCs and the paratumor tissue was determined by polymerase chain reaction direct sequencing. Hepatitis B virus integration was detected by a high‐throughput capture sequencing method. The expression analysis of the genes targeted by HBV in ICC was undertaken in The Cancer Genome Atlas dataset. Results: Hepatitis B virus S and/or C gene fragments were detected in 71.43% (10/14) ICCs and 57.14% (8/14) paratumor tissues. Using the high‐throughput capture sequencing approach, 139 and 183 HBV integration breakpoints were identified from seven ICC and seven paired paratumor tissues, respectively. Seven genes (TERT, CEACAM20, SPATA18, TRERF1, ZNF23, LINC01449, and LINC00486) were recurrently targeted by HBV‐DNA in different ICC tissues or different cell populations of the same tissue. TERT, which is the most preferential HBV target gene in HCC, was found to be repeatedly interrupted by HBV‐DNA in three different ICC tissues. Based on The Cancer Genome Atlas dataset, TERT, as well as three other HBV recurrently targeted genes (SPATA18, TRERF1, and ZNF23), showed differential expression levels between ICC and para‐ICC tissues. Conclusions: Taken together, HBV integration is a common event in HBV‐related ICC. The HBV recurrent integration genes identified from this study, such as TERT, provide new clues for further research on the causative link between HBV infection and ICC. [ABSTRACT FROM AUTHOR]

Aims/Introduction It has not been reported whether chronic hepatitis B virus infection ( CHB) is associated with a specific type of diabetes. We sought to investigate the prevalence of CHB status in different diabetes subtypes among a Chinese population. Materials and Methods This was a cross-sectional study. A total of 381 patients with adult-onset autoimmune diabetes, 1,365 patients with type 2 diabetes and 1,365 non-diabetic controls were recruited from June 2005 to February 2014. The exclusion criteria included: (i) hepatitis C virus antibody positive; (ii) hepatic cirrhosis; and (iii) malignant neoplasm and severe renal dysfunction (serum creatinine >450 μmol/L). Patients were grouped as hepatitis B virus-negative and CHB status. Results Patients with type 2 diabetes had a higher prevalence of CHB than the controls in the overall population (13.5 vs 10.0%, P = 0.004) and among patients with normal hepatic function (13.3 vs 8.8%, P = 0.002). There was no difference in the prevalence of CHB status between patients with adult-onset autoimmune diabetes and the controls. Multiple logistic regression analysis showed that the odds ratio of CHB increased by ~1.5-fold in patients with type 2 diabetes than in the control group after adjustment for age, sex and body mass index, regardless of hepatic function status. Conclusions CHB status was more prevalent in patients with type 2 diabetes than in individuals with adult-onset autoimmune diabetes and the controls among the Chinese population. Further research is required to ascertain whether CHB status increases the risk of developing type 2 diabetes, or whether type 2 diabetes, but not adult-onset autoimmune diabetes, increases the risk of CHB. [ABSTRACT FROM AUTHOR]

Objectives: To characterize the mutation pattern of a hepatitis B virus (HBV) core protein (HBcAg) derived from hepatocellular carcinoma (HCC) and adjacent nontumor tissues. Methods: HBV core gene fragments (nt. 1901-2365) were amplified from 98 HBV-related HCC tissues and 33 adjacent nontumor tissues. The deduced amino acids (AAs) of the core gene were aligned with the prototype sequences of HBV genotypes B and C. Results: In total, there were 54 positions that showed polymorphism at the deduced AA level. The mutations were predominantly located in three major (codons 83-87, 95-104 and 130-135) and three minor (codons 21-38, 59-63 and 151-155) mutation-clustering regions (MCRs). The substitution rate in MCRs was significantly higher than in mutation-devoid regions (p < 0.001). The most frequently occurring mutations in rank were codon P130T (38.8%), I97L (37.8%) and S87G (23.5%). In addition, there were 7 patients that showed internal deletions in the middle of HBcAg with sizes ranging from 34 to 59 AAs. Unexpectedly, the core genes isolated from tumor tissues had fewer mutations compared with those isolated from adjacent nontumor tissues from the same patients (p < 0.05). Conclusions: Accumulation of naturally occurring mutations in certain restricted segments of HBcAg may be related to the development of HCC. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]