Noninvasive chimeric DNA profiling identifies tumor-originated HBV integrants contributing to viral antigen expression in liver cancer

Chen, Wei; Zhang, Ke; Dong, Paul R; Fanning, Gregory; Tao, Chengcheng; Zhang, Haikun; Guo, Shicheng; Wang, Zheng; Hong, Yaqiang; Yang, Xiaobo; Lai, Syeling; Ding, Huiguo; Zhao, Haitao; Zeng, Changqing; Protzer, Ulrike; Zhang, Dake

doi:10.1007/s12072-020-10016-2

Cited by 26 publications

(30 citation statements)

References 23 publications

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“…In relative homogeneous populations of cell lines carrying HBV integrations, there are no more than 10 dominant integrations. For instance, the HepG2.2.15 cell line may contain at most five integrations, 21 and the PLC/PRF/5 cell line had nine integration regions reported. 23 Among the cell populations of the infected liver, it is estimated that there is about 1 integration per 10 3 ∼10 4 cells according to observations in an in vitro infection model.…”

Section: Hbv Integration Detection: Hybridization Cloning Amplification and Next-generation Sequencing (Ngs) Solutionsmentioning

confidence: 99%

“…1 ), and they may overestimate the number of integrations in each sample. 21 Fortunately, different integration events are likely to be far apart from each other in the cellular genome of hepatocytes. Therefore, we developed a strategy to pair adjacent breakpoints in the human genome for the same integration event.…”

Section: Hbv Integration Detection: Hybridization Cloning Amplification and Next-generation Sequencing (Ngs) Solutionsmentioning

confidence: 99%

“…Therefore, we developed a strategy to pair adjacent breakpoints in the human genome for the same integration event. 21 After the breakpoints in the human genome have been successfully paired, the corresponding viral breakpoints can then be paired. The boundaries of integration events are indicated by the sharp and consistent positions of the mapped reads, the particular distribution patterns of which have shown diverse modes of integrations ( Fig.…”

Section: Hbv Integration Detection: Hybridization Cloning Amplification and Next-generation Sequencing (Ngs) Solutionsmentioning

confidence: 99%

“…Nevertheless, we found the most common repeat region, was directly interrupted rather than abutting the cancer-enriched human alpha satellite (ALR/Alpha) identified in over 40% of the HCC cases. 21 …”

Section: Recurrent Genes Interrupted By Integration Eventsmentioning

confidence: 99%

“…Besides, we found the L1ME1 of family LINE-1 (L1) (−20% cases) is the most frequently affected LINE element. 21 Interestingly, more evidence has been provided revealing that the activation of L1 contributes to hepatitis virus-related HCC. 69 , 75 Particularly, HBV infection suppresses interferon signal transduction by disrupting either STAT1 nuclear import or phosphorylation.…”

Section: Recurrent Genes Interrupted By Integration Eventsmentioning

confidence: 99%

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HBV Integration Induces Complex Interactions between Host and Viral Genomic Functions at the Insertion Site

Zhang

Protzer

et al. 2021

Journal of Clinical and Translational Hepatology

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Hepatitis B virus (HBV), one of the well-known DNA oncogenic viruses, is the leading cause of hepatocellular carcinoma (HCC). In infected hepatocytes, HBV DNA can be integrated into the host genome through an insertional mutagenesis process inducing tumorigenesis. Dissection of the genomic features surrounding integration sites will deepen our understanding of mechanisms underlying integration. Moreover, the quantity and biological activity of integration sites may reflect the DNA damage within affected cells or the potential survival benefits they may confer. The well-known human genomic features include repeat elements, particular regions (such as telomeres), and frequently interrupted genes (e.g., telomerase reverse transcriptase [i.e. TERT ], lysine methyltransferase 2B [i.e. KMT2B ], cyclin E1 [ CCNE1 ], and cyclin A2 [ CCNA2 ]). Consequently, distinct genomic features within diverse integrations differentiate their biological functions. Meanwhile, accumulating evidence has shown that viral proteins produced by integrants may cause cell damage even after the suppression of HBV replication. The integration-derived gene products can also serve as tumor markers, promoting the development of novel therapeutic strategies for HCC. Viral integrants can be single copy or multiple copies of different fragments with complicated rearrangement, which warrants elucidation of the whole viral integrant arrangement in future studies. All of these considerations underlie an urgent need to develop novel methodology and technology for sequence characterization and function evaluation of integration events in chronic hepatitis B-associated disease progression by monitoring both host genomic features and viral integrants. This endeavor may also serve as a promising solution for evaluating the risk of tumorigenesis and as a companion diagnostic for designing therapeutic strategies targeting integration-related disease complications.

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Section: Hbv Integration Detection: Hybridization Cloning Amplification and Next-generation Sequencing (Ngs) Solutionsmentioning

confidence: 99%

Section: Hbv Integration Detection: Hybridization Cloning Amplification and Next-generation Sequencing (Ngs) Solutionsmentioning

confidence: 99%

Section: Hbv Integration Detection: Hybridization Cloning Amplification and Next-generation Sequencing (Ngs) Solutionsmentioning

confidence: 99%

Section: Recurrent Genes Interrupted By Integration Eventsmentioning

confidence: 99%

Section: Recurrent Genes Interrupted By Integration Eventsmentioning

confidence: 99%

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HBV Integration Induces Complex Interactions between Host and Viral Genomic Functions at the Insertion Site

Zhang

Protzer

et al. 2021

Journal of Clinical and Translational Hepatology

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Detection of Hepatitis B Virus–Host Junction Sequences in Urine of Infected Patients

Lin

Trauger

et al. 2021

Hepatol Commun

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Integrated hepatitis B virus (HBV) DNA, found in more than 85% of HBV-associated hepatocellular carcinomas (HBV-HCCs), can play a significant role in HBV-related liver disease progression. HBV-host junction sequences (HBV-JSs), 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. Using an HBV-targeted next-generation sequencing (NGS) assay, we first identified HBV-JSs in eight HBV-HCC tissues and designed short-amplicon junction-specific polymerase chain reaction assays to detect HBV-JSs in matched urine. We detected and validated tissue-derived junctions in five of eight matched urine samples. Next, we screened 32 urine samples collected from 25 patients infected with HBV (5 with hepatitis, 10 with cirrhosis, 4 with HCC, and 6 post-HCC). Encouragingly, all 32 urine samples contained HBV-JSs detectable by HBV-targeted NGS. Of the 712 total HBV-JSs detected in urine, 351 were in gene-coding regions, 11 of which, including TERT (telomerase reverse transcriptase), had previously been reported as recurrent integration sites in HCC tissue and were found only in the urine patients with cirrhosis or HCC. The integration breakpoints of HBV DNA detected in urine were found predominantly (~70%) at a previously identified integration hotspot, HBV DR1-2 (down-regulator of transcription 1-2). Conclusion: HBV viral-host junction DNA can be detected in urine of patients infected with HBV. This study demonstrates the potential for a noninvasive urine liquid biopsy of integrated HBV DNA to monitor patients infected with HBV for HBV-associated liver diseases and the efficacy of antiviral therapy. (Hepatology Communications 2021;0:1-11).

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Efficacy and Safety of Saroglitazar in Patients with Cardiometabolic Diseases: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

et al. 2022

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Noninvasive chimeric DNA profiling identifies tumor-originated HBV integrants contributing to viral antigen expression in liver cancer

Cited by 26 publications

References 23 publications

HBV Integration Induces Complex Interactions between Host and Viral Genomic Functions at the Insertion Site

HBV Integration Induces Complex Interactions between Host and Viral Genomic Functions at the Insertion Site

Detection of Hepatitis B Virus–Host Junction Sequences in Urine of Infected Patients

Efficacy and Safety of Saroglitazar in Patients with Cardiometabolic Diseases: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

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