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.

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.

Reviewing Editor

  1. Nicholas Wallace, Kansas State University, United States

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.

Metrics

  • 939
    Page views
  • 202
    Downloads
  • 6
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Cancer Biology
    Sen Qin, Yawei Xu ... Zheng Zhang
    Research Article

    Pheochromocytomas (PCCs) are rare neuroendocrine tumors that originate from chromaffin cells in the adrenal gland. However, the cellular molecular characteristics and immune microenvironment of PCCs are incompletely understood. Here, we performed single-cell RNA sequencing (scRNA-seq) on 16 tissues from 4 sporadic unclassified PCC patients and 1 hereditary PCC patient with Von Hippel-Lindau (VHL) syndrome. We found that intra-tumoral heterogeneity was less extensive than the inter-individual heterogeneity of PCCs. Further, the unclassified PCC patients were divided into two types, metabolism-type (marked by NDUFA4L2 and COX4I2) and kinase-type (marked by RET and PNMT), validated by immunohistochemical staining. Trajectory analysis of tumor evolution revealed that metabolism-type PCC cells display phenotype of consistently active metabolism and increased metastasis potential, while kinase-type PCC cells showed decreased epinephrine synthesis and neuron-like phenotypes. Cell-cell communication analysis showed activation of the annexin pathway and a strong inflammation reaction in metabolism-type PCCs and activation of FGF signaling in the kinase-type PCC. Although multispectral immunofluorescence staining showed a lack of CD8+ T cell infiltration in both metabolism-type and kinase-type PCCs, only the kinase-type PCC exhibited downregulation of HLA-I molecules that possibly regulated by RET, suggesting the potential of combined therapy with kinase inhibitors and immunotherapy for kinase-type PCCs; in contrast, the application of immunotherapy to metabolism-type PCCs (with antigen presentation ability) is likely unsuitable. Our study presents a single-cell transcriptomics-based molecular classification and microenvironment characterization of PCCs, providing clues for potential therapeutic strategies to treat PCCs.

    1. Cancer Biology
    Qiaomu Tian, Peng Zhang ... Anita S Chong
    Research Article Updated

    Pancreatic cancer is the seventh leading cause of cancer-related death worldwide, and despite advancements in disease management, the 5 -year survival rate stands at only 12%. Triptolides have potent anti-tumor activity against different types of cancers, including pancreatic cancer, however poor solubility and toxicity limit their translation into clinical use. We synthesized a novel pro-drug of triptolide, (E)–19-[(1’-benzoyloxy-1’-phenyl)-methylidene]-Triptolide (CK21), which was formulated into an emulsion for in vitro and in vivo testing in rats and mice, and used human pancreatic cancer cell lines and patient-derived pancreatic tumor organoids. A time-course transcriptomic profiling of tumor organoids treated with CK21 in vitro was conducted to define its mechanism of action, as well as transcriptomic profiling at a single time point post-CK21 administration in vivo. Intravenous administration of emulsified CK21 resulted in the stable release of triptolide, and potent anti-proliferative effects on human pancreatic cancer cell lines and patient-derived pancreatic tumor organoids in vitro, and with minimal toxicity in vivo. Time course transcriptomic profiling of tumor organoids treated with CK21 in vitro revealed <10 differentially expressed genes (DEGs) at 3 hr and ~8,000 DEGs at 12 hr. Overall inhibition of general RNA transcription was observed, and Ingenuity pathway analysis together with functional cellular assays confirmed inhibition of the NF-κB pathway, increased oxidative phosphorylation and mitochondrial dysfunction, leading ultimately to increased reactive oxygen species (ROS) production, reduced B-cell-lymphoma protein 2 (BCL2) expression, and mitochondrial-mediated tumor cell apoptosis. Thus, CK21 is a novel pro-drug of triptolide that exerts potent anti-proliferative effects on human pancreatic tumors by inhibiting the NF-κB pathway, leading ultimately to mitochondrial-mediated tumor cell apoptosis.