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Cellular and Molecular Biology

Unraveling the role of hepatitis B virus DNA integration in B-cell lymphomagenesis

British Journal of Cancer volume 131, pages 996–1004 (2024)Cite this article

Subjects

Abstract

Background

Studies have shown that hepatitis B virus (HBV)-associated B-cell non-Hodgkin lymphoma (NHL) constitutes a unique subgroup with distinct clinical features. It still leaves open the question of whether the integration of HBV DNA into the B-cell genome is a causal mechanism in the development of lymphoma.

Methods

Using the hybridisation capture-based next generation sequencing and RNA sequencing, we characterised the HBV integration pattern in 45 HBV-associated B-cell NHL tumour tissues.

Results

A total of 354 HBV integration sites were identified in 13 (28.9%) samples, indicating the relatively low integration frequency in B-cell NHLs. High plasma HBV DNA loads were not associated with the existence of HBV integration. The insertion sites distributed randomly across all the lymphoma genome without any preferential hotspot neither at the chromosomal level nor at the genetic level. Intriguingly, most HBV integrations were nonclonal in B-cell NHLs, implying that they did not confer a survival advantage. Analysis of the paired diagnosis-relapse samples showed the unstable status of HBV integrations during disease progression. Furthermore, transcriptomic analysis revealed the limited biological impact of HBV integration.

Conclusion

Our study provides an unbiased HBV integration map in B-cell NHLs, revealing the insignificant role of HBV DNA integration in B-cell lymphomagenesis.

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Fig. 1: Distribution of the integration breakpoints in the hepatitis B virus (HBV) genome.
Fig. 2: Distribution of the hepatitis B virus (HBV) integration breakpoints across the human genome.
Fig. 3: Chromosome enrichment of hepatitis B virus (HBV) integration in human genome.
Fig. 4: Functional analysis and characterisation of tumour infiltrating immune cell composition in the B-cell non-Hodgkin lymphoma (NHL) samples with or without hepatitis B virus (HBV) integration.
Fig. 5: Comparison of the somatic mutations and tumour mutation burden (TMB) in the coding genome between the B-cell non-Hodgkin lymphoma samples with and without hepatitis B virus (HBV) integration.

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Data availability

All data generated or analysed during this study are included in this published article and its supplementary file.

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Acknowledgements

This work was supported by the High-throughput Genomics & Dig Data Analysis Core, Department of Medical Research, National Taiwan University Hospital for technical support and the National Center for High-performance Computing (NCHC) for providing computational and storage resources. We also thank the relevant medical staff and patients who contributed to this study.

Funding

This work was sponsored by the general research project grants from the National Science and Technology Council, Taiwan (NSTC 109-2314-B-002-276, NSTC 111-2314-B-002-126, and NSTC 112-2314-B-002-188).

Author information

Authors and Affiliations

  1. Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, ROC

    Chieh-Lung Cheng & Hwei-Fang Tien

  2. Genome and Systems Biology Degree Program, Academia Sinica and National Taiwan University, Taipei, Taiwan, ROC

    You-Yu Lin

  3. Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan, ROC

    Chia-Lang Hsu

  4. Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan, ROC

    Chiao-Ling Li & Shiou-Hwei Yeh

  5. Department of Pathology, National Taiwan University Cancer Center, Taipei, Taiwan, ROC

    Chang-Tsu Yuan

  6. Microbial Genomics Core Laboratory, Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan, ROC

    Ya-Yun Lai & Pei-Jer Chen

  7. Division of New Drug, Center for Drug Evaluation, Taipei, Taiwan, ROC

    Wei-Quan Fang

  8. Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan, ROC

    Pei-Jer Chen & Shiou-Hwei Yeh

  9. Department of Laboratory Medicine, National Taiwan University College of Medicine, Taipei, Taiwan, ROC

    Shiou-Hwei Yeh

  10. Department of Internal Medicine, Far-Eastern Memorial Hospital, New Taipei City, Taiwan, ROC

    Hwei-Fang Tien

Authors
  1. Chieh-Lung Cheng
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Contributions

CC designed the study, interpreted data, did statistical analysis, and wrote the manuscript. YL interpreted next-generation sequencing data and performed bioinformatics analysis. CH performed transcriptome analysis. CL participated in the assembly of data and wrote the manuscript. CY performed an independent review of all pathology data. YL was responsible for DNA extraction and quantitative polymerase chain reaction. WF did a statistical analysis. PC designed the study, interpreted data, obtained funding, and wrote the manuscript. SY designed the study, interpreted data, obtained funding, and supervised the study. HT obtained funding, coordinated the study over the entire period, and wrote the manuscript.

Corresponding authors

Correspondence to Shiou-Hwei Yeh or Hwei-Fang Tien.

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Ethics approval and consent to participate

This study was approved by the Research Ethics Committee of the National Taiwan University Hospital and was performed in compliance with the Declaration of Helsinki (IRB No. 201911040RINB). Informed consent was obtained from all individual participants included in the study.

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The authors declare no competing interests.

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Cheng, CL., Lin, YY., Hsu, CL. et al. Unraveling the role of hepatitis B virus DNA integration in B-cell lymphomagenesis. Br J Cancer 131, 996–1004 (2024). https://doi.org/10.1038/s41416-024-02763-y

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