Evidence for virus-mediated oncogenesis in bladder cancers arising in solid organ transplant recipients
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.
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.
Article and author information
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.
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.
- Nicholas Wallace, Kansas State University, United States
- Received: August 13, 2022
- Accepted: March 22, 2023
- Accepted Manuscript published: March 24, 2023 (version 1)
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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