scholarly journals Earliest hepatitis B virus-hepatocyte genome integration: sites, mechanism, and significance in carcinogenesis

2021 ◽  
Vol 2021 ◽  
Author(s):  
Ranjit Chauhan ◽  
Tomasz I. Michalak
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Genome Integration ◽  
B Virus ◽  
Integration Sites

scholarly journals Persistence of intrahepatic hepatitis B virus DNA integration in patients developing hepatocellular carcinoma after hepatitis B surface antigen seroclearance

2021 ◽  
Vol 27 (1) ◽  
pp. 207-218
Author(s):  
Jeong Won Jang ◽  
Jin Seoub Kim ◽  
Hye Seon Kim ◽  
Kwon Yong Tak ◽  
Heechul Nam ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Surface Antigen ◽  
Hepatitis B Surface Antigen ◽  
Next Generation Sequencing Technology ◽  
Tumor Tissues ◽  
Hbsag Seroclearance ◽  
B Virus ◽  
Integration Sites

Background/Aims: The role of hepatitis B virus (HBV) integration into the host genome in hepatocarcinogenesis following hepatitis B surface antigen (HBsAg) seroclearance remains unknown. Our study aimed to investigate and characterize HBV integration events in chronic hepatitis B (CHB) patients who developed hepatocellular carcinoma (HCC) after HBsAg seroclearance.<br/>Methods: Using probe-based HBV capturing followed by next-generation sequencing technology, HBV integration was examined in 10 samples (seven tumors and three non-tumor tissues) from seven chronic carriers who developed HCC after HBsAg loss. Genomic locations and patterns of HBV integration were investigated.<br/>Results: HBV integration was observed in six patients (85.7%) and eight (80.0%) of 10 tested samples. HBV integration breakpoints were detected in all of the non-tumor (3/3, 100%) and five of the seven (71.4%) tumor samples, with an average number of breakpoints of 4.00 and 2.43, respectively. Despite the lower total number of tumoral integration breakpoints, HBV integration sites in the tumors were more enriched within the genic area. In contrast, non-tumor tissues more often showed intergenic integration. Regarding functions of the affected genes, tumoral genes with HBV integration were mostly associated with carcinogenesis. At enrollment, patients who did not remain under regular HCC surveillance after HBsAg seroclearance had a large HCC, while those on regular surveillance had a small HCC.<br/>Conclusions: The biological functions of HBV integration are almost comparable between HBsAg-positive and HBsAgserocleared HCCs, with continuing pro-oncogenic effects of HBV integration. Thus, ongoing HCC surveillance and clinical management should continue even after HBsAg seroclearance in patients with CHB.

scholarly journals DeepHBV: A deep learning model to predict hepatitis B virus (HBV) integration sites.

2021 ◽  
Author(s):  
Canbiao Wu ◽  
Xiaofang Guo ◽  
Mengyuan Li ◽  
Xiayu Fu ◽  
Zeliang Hou ◽  
...  
Keyword(s):  
Deep Learning ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Binding Sites ◽  
Learning Model ◽  
Validation Dataset ◽  
B Virus ◽  
Integration Sites ◽  
Deep Learning Model ◽  
Pan Cancer

Hepatitis B virus (HBV) is one of the main causes for viral hepatitis and liver cancer. Previous studies showed HBV can integrate into host genome and further promote malignant transformation. In this study, we developed an attention-based deep learning model DeepHBV to predict HBV integration sites by learning local genomic features automatically. We trained and tested DeepHBV using the HBV integration sites data from dsVIS database. Initially, DeepHBV showed AUROC of 0.6363 and AUPR of 0.5471 on the dataset. Adding repeat peaks and TCGA Pan Cancer peaks can significantly improve the model performance, with an AUROC of 0.8378 and 0.9430 and an AUPR of 0.7535 and 0.9310, respectively. On independent validation dataset of HBV integration sites from VISDB, DeepHBV with HBV integration sequences plus TCGA Pan Cancer (AUROC of 0.7603 and AUPR of 0.6189) performed better than HBV integration sequences plus repeat peaks (AUROC of 0.6657 and AUPR of 0.5737). Next, we found the transcriptional factor binding sites (TFBS) were significantly enriched near genomic positions that were paid attention to by convolution neural network. The binding sites of AR-halfsite, Arnt, Atf1, bHLHE40, bHLHE41, BMAL1, CLOCK, c-Myc, COUP-TFII, E2A, EBF1, Erra and Foxo3 were highlighted by DeepHBV attention mechanism in both dsVIS dataset and VISDB dataset, revealing the HBV integration preference. In summary, DeepHBV is a robust and explainable deep learning model not only for the prediction of HBV integration sites but also for further mechanism study of HBV induced cancer.

scholarly journals DeepHBV: a deep learning model to predict hepatitis B virus (HBV) integration sites

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Canbiao Wu ◽  
Xiaofang Guo ◽  
Mengyuan Li ◽  
Jingxian Shen ◽  
Xiayu Fu ◽  
...  
Keyword(s):  
Deep Learning ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Binding Sites ◽  
Integration Site ◽  
Learning Model ◽  
Genomic Features ◽  
B Virus ◽  
Integration Sites ◽  
Deep Learning Model

Abstract Background The hepatitis B virus (HBV) is one of the main causes of viral hepatitis and liver cancer. HBV integration is one of the key steps in the virus-promoted malignant transformation. Results An attention-based deep learning model, DeepHBV, was developed to predict HBV integration sites. By learning local genomic features automatically, DeepHBV was trained and tested using HBV integration site data from the dsVIS database. Initially, DeepHBV showed an AUROC of 0.6363 and an AUPR of 0.5471 for the dataset. The integration of genomic features of repeat peaks and TCGA Pan-Cancer peaks significantly improved model performance, with AUROCs of 0.8378 and 0.9430 and AUPRs of 0.7535 and 0.9310, respectively. The transcription factor binding sites (TFBS) were significantly enriched near the genomic positions that were considered. The binding sites of the AR-halfsite, Arnt, Atf1, bHLHE40, bHLHE41, BMAL1, CLOCK, c-Myc, COUP-TFII, E2A, EBF1, Erra, and Foxo3 were highlighted by DeepHBV in both the dsVIS and VISDB datasets, revealing a novel integration preference for HBV. Conclusions DeepHBV is a useful tool for predicting HBV integration sites, revealing novel insights into HBV integration-related carcinogenesis.

scholarly journals Characterization of Hepatitis B Virus Integrations Identified in Hepatocellular Carcinoma Genomes

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 245
Author(s):  
Pranav Mathkar ◽  
Xun Chen ◽  
Arvis Sulovari ◽  
Dawei Li
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Enrichment Analysis ◽  
Pathway Enrichment Analysis ◽  
Accurate Identification ◽  
Diagnostic Potential ◽  
B Virus ◽  
Integration Sites

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. Almost half of HCC cases are associated with hepatitis B virus (HBV) infections, which often lead to HBV sequence integrations in the human genome. Accurate identification of HBV integration sites at a single nucleotide resolution is critical for developing a better understanding of the cancer genome landscape and of the disease itself. Here, we performed further analyses and characterization of HBV integrations identified by our recently reported VIcaller platform in recurrent or known HCC genes (such as TERT, MLL4, and CCNE1) as well as non-recurrent cancer-related genes (such as CSMD2, NKD2, and RHOU). Our pathway enrichment analysis revealed multiple pathways involving the alcohol dehydrogenase 4 gene, such as the metabolism pathways of retinol, tyrosine, and fatty acid. Further analysis of the HBV integration sites revealed distinct patterns involving the integration upper breakpoints, integrated genome lengths, and integration allele fractions between tumor and normal tissues. Our analysis also implies that the VIcaller method has diagnostic potential through discovering novel clonal integrations in cancer-related genes. In conclusion, although VIcaller is a hypothesis free virome-wide approach, it can still be applied to accurately identify genome-wide integration events of a specific candidate virus and their integration allele fractions.

Cell‐Free Virus‐Host Chimera DNA From Hepatitis B Virus Integration Sites as a Circulating Biomarker of Hepatocellular Cancer

Hepatology ◽  
2020 ◽  
Vol 72 (6) ◽  
pp. 2063-2076
Author(s):  
Chiao‐Ling Li ◽  
Ming‐Chih Ho ◽  
You‐Yu Lin ◽  
Sheng‐Tai Tzeng ◽  
Yun‐Ju Chen ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hepatocellular Cancer ◽  
Free Virus ◽  
Circulating Biomarker ◽  
B Virus ◽  
Integration Sites ◽  
Virus Integration

scholarly journals Detection of hepatitis B virus-host junction sequences in urine of infected patients

2021 ◽  
Author(s):  
Selena Y. Lin ◽  
Yih-Ping Su ◽  
Evan R. Trauger ◽  
Benjamin P. Song ◽  
Emilie G. C. Thompson ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Liquid Biopsy ◽  
Hbv Dna ◽  
Urine Samples ◽  
Specific Pcr ◽  
B Virus ◽  
Targeted Ngs ◽  
Integration Sites ◽  
Related Liver Disease

ABSTRACTBackground & AimsIntegrated hepatitis B virus (HBV) DNA, found in >85% of HBV-associated hepatocellular carcinomas (HBV-HCC), can play a significant role in HBV-related liver disease progression. HBV-host junction sequences (HBV-JS’s), created through integration events, have been used to determine HBV-HCC clonality. Here, we investigate the feasibility of analyzing HBV integration in a noninvasive urine liquid biopsy.Approach & ResultsUtilizing an HBV-targeted NGS assay, we first identified HBV-JS’s in 8 HBV-HCC tissues and designed short-amplicon junction-specific PCR assays to detect HBV-JSs in matched urine. We detected and validated tissue-derived junctions in 5 of 8 matched urine samples. Next, we screened 32 urine samples collected from 25 HBV-infected patients (5 with hepatitis, 10 with cirrhosis, 4 with HCC, and 6 post-HCC). Encouragingly, all 32 urine samples contained HBV-JS’s detectable by HBV-targeted NGS. Of the 712 total HBV-JS’s detected in urine, 351 were in gene-coding regions, 11 of which, including TERT, had previously been reported as recurrent integration sites in HCC tissue and were found in urine of cirrhosis or HCC patients only. The integration breakpoints of HBV DNA detected in urine were found predominantly (∼70%) at a previously identified integration hotspot, HBV DR1-2.ConclusionsHBV viral-host junction DNA can be detected in urine of HBV-infected patients. This study is the first study to demonstrate the potential for a noninvasive urine liquid biopsy of integrated HBV DNA to monitor HBV-infected patients for HBV-associated liver diseases and the efficacy of antiviral therapy.

scholarly journals Tight clustering of human hepatitis B virus integration sites in hepatomas near a triple-stranded region.

1987 ◽  
Vol 61 (11) ◽  
pp. 3491-3498 ◽  
Author(s):  
C Shih ◽  
K Burke ◽  
M J Chou ◽  
J B Zeldis ◽  
C S Yang ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Human Hepatitis ◽  
B Virus ◽  
Integration Sites ◽  
Virus Integration

scholarly journals Detection of Clonally Expanded Hepatocytes in Chimpanzees with Chronic Hepatitis B Virus Infection

2009 ◽  
Vol 83 (17) ◽  
pp. 8396-8408 ◽  
Author(s):  
William S. Mason ◽  
Huey-Chi Low ◽  
Chunxiao Xu ◽  
Carol E. Aldrich ◽  
Catherine A. Scougall ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Hepatitis Virus ◽  
Integration Site ◽  
Clonal Expansion ◽  
Cell Junctions ◽  
Viral Dna ◽  
Chronic Hepatitis B Virus ◽  
B Virus ◽  
Integration Sites

ABSTRACT During a hepadnavirus infection, viral DNA integrates at a low rate into random sites in the host DNA, producing unique virus-cell junctions detectable by inverse nested PCR (invPCR). These junctions serve as genetic markers of individual hepatocytes, providing a means to detect their subsequent proliferation into clones of two or more hepatocytes. A previous study suggested that the livers of 2.4-year-old woodchucks (Marmota monax) chronically infected with woodchuck hepatitis virus contained at least 100,000 clones of >1,000 hepatocytes (W. S. Mason, A. R. Jilbert, and J. Summers, Proc. Natl. Acad. Sci. USA 102:1139-1144, 2005). However, possible correlations between sites of viral-DNA integration and clonal expansion could not be explored because the woodchuck genome has not yet been sequenced. In order to further investigate this issue, we looked for similar clonal expansion of hepatocytes in the livers of chimpanzees chronically infected with hepatitis B virus (HBV). Liver samples for invPCR were collected from eight chimpanzees chronically infected with HBV for at least 20 years. Fifty clones ranging in size from ∼35 to 10,000 hepatocytes were detected using invPCR in 32 liver biopsy fragments (∼1 mg) containing, in total, ∼3 × 107 liver cells. Based on searching the analogous human genome, integration sites were found on all chromosomes except Y, ∼30% in known or predicted genes. However, no obvious association between the extent of clonal expansion and the integration site was apparent. This suggests that the integration site per se is not responsible for the outgrowth of large clones of hepatocytes.

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