Evidence for virus-mediated oncogenesis in bladder cancers arising in solid organ transplant recipients

  1. Gabriel J Starrett  Is a corresponding author
  2. Kelly Yu
  3. Yelena Golubeva
  4. Petra Lenz
  5. Mary L Piaskowski
  6. David Petersen
  7. Michael Dean
  8. Ajay Israni
  9. Brenda Y Hernandez
  10. Thomas C Tucker
  11. Iona Cheng
  12. Lou Gonsalves
  13. Cyllene R Morris
  14. Shehnaz K Hussain
  15. Charles F Lynch
  16. Reuben S Harris
  17. Ludmila Prokunina-Olsson
  18. Paul S Meltzer
  19. Christopher B Buck
  20. Eric A Engels
  1. National Cancer Institute, United States
  2. Leidos Biomedical Research Inc, United States
  3. University of Minnesota, United States
  4. University of Hawaii, United States
  5. University of Kentucky, United States
  6. University of California, San Francisco, United States
  7. Connecticut Department of Public Health, United States
  8. University of California, Davis, United States
  9. Cedars-Sinai Medical Center, United States
  10. University of Iowa, United States
  11. Howard Hughes Medical Institute, University of Minnesota-Twin Cities, United States

Abstract

A small percentage of bladder cancers in the general population have been found to harbor DNA viruses. In contrast, up to 25% of tumors of solid organ transplant recipients, who are at an increased risk of developing bladder cancer and have overall poorer outcome, harbor BK polyomavirus (BKPyV). To better understand the biology of the tumors and the mechanisms of carcinogenesis from potential oncoviruses, we performed whole genome and transcriptome sequencing on bladder cancer specimens from 43 transplant patients. Nearly half of tumors from this patient population contained viral sequences. The most common were from BKPyV (N=9, 21%), JC polyomavirus (N=7, 16%), carcinogenic human papillomaviruses (N=3, 7%), and torque teno viruses (N=5, 12%). Immunohistochemistry revealed variable Large T antigen expression in BKPyV-positive tumors ranging from 100% positive staining of tumor tissue to less than 1%. In most cases of BKPyV-positive tumors, the viral genome appeared to be clonally integrated into the host chromosome consistent with microhomology-mediated end joining and coincided with focal amplifications of the tumor genome similar to other virus-mediated cancers. Significant changes in host gene expression consistent with the functions of BKPyV Large T antigen were also observed in these tumors. Lastly, we identified four mutation signatures in our cases with those attributable to APOBEC3 and SBS5 being the most abundant. Mutation signatures associated with the antiviral drug, ganciclovir, and aristolochic acid, a nephrotoxic compound found in some herbal medicines, were also observed. The results suggest multiple pathways to carcinogenesis in solid organ transplant recipients with a large fraction being virus-associated.

Data availability

All refseqs for human papillomaviruses were downloaded from PaVE and refseqs for human polyomaviruses were downloaded from NCBI as of November 2018. All sequencing data generated in this study are available from dbGaP under accession phs003012.v1.p1. Viral contigs from this study are deposited in GenBank under accessions OQ469311 and OQ469312. All other contigs and larger IHC images are deposited in figshare (https://figshare.com/projects/Common_Mechanisms_of_Virus-Mediated_Oncogenesis_in_Bladder_Cancers_Arising_in_Solid_Organ_Transplant_Recipients/132833). Code used in this manuscript are available from www.github.com/gstarrett/oncovirus_tools.

The following data sets were generated

Article and author information

Author details

  1. Gabriel J Starrett

    Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, United States
    For correspondence
    gabe.starrett@nih.gov
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5871-5306
  2. Kelly Yu

    National Cancer Institute, Rockville, United States
    Competing interests
    No competing interests declared.
  3. Yelena Golubeva

    Leidos Biomedical Research Inc, Frederick, United States
    Competing interests
    Yelena Golubeva, is affiliated with Leidos Biomedical Research Inc. The author has no financial interests to declare..
  4. Petra Lenz

    Leidos Biomedical Research Inc, Frederick, United States
    Competing interests
    Petra Lenz, is affiliated with Leidos Biomedical Research Inc. The author has no financial interests to declare..
  5. Mary L Piaskowski

    Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8453-6416
  6. David Petersen

    Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, United States
    Competing interests
    No competing interests declared.
  7. Michael Dean

    National Cancer Institute, Rockville, United States
    Competing interests
    No competing interests declared.
  8. Ajay Israni

    Department of Medicine, University of Minnesota, Minneapolis, United States
    Competing interests
    No competing interests declared.
  9. Brenda Y Hernandez

    Cancer Center, University of Hawaii, Honolulu, United States
    Competing interests
    No competing interests declared.
  10. Thomas C Tucker

    The Kentucky Cancer Registry, University of Kentucky, Lexington, United States
    Competing interests
    No competing interests declared.
  11. Iona Cheng

    Department of Epidemiology and Biostatistics, University of California, San Francisco, Fremont, United States
    Competing interests
    No competing interests declared.
  12. Lou Gonsalves

    Connecticut Tumor Registry, Connecticut Department of Public Health, Hartford, United States
    Competing interests
    No competing interests declared.
  13. Cyllene R Morris

    California Cancer Reporting and Epidemiologic Surveillance Program, University of California, Davis, Davis, United States
    Competing interests
    No competing interests declared.
  14. Shehnaz K Hussain

    Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States
    Competing interests
    No competing interests declared.
  15. Charles F Lynch

    The Iowa Cancer Registry, University of Iowa, Iowa City, United States
    Competing interests
    No competing interests declared.
  16. Reuben S Harris

    Howard Hughes Medical Institute, University of Minnesota-Twin Cities, Minneapolis, United States
    Competing interests
    Reuben S Harris, is a co-founder, shareholder, and consultant of ApoGen Biotechnologies Inc. The remaining authors have no competing interests to declare..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9034-9112
  17. Ludmila Prokunina-Olsson

    National Cancer Institute, Rockville, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9622-2091
  18. Paul S Meltzer

    Molecular Genetics Section, National Cancer Institute, Bethesda, United States
    Competing interests
    No competing interests declared.
  19. Christopher B Buck

    Lab of Cellular Oncology, National Cancer Institute, Bethesda, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3165-8094
  20. Eric A Engels

    National Cancer Institute, Rockville, United States
    Competing interests
    No competing interests declared.

Funding

National Institutes of Health (Intramural Research Program)

  • Gabriel J Starrett
  • Christopher B Buck
  • Eric A Engels

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Nicholas Wallace, Kansas State University, United States

Ethics

Human subjects: The TCM Study is considered non-human subjects research at the National Institutes of Health because researchers do not receive identifying information on patients, and the present project utilizes materials collected previously for clinical purposes. The TCM Study was reviewed, as required, by human subjects committees at participating cancer registries.

Version history

  1. Preprint posted: November 11, 2021 (view preprint)
  2. Received: August 13, 2022
  3. Accepted: March 22, 2023
  4. Accepted Manuscript published: March 24, 2023 (version 1)
  5. Version of Record published: August 23, 2023 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Gabriel J Starrett
  2. Kelly Yu
  3. Yelena Golubeva
  4. Petra Lenz
  5. Mary L Piaskowski
  6. David Petersen
  7. Michael Dean
  8. Ajay Israni
  9. Brenda Y Hernandez
  10. Thomas C Tucker
  11. Iona Cheng
  12. Lou Gonsalves
  13. Cyllene R Morris
  14. Shehnaz K Hussain
  15. Charles F Lynch
  16. Reuben S Harris
  17. Ludmila Prokunina-Olsson
  18. Paul S Meltzer
  19. Christopher B Buck
  20. Eric A Engels
(2023)
Evidence for virus-mediated oncogenesis in bladder cancers arising in solid organ transplant recipients
eLife 12:e82690.
https://doi.org/10.7554/eLife.82690

Share this article

https://doi.org/10.7554/eLife.82690

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