At least 20% of all cancers are attributable to viral, bacterial, or parasitic infections (de Martel et al., 2020). The advent of high-throughput deep sequencing has provided unprecedented opportunities to learn how infectious agents are involved in cancer in an unbiased manner. Several previous studies have searched for microbial nucleotide sequences in The Cancer Genome Atlas (TCGA), the International Cancer Genome Consortium (ICGC), and PanCancer Analysis of Whole Genomes (PCAWG) datasets (Zapatka et al., 2020; Cantalupo et al., 2018). In addition to confirming known associations, such as the presence of human papillomaviruses (HPVs) in cervical cancer, these studies also uncovered rare cases in which viral sequences were unexpectedly found in other major cancers affecting the general population (Cantalupo et al., 2018).

Despite the immense amount of tumor sequencing data generated to date, the identification of microorganisms in common cancers through these studies has been limited. A more focused assessment of groups at increased risk for virus-associated cancers may be needed. In particular, oncogenic viruses may contribute to a larger fraction of cancer cases among immunosuppressed individuals, such as those with human immunodeficiency virus (HIV) infection and organ transplant recipients. These populations have been previously shown to be at increased risk for developing papillomavirus-mediated cancers, and oncogenic viruses, such as Kaposi’s sarcoma-associated herpesvirus and Merkel cell polyomavirus (MCPyV), were discovered in these patient populations (Chang et al., 1994; Feng et al., 2008; D’Arcy et al., 2021).

Roughly a dozen ‘high-risk’ HPV types cause nearly all cervical cancers, a large majority of other anogenital cancers, and about half of all oropharyngeal cancers (Graham, 2017). The carcinogenic effects of these small circular double-stranded DNA viruses are primarily dependent on the expression of the E6 and E7 oncogenes which, among a wide range of other functions, inactivate the tumor suppressor proteins p53 and Rb, respectively (Rosty et al., 2005; Crook et al., 1991; Mirabello et al., 2017; DeCaprio, 2014; Barbosa et al., 1990).

Polyomaviruses share many biological features with papillomaviruses. In particular, polyomavirus T antigens perform many of the same functions as papillomavirus oncoproteins and are similarly oncogenic in cellular and animal models (Moens and Macdonald, 2019). MCPyV has been identified as an etiological factor in a rare skin cancer, Merkel cell carcinoma (Feng et al., 2008; Shuda et al., 2008; Kassem et al., 2008). Another human polyomavirus, BKPyV, has a long-debated history as a candidate cancer-causing virus. Several case reports have described the detection of BKPyV in bladder cancers arising in transplant recipients, and kidney recipients who develop BKPyV viremia or BKPyV-induced nephropathy (BKVN) after transplant are at increased risk of bladder cancer (Gupta et al., 2018; Vajdic and van Leeuwen, 2009; Li et al., 2021; Papadimitriou et al., 2016).

Similar to HPV-induced cervical and oropharyngeal cancers, bladder cancers exhibit somatic point mutations that are largely attributable to the activity of APOBEC3 family cytosine deaminases (Robertson et al., 2017; Burns et al., 2013; Roberts et al., 2013). These enzymes normally function as innate immune defenses against viruses by deaminating cytosines in single-stranded DNA, leading to hypermutation of the viral genome (Poulain et al., 2020). Commonly, APOBEC3 enzymes, particularly APOBEC3A and APOBEC3B, can become dysregulated and cause carcinogenic damage to cellular DNA during the development of various types of cancer (Swanton et al., 2015). APOBEC3A and APOBEC3B are upregulated in response to the expression of HPV E6 and E7, and APOBEC3A can restrict HPV replication (Mori et al., 2017; Warren et al., 2017; Ahasan et al., 2015; Warren et al., 2015b; Vieira et al., 2014). The large T antigens (LTags) of BKPyV and JC polyomavirus (JCPyV, a close relative of BKPyV) also upregulate APOBEC3B expression and activity (Starrett et al., 2019; Peretti et al., 2018; Verhalen et al., 2016).

To characterize the mutational, transcriptomic, and viral landscapes of bladder cancers arising in immunosuppressed individuals, we evaluated archived tissues from 43 solid organ transplant recipients who developed this malignancy. We performed total RNA sequencing and whole genome sequencing (WGS) from these tissues. We utilized high-sensitivity methods and comprehensive reference databases of sequences for conserved viral proteins to identify known viral species and to search for divergent viruses. Once viruses were identified, we further evaluated the sequence data for integration events, point mutations, mutation signatures, and differentially expressed genes to identify differences correlating with the presence of these viruses and their integration state.

This report presents a comprehensive molecular assessment of 43 bladder cancers arising in solid organ transplant recipients by WGS and total RNA sequencing. DNA and/or RNA sequences of human BK or JC polyomaviruses were detected in 16 tumors (37%). Expression of the polyomavirus LTag was documented immunohistochemically in 10 cases. HPV sequences were detected in six cases, including four cases with HPV types known to cause cervical cancer. Overall, this is a much higher frequency of small DNA tumor virus sequence detection compared to prior surveys of bladder cancers affecting the general population, where fewer than 5% of tumors harbor small DNA tumor virus sequences (Cantalupo et al., 2018; Llewellyn et al., 2018). The results suggest that human polyomaviruses and papillomaviruses can play a carcinogenic role in the development of bladder cancer, particularly among transplant recipients.

BKPyV infection in organotypic urothelial cell culture has been shown to promote cellular proliferation (Schneidewind et al., 2020). This is most likely through the transforming effects of viral T antigens, as is supported here and in previous studies by the loss of late region transcripts and enrichment of early region transcription in primary tumors, and maintenance of these transcripts in metastatic lesions (Müller et al., 2018). Interestingly, we observed frequent clonal loss of the p53-inactivating helicase domain of BKPyV LTag due to deletions and point mutations in the integrated virus. While such deletions in LTag are commonly observed in MCPyV-positive Merkel cell carcinoma (Shuda et al., 2008), MCPyV LTag lacks the p53-inactivating activity of the C-terminal helicase domain of BKPyV. One might thus have expected the C-terminal portion of BKPyV LTag to be preserved in tumor cells. We speculate that the loss of the BKPyV helicase domain is driven by negative selection against deleterious effects of LTag on tumor survival (e.g. LTag might unwind the integrated BKPyV origin of replication and initiate ‘onion skin’ DNA structures leading to chromosomal instability and cell death). The absence of the p53-binding domain may be compensated for in some BKPyV-positive tumors through the significantly increased expression of the ubiquitin ligase TRIM71 that we observed. TRIM71 has been shown to bind and poly-ubiquitinate p53 for proteasomal degradation and prevent apoptosis during stem cell differentiation (Nguyen et al., 2017).

We also observed amplification of the host genome surrounding BKPyV integration sites, consistent with circular DNA intermediates and/or MMEJ break-induced replication. Similar findings have been reported for HPV and MCPyV-associated tumors (Starrett et al., 2020; Czech-Sioli et al., 2020). These amplification events result in a variable number of tandem head-to-tail copies of the virus and host genome that are thought to create super-enhancers affecting viral and host gene expression (Warburton et al., 2018; Dooley et al., 2016). In cervical cancer, frequently only one integration event is transcriptionally active; however, in tumors carrying integrated BKPyV sequences, the abundance of viral DNA and RNA are positively correlated, suggesting that each integrated copy produces viral transcripts. While the observed integration sites in this study are unique and have not been observed in Merkel cell carcinoma, HPV16 integration has been reported previously in BCAR3 (Jeannot et al., 2018). Elevated expression of BCAR3 has been shown to increase the proliferation, motility, and invasiveness of estrogen receptor-positive breast cancer cells after treatment with antiestrogens (Wallez et al., 2014; Wilson et al., 2013).

In five tumors harboring integrated BKPyV sequences (TBC02, TBC03, TBC05, TBC06, and TBC08), we observed significant upregulation of genes associated with cell cycle progression, DNA damage, histones, and the mitotic spindle. Tumors with evidence of BKPyV integration also exhibited significant downregulation of keratins and cell adhesion genes. The latter may contribute to the high-grade and invasive behavior of BKPyV-positive tumors observed in this study and others (Alexiev et al., 2013; Sirohi et al., 2018; Kenan et al., 2015; Kenan et al., 2017; Nickeleit et al., 2018).

Many of the observed gene expression changes are consistent with known effects of BKPyV infection and the specific activities of LTag, which binds Rb-family proteins and alters the active pool of E2F transcription factors in the cell (Caller et al., 2019; Harris et al., 1996). Recent studies have shown that APOBEC3B expression is repressed by the DREAM complex (which is composed of Rb-family proteins and E2F transcription factors Starrett et al., 2019) and, accordingly, we found that APOBEC3B is more highly expressed in BKPyV-positive tumors compared to normal tissues and tumors without tumor virus sequences, likely due to LTag activity. However, despite this increased expression, the mutation signature commonly attributed to APOBEC3B did not appear enriched in BKPyV-positive tumors. It is possible that tumors expressing BKPyV LTag and increased APOBEC3B manifested greater intratumor mutational heterogeneity, but we were unable to detect possible low-frequency APOBEC3-mediated variants from FFPE tissue without deeper and more accurate sequencing. Additionally, consistent with the disruption of the DREAM complex in these tumors, we observed higher expression of MYBL2, a key component of the MMB complex, and one of its targets, FOXM1, which regulates numerous genes required for G2/M progression. We also observed increased expression of FOXM1 downstream targets associated with the centromere and kinetochore, which have been shown to promote improper chromosome segregation and tumorigenesis (Fischer and Müller, 2017; Sadasivam et al., 2012; Schade et al., 2019).

BKPyV-positive tumors in our study had significantly higher expression of a number of genes that promote homologous recombination (e.g. RAD51, RAD54L, BRCA1, and BRCA2) and protect against replication fork stalling and collapse (e.g. RAD51, XRCC2, and FANCB) relative to virus-negative tumors (Tye et al., 2021). Claspin (CLSPN) and TIMELESS, which interact with replicative polymerases and helicases, are also highly expressed in BKPyV-positive tumors, further promoting replication fork progression and genome stability (Bianco et al., 2019). This expression pattern might promote cell survival in the face of genomic damage caused by viral genome integration, oncogene expression, and APOBEC3B upregulation.

While HPVs are not generally considered causative agents of bladder cancer, they have been detected in rare cases of bladder cancer affecting immunocompetent and immunosuppressed patients (Zapatka et al., 2020; Cantalupo et al., 2018; Guma et al., 2016). In the current study, we identified four tumors with carcinogenic Alphapapillomavirus sequences (HPV16 or HPV51). Alphapapillomaviruses are believed to cause cancer through the sustained expression of their E6 and E7 oncoproteins, which is frequently associated with the integration of the papillomavirus genome into the tumor genome.

One case in the panel carried sequences of HPV20, a Betapapillomavirus that can cause cutaneous squamous cell carcinoma in animal model systems (Michel et al., 2006). The possible involvement of Betapapillomaviruses in skin cancer in the general population remains controversial (Viarisio et al., 2018). In epidermodysplasia verruciformis, a rare syndrome caused by defects in zinc-binding proteins EVER1 and EVER2, patients frequently develop non-melanoma skin cancers containing Betapapillomaviruses (Dell’Oste et al., 2009). Expression of E6 and E7 from Betapapillomaviruses has been shown to promote cell survival in the face of ultraviolet radiation damage and other carcinogenic insults (Michel et al., 2006; Viarisio et al., 2018; Viarisio et al., 2016). In the context of bladder cancer, it is possible that cutaneous papillomaviruses likewise enable the accumulation of carcinogenic DNA damage. Additionally, the identification of HPV28, an Alphapapillomavirus that is not generally associated with cervical cancer, suggests more abundant papillomavirus infections of the bladder than previously assumed, with unknown implications for carcinogenesis.

An explanation for the observation that viruses are more prevalent in bladder cancers affecting solid organ transplant recipients compared to cases in the general population is that, in combination with immune suppression, transplant recipients may often become newly infected through transmission from the donor graft at the time of transplantation, perhaps with a different viral genotype than present in the host previously. This phenomenon is commonly observed in kidney transplantation and is associated with BKVN (Solis et al., 2018), but has not been documented for heart, lung, or liver transplant recipients, who are also included in the current study. Additionally, this study and one prior study (Querido et al., 2020) identified JCPyV in bladder tumors. Based on the high degree of similarity between JCPyV and BKPyV, it seems reasonable to expect that the two species would behave similarly. However, the low abundance of JCPyV RNA and DNA in these specimens and the absence of integration, together with the ubiquity of latent JCPyV infections in the urinary tract, raises the possibility that these observations reflect incidental detection events.

The data from this study and others suggest that in the context of strong immune the suppression BKPyV can cause bladder cancer through clonal integration but is rarely detected in tumors of the general population. While most adults are seropositive for BKPyV, with at least 10% having detectable BKPyV in the urine, BKPyV is only observed in upwards of 4% of NMIBC cases and less than 0.25% in muscle-invasive bladder cancers in the general population (Cantalupo et al., 2018; Llewellyn et al., 2018). This implies that, while BKPyV LTag can provide a growth advantage to cells in culture, the large multi-domain antigen may be relatively immunogenic compared to the much smaller oncoproteins encoded by high-risk HPVs or the highly truncated MCPyV LTag isoforms typically observed in Merkel cell carcinomas. Immunologic recognition of these tumors may also be impacted by the increased expression of APOBEC3B, which can generate immunogenic neoantigens (Serebrenik et al., 2019; Chen et al., 2019). Several reports of regression of patients’ BKPyV-positive tumors after reduction of immune suppression support the idea that tumors constitutively expressing BKPyV gene products are readily targeted and controlled by the immune system (Meier et al., 2021; Cuenca et al., 2020; Fu et al., 2018). The theoretical immunological costs of viral gene expression for a nascent tumor cell raise the possibility of ‘hit-and-run’ carcinogenesis. The hit-and-run hypothesis invokes the idea that a virus may play a causal role in the early stages of carcinogenesis but then become undetectable at more advanced stages of tumor development. Infection of a premalignant cell may promote its growth and survival through the expression of the viral oncogenes. Additionally, the expression of viral oncogenes may promote genome instability through the expression of the mutagenic APOBEC3 enzymes or other mechanisms that further push the cell towards transformation, as has been suggested by a recent study of BKPyV infection in differentiated urothelium (Baker et al., 2022).

The heterogeneous expression of LTag observed in this study could represent transcriptional silencing or loss of BKPyV DNA from one part of the tumor, supporting the idea that tumors can lose the need for LTag expression. Alternatively, our observations could be accounted for by a multistage integration and carcinogenesis process proposed by other recent studies on BKPyV-positive urinary tumors from kidney transplant recipients (Jin et al., 2021; Wang et al., 2020). However, our sequencing experiments support a dominant clonally integrated form likely established early during tumor development in most BKPyV-positive tumors in this study. The only exception to this observation is TBC01, which appears to exhibit a viable BKPyV episome with a rearranged regulatory region present in a small subset of tumor cells. This tumor likely represents a passenger infection of an existing tumor (Dalianis and Hirsch, 2013). Future studies should investigate the hypothesis that passenger infections might play an oncomodulatory role in tumor development. This also suggests that archetypal BKPyV, rather than the more pathogenic rearranged strains found in cases of nephropathy, is more likely to integrate and be preserved into nascent tumor cells. In support of the idea that integration may be a more common aspect of BKPyV infection than previously assumed, we identified a clonal BKPyV integrant in the normal bladder specimen from case TBC09 in both the RNA and WGS sequencing that was distinct from the BKPyV integrant observed in the tumor sample. The normal tissue integrant had multiple copies of small T antigen and a large deletion in the regulatory regions (Figure 1—figure supplement 1). Only a few reads from RNA sequencing mapped to the small T antigen region, and histology of the section indicates no tumor cells or LTag staining, suggesting that the virus did not integrate into the right genomic location or maintain the needed components to drive carcinogenesis.

It remains to be seen whether TTVs contribute to disease in the context of immune suppression. A general model is that these ubiquitous viruses establish a chronic infection that the immune system generally keeps in check, but immune suppression results in increases not only in the abundance but also in the diversity of TTVs observed in hosts (De Vlaminck et al., 2013). Indeed, the detection of TTVs can serve as an indicator of the degree of overall immune suppression in transplant recipients (Blatter et al., 2018). Interestingly, these viruses, like papillomaviruses and polyomaviruses, also appear to be depleted for APOBEC3 target motifs, consistent with the effects of an evolutionary virus-host arms race (Poulain et al., 2020; Verhalen et al., 2016; Warren et al., 2015a).

Until recently, this type of molecular assessment from FFPE tissues would have been nearly impossible or badly muddled by the highly damaging effects of formalin fixation and oxidation of nucleic acids over time. Recent advancements in the isolation of nucleic acids, such as low temperature and organic solvent-free deparaffinization, combined with efficient library preparation from low-concentration highly degraded sources, yielded sufficiently high-quality material for WGS variant calling and total RNA sequencing (Robbe et al., 2018). To address the difficulty of accurately calling somatic variants (which can be problematic even from flash-frozen or fresh tissues), we called variants using the consensus of three modern variant callers. The lack of matched normal tissues for most cases is a limitation of this work, but our analytical approach accounted for this by focusing the analysis on mutations with >10% allele frequency and those with potential functional effects, and by excluding known germline variants. Our methods were validated internally through the sequencing of separate regions from the same tumor and of primary-metastatic pairs, which reveal similar concordance of mutations as has been reported from flash-frozen tissues (Zhang et al., 2014). Our variant calling approach was also validated by the observation that we detected four deconvoluted mutation signatures that match those expected from prior surveys of bladder cancer. However, the low overall coverage of our WGS remains a limitation of this study.

We identified four bladder cancers in kidney transplant recipients that exhibited abundant mutations attributable to aristolochic acid-mediated DNA adducts. Aristolochic acid is a highly nephrotoxic and mutagenic compound produced by birthwort plants, which sometimes contaminates certain types of herbal medicines and grains (Poon et al., 2015). Exposure to this compound likely contributed to the patients’ need for kidney transplantation, as well as their eventual development of bladder cancer. Highlighting the highly mutagenic nature of this compound, the four cases with dominant aristolochic acid signatures were in the top seven for total mutation burden (Figure 6). None of the three tumors had detectable oncogenic viral sequences, but one had detectable TTV. We also identified likely ganciclovir-mediated mutations (de Kanter et al., 2021) in most patients indicating that this common treatment to prevent reactivation of cytomegalovirus in solid organ transplant recipients may promote mutagenesis in the urinary bladder. Unfortunately, ganciclovir treatment history was unavailable to confirm that this is the origin of this mutation signature in these cases. Ever-decreasing sequencing costs will facilitate additional studies of this type and shed light on rare and understudied tumor types, as well as analyses of lower-grade and pre-cancerous lesions.

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 https://github.com/gstarrett/oncovirus_tools (Starrett, 2020).

1. 1. Starrett GJ

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   ID OQ469312. Anellovirus sp. isolate TBC35T_k141_22964 ORF1 (ORF1) gene, partial cds; and ORF2 (ORF2) gene, complete cds.

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Author details

1. Gabriel J Starrett

   CCR, NCI, NIH, Bethesda, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   For correspondence

   gabe.starrett@nih.gov

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5871-5306

2. Kelly Yu

   DCEG, NCI, NIH, Rockville, United States

   Contribution

   Data curation, Validation, Project administration, Writing – review and editing

   Competing interests

   No competing interests declared

3. Yelena Golubeva

   Leidos Biomedical Research Inc, Frederick, United States

   Contribution

   Investigation, Writing – review and editing

   Competing interests

   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

   Contribution

   Formal analysis, Validation, Writing – review and editing

   Competing interests

   is affiliated with Leidos Biomedical Research Inc. The author has no financial interests to declare

5. Mary L Piaskowski

   CCR, NCI, NIH, Bethesda, United States

   Contribution

   Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8453-6416

6. David Petersen

   CCR, NCI, NIH, Bethesda, United States

   Contribution

   Validation, Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

7. Michael Dean

   DCEG, NCI, NIH, Rockville, United States

   Contribution

   Resources, Writing – review and editing

   Competing interests

   No competing interests declared

8. Ajay Israni

   Department of Medicine, Nephrology Division, Hennepin Healthcare System, University of Minnesota, Minneapolis, United States

   Contribution

   Resources, Writing – review and editing

   Competing interests

   No competing interests declared

9. Brenda Y Hernandez

   Cancer Center, University of Hawaii, Honolulu, United States

   Contribution

   Resources, Writing – review and editing

   Competing interests

   No competing interests declared

10. Thomas C Tucker

    The Kentucky Cancer Registry, University of Kentucky, Lexington, United States

    Contribution

    Resources, Writing – review and editing

    Competing interests

    No competing interests declared

11. Iona Cheng

    Department of Epidemiology and Biostatistics,and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, Fremont, United States

    Contribution

    Resources, Writing – review and editing

    Competing interests

    No competing interests declared

12. Lou Gonsalves

    Connecticut Tumor Registry, Connecticut Department of Public Health, Hartford, United States

    Contribution

    Resources, Writing – review and editing

    Competing interests

    No competing interests declared

13. Cyllene R Morris

    California Cancer Reporting and Epidemiologic Surveillance Program, University of California, Davis, Davis, United States

    Contribution

    Resources, Writing – review and editing

    Competing interests

    No competing interests declared

14. Shehnaz K Hussain

    Cedars-Sinai Cancer and Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, United States

    Contribution

    Resources, Writing – review and editing

    Competing interests

    No competing interests declared

15. Charles F Lynch

    The Iowa Cancer Registry, University of Iowa, Iowa City, United States

    Contribution

    Resources, Writing – review and editing

    Competing interests

    No competing interests declared

16. Reuben S Harris

    Howard Hughes Medical Institute, University of Minnesota, Minneapolis, United States

    Contribution

    Resources, Writing – review and editing

    Competing interests

    is a co-founder, shareholder, and consultant of ApoGen Biotechnologies Inc

    "This ORCID iD identifies the author of this article:" 0000-0002-9034-9112

17. Ludmila Prokunina-Olsson

    DCEG, NCI, NIH, Rockville, United States

    Contribution

    Resources, Writing – review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-9622-2091

18. Paul S Meltzer

    CCR, NCI, NIH, Bethesda, United States

    Contribution

    Resources, Writing – review and editing

    Competing interests

    No competing interests declared

19. Christopher B Buck

    CCR, NCI, NIH, Bethesda, United States

    Contribution

    Conceptualization, Resources, Supervision, Funding acquisition, Writing – original draft, Project administration, Writing – review and editing

    Contributed equally with

    Eric A Engels

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-3165-8094

20. Eric A Engels

    DCEG, NCI, NIH, Rockville, United States

    Contribution

    Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Writing – original draft, Project administration, Writing – review and editing

    Contributed equally with

    Christopher B Buck

    Competing interests

    No competing interests declared

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