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Genome-wide profiling of BK polyomavirus integration in bladder cancer of kidney transplant recipients reveals mechanisms of the integration at the nucleotide level

Oncogene volume 40, pages 46–54 (2021)Cite this article

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Abstract

Chronic BK polyomavirus (BKPyV) infection is recognized as a potential oncogenic factor of urothelial carcinoma (UC) in renal transplant recipients. Recent studies have reported a positive correlation among BKPyV integration, persistent overexpression of viral large T antigen (TAg), and malignancy, yet little is known about the specific integration mechanisms and the impacts of viral integration. Here, we performed whole-genome sequencing (WGS) and viral capture-based sequencing on high-grade immunohistochemically TAg-positive UCs in two renal transplant recipients. A total of 181 integration sites, including the three found by WGS, were identified by viral capture-based sequencing, indicating its enhanced sensitivity and ability in identifying low-read integration sites in subpopulations of the tumor cells. The microhomologies between human and BKPyV genomes were significantly enriched in the flanking regions of 84.5% the integration sites, with a median length of 7 bp. Notably, 75 human genes formed fusion sequences due to viral insertional integration. Among them, the expression of 15 genes were statistically associated with UC based on GEO2R expression analysis. Our results indicated a multisite and multifragment linear integration pattern and a potential microhomology or nonhomologous end joining integration mechanism at the single-nucleotide level. We put forward a potential selection mechanism driven by immunity and centered on viral integration in the carcinogenesis of BKPyV.

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Fig. 1: CT images and pathology of case 1.
Fig. 2: Pathological features in case 2.
Fig. 3: Distribution of breakpoints on human chromosomes and BKPyV genomes.
Fig. 4: A potential viral integration pattern revealed by nucleotide analysis.
Fig. 5: Diagrammatic representation of a hypothetical BKPyV integration pattern.
Fig. 6: Hypothesis of pathogenic model based on BKPyV integration.

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Acknowledgements

This work was funded by the National Natural Science Foundation of China (81500573), the Science Foundation of Guangdong Province (2020A1515010674), the Science and Technology Planning Project of Guangzhou (201803010109), the President Funding of Nanfang Hospital (2018B009, 2018C003) and College Students’ Innovative Entrepreneurial Training Plan Program (201812121148, X202012121239, 202012121046).

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Author notes

  1. These authors contributed equally: Yu Jin, Yi Zhou, Wenfeng Deng, Yuchen Wang

Authors and Affiliations

  1. Division of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Yu Jin, Yi Zhou, Wenfeng Deng, Yuchen Wang, Yanna Liu, Yangcheng Hu, Rumin Liu, Bowen Guan, Jian Geng, Jian Xu & Yun Miao

  2. Departments of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Richard J. Lee

  3. Departments of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Nahel Elias

  4. State Key Laboratory of Virology, CAS Center for Excellence in Brain Science and Intelligence Technology, Wuhan Institute of Virology, Wuhan, China

    Min-Hua Luo

  5. Mygenostics co., Beijing, China

    Junfeng Ma, Jiapeng Zhou & Na Liu

  6. Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Michael L. Blute & Chin-Lee Wu

  7. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Robert B. Colvin & Chin-Lee Wu

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Contributions

CLW and YM designed and directed the study. YJ, YZ, WFD, and YCW wrote the manuscript. RJL, YNL, NE, and JG performed sample preparation, sequencing and statistical analysis and validation. MHL, RML, and BWG performed experimental work and analyzed the data. YCH, JFM, JPZ, and NL took charge for data visualization. HQN, JX, MLB, and RBC revised the manuscript. All authors read and approved the final version.

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Correspondence to Chin-Lee Wu or Yun Miao.

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Jin, Y., Zhou, Y., Deng, W. et al. Genome-wide profiling of BK polyomavirus integration in bladder cancer of kidney transplant recipients reveals mechanisms of the integration at the nucleotide level. Oncogene 40, 46–54 (2021). https://doi.org/10.1038/s41388-020-01502-w

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