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

   (2022) NCBI dbGaP

   ID phs003012.v1.p1. Multi-omics of Bladder Cancers of Solid Organ Transplant Recipients.

   https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs003012.v1.p1
2. 1. Starrett GJ

   (2023) figshare

   pAb416 IHC images.

   https://doi.org/10.6084/m9.figshare.19199723.v1
3. 1. Starrett GJ

   (2023) figshare

   Anelloviridae contigs.

   https://doi.org/10.6084/m9.figshare.22124240.v1
4. 1. Starrett GJ

   (2023) NCBI Nucleotide

   ID OQ469311. Anellovirus sp. isolate TBC35T_k141_20313 ORF2/4 (ORF2/4) gene, complete cds; and ORF1 (ORF1) gene, partial cds.

   https://www.ncbi.nlm.nih.gov/nuccore/OQ469311
5. 1. Starrett GJ

   (2023) NCBI Nucleotide

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

   https://www.ncbi.nlm.nih.gov/nuccore/OQ469312

1. 1. Ahasan MM
   2. Wakae K
   3. Wang Z
   4. Kitamura K
   5. Liu G
   6. Koura M
   7. Imayasu M
   8. Sakamoto N
   9. Hanaoka K
   10. Nakamura M
   11. Kyo S
   12. Kondo S
   13. Fujiwara H
   14. Yoshizaki T
   15. Mori S
   16. Kukimoto I
   17. Muramatsu M

   (2015) Apobec3A and 3C decrease human papillomavirus 16 pseudovirion infectivity

   Biochemical and Biophysical Research Communications 457:295–299.

   https://doi.org/10.1016/j.bbrc.2014.12.103

   • PubMed
   • Google Scholar
2. 1. Akagi K
   2. Li J
   3. Broutian TR
   4. Padilla-Nash H
   5. Xiao W
   6. Jiang B
   7. Rocco JW
   8. Teknos TN
   9. Kumar B
   10. Wangsa D
   11. He D
   12. Ried T
   13. Symer DE
   14. Gillison ML

   (2014) Genome-Wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability

   Genome Research 24:185–199.

   https://doi.org/10.1101/gr.164806.113

   • PubMed
   • Google Scholar
3. 1. Alexiev BA
   2. Randhawa P
   3. Vazquez Martul E
   4. Zeng G
   5. Luo C
   6. Ramos E
   7. Drachenberg CB
   8. Papadimitriou JC

   (2013) Bk virus-associated urinary bladder carcinoma in transplant recipients: report of 2 cases, review of the literature, and proposed pathogenetic model

   Human Pathology 44:908–917.

   https://doi.org/10.1016/j.humpath.2012.09.019

   • PubMed
   • Google Scholar
4. 1. Baker SC
   2. Mason AS
   3. Slip RG
   4. Skinner KT
   5. Macdonald A
   6. Masood O
   7. Harris RS
   8. Fenton TR
   9. Periyasamy M
   10. Ali S
   11. Southgate J

   (2022) Induction of APOBEC3-mediated genomic damage in urothelium implicates BK polyomavirus (bkpyv) as a Hit-and-run driver for bladder cancer

   Oncogene 41:2139–2151.

   https://doi.org/10.1038/s41388-022-02235-8

   • PubMed
   • Google Scholar
5. 1. Bankevich A
   2. Nurk S
   3. Antipov D
   4. Gurevich AA
   5. Dvorkin M
   6. Kulikov AS
   7. Lesin VM
   8. Nikolenko SI
   9. Pham S
   10. Prjibelski AD
   11. Pyshkin AV
   12. Sirotkin AV
   13. Vyahhi N
   14. Tesler G
   15. Alekseyev MA
   16. Pevzner PA

   (2012) SPAdes: a new genome assembly algorithm and its applications to single-cell sequencing

   Journal of Computational Biology 19:455–477.

   https://doi.org/10.1089/cmb.2012.0021

   • PubMed
   • Google Scholar
6. 1. Barbosa MS
   2. Edmonds C
   3. Fisher C
   4. Schiller JT
   5. Lowy DR
   6. Vousden KH

   (1990) The region of the HPV E7 oncoprotein homologous to adenovirus E1A and SV40 large T antigen contains separate domains for Rb binding and casein kinase II phosphorylation

   The EMBO Journal 9:153–160.

   https://doi.org/10.1002/j.1460-2075.1990.tb08091.x

   • PubMed
   • Google Scholar
7. 1. Bianco JN
   2. Bergoglio V
   3. Lin Y-L
   4. Pillaire M-J
   5. Schmitz A-L
   6. Gilhodes J
   7. Lusque A
   8. Mazières J
   9. Lacroix-Triki M
   10. Roumeliotis TI
   11. Choudhary J
   12. Moreaux J
   13. Hoffmann J-S
   14. Tourrière H
   15. Pasero P

   (2019) Overexpression of Claspin and timeless protects cancer cells from replication stress in a checkpoint-independent manner

   Nature Communications 10:910.

   https://doi.org/10.1038/s41467-019-08886-8

   • PubMed
   • Google Scholar
8. 1. Blatter JA
   2. Sweet SC
   3. Conrad C
   4. Danziger-Isakov LA
   5. Faro A
   6. Goldfarb SB
   7. Hayes D
   8. Melicoff E
   9. Schecter M
   10. Storch G
   11. Visner GA
   12. Williams NM
   13. Wang D

   (2018) Anellovirus loads are associated with outcomes in pediatric lung transplantation

   Pediatric Transplantation 22:13069.

   https://doi.org/10.1111/petr.13069

   • PubMed
   • Google Scholar
9. 1. Burns MB
   2. Temiz NA
   3. Harris RS

   (2013) Evidence for APOBEC3B mutagenesis in multiple human cancers

   Nature Genetics 45:977–983.

   https://doi.org/10.1038/ng.2701

   • PubMed
   • Google Scholar
10. 1. Bushmanova E
    2. Antipov D
    3. Lapidus A
    4. Prjibelski AD

    (2019) RnaSPAdes: a de novo transcriptome assembler and its application to RNA-Seq data

    GigaScience 8:giz100.

    https://doi.org/10.1093/gigascience/giz100

    • PubMed
    • Google Scholar
11. 1. Caller LG
    2. Davies CTR
    3. Antrobus R
    4. Lehner PJ
    5. Weekes MP
    6. Crump CM

    (2019) Temporal proteomic analysis of BK polyomavirus infection reveals virus-induced g₂ arrest and highly effective evasion of innate immune sensing

    Journal of Virology 93:e00595-19.

    https://doi.org/10.1128/JVI.00595-19

    • PubMed
    • Google Scholar
12. 1. Cancer T
    2. Atlas G
    3. Weinstein JN
    4. Akbani R
    5. Broom BM
    6. Wang W

    (2014) Comprehensive molecular characterization of urothelial bladder carcinoma

    Nature 507:315–322.

    https://doi.org/10.1038/nature12965

    • PubMed
    • Google Scholar
13. 1. Cantalupo PG
    2. Katz JP
    3. Pipas JM

    (2018) Viral sequences in human cancer

    Virology 513:208–216.

    https://doi.org/10.1016/j.virol.2017.10.017

    • PubMed
    • Google Scholar
14. 1. Chang Y
    2. Cesarman E
    3. Pessin MS
    4. Lee F
    5. Culpepper J
    6. Knowles DM
    7. Moore PS

    (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma

    Science 266:1865–1869.

    https://doi.org/10.1126/science.7997879

    • PubMed
    • Google Scholar
15. 1. Chen EY
    2. Tan CM
    3. Kou Y
    4. Duan Q
    5. Wang Z
    6. Meirelles GV
    7. Clark NR
    8. Ma’ayan A

    (2013) Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool

    BMC Bioinformatics 14:128.

    https://doi.org/10.1186/1471-2105-14-128

    • PubMed
    • Google Scholar
16. 1. Chen Z
    2. Wen W
    3. Bao J
    4. Kuhs KL
    5. Cai Q
    6. Long J
    7. Shu X-O
    8. Zheng W
    9. Guo X

    (2019) Integrative genomic analyses of APOBEC-mutational signature, expression and germline deletion of APOBEC3 genes, and immunogenicity in multiple cancer types

    BMC Medical Genomics 12:131.

    https://doi.org/10.1186/s12920-019-0579-3

    • PubMed
    • Google Scholar
17. 1. Crook T
    2. Tidy JA
    3. Vousden KH

    (1991) Degradation of p53 can be targeted by HPV E6 sequences distinct from those required for p53 binding and trans-activation

    Cell 67:547–556.

    https://doi.org/10.1016/0092-8674(91)90529-8

    • PubMed
    • Google Scholar
18. 1. Cuenca AG
    2. Rosales I
    3. Lee RJ
    4. Wu C-L
    5. Colvin R
    6. Feldman AS
    7. Efstathiou JA
    8. Tolkoff-Rubin N
    9. Elias N

    (2020) Resolution of A high grade and metastatic BK polyomavirus-associated urothelial cell carcinoma following radical allograft nephroureterectomy and immune checkpoint treatment: A case report

    Transplantation Proceedings 52:2720–2725.

    https://doi.org/10.1016/j.transproceed.2020.06.012

    • PubMed
    • Google Scholar
19. 1. Czech-Sioli M
    2. Günther T
    3. Therre M
    4. Spohn M
    5. Indenbirken D
    6. Theiss J
    7. Riethdorf S
    8. Qi M
    9. Alawi M
    10. Wülbeck C
    11. Fernandez-Cuesta I
    12. Esmek F
    13. Becker JC
    14. Grundhoff A
    15. Fischer N

    (2020) High-resolution analysis of merkel cell polyomavirus in merkel cell carcinoma reveals distinct integration patterns and suggests NHEJ and MMBIR as underlying mechanisms

    PLOS Pathogens 16:e1008562.

    https://doi.org/10.1371/journal.ppat.1008562

    • PubMed
    • Google Scholar
20. 1. Dalianis T
    2. Hirsch HH

    (2013) Human polyomaviruses in disease and cancer

    Virology 437:63–72.

    https://doi.org/10.1016/j.virol.2012.12.015

    • PubMed
    • Google Scholar
21. 1. D’Arcy ME
    2. Castenson D
    3. Lynch CF
    4. Kahn AR
    5. Morton LM
    6. Shiels MS
    7. Pfeiffer RM
    8. Engels EA

    (2021) Risk of rare cancers among solid organ transplant recipients

    Journal of the National Cancer Institute 113:199–207.

    https://doi.org/10.1093/jnci/djaa078

    • PubMed
    • Google Scholar
22. 1. DeCaprio JA

    (2014) Human papillomavirus type 16 E7 perturbs DREAM to promote cellular proliferation and mitotic gene expression

    Oncogene 33:4036–4038.

    https://doi.org/10.1038/onc.2013.449

    • PubMed
    • Google Scholar
23. 1. de Kanter JK
    2. Peci F
    3. Bertrums E
    4. Rosendahl Huber A
    5. van Leeuwen A
    6. van Roosmalen MJ
    7. Manders F
    8. Verheul M
    9. Oka R
    10. Brandsma AM
    11. Bierings M
    12. Belderbos M
    13. van Boxtel R

    (2021) Antiviral treatment causes a unique mutational signature in cancers of transplantation recipients

    Cell Stem Cell 28:1726–1739.

    https://doi.org/10.1016/j.stem.2021.07.012

    • PubMed
    • Google Scholar
24. 1. Dell’Oste V
    2. Azzimonti B
    3. De Andrea M
    4. Mondini M
    5. Zavattaro E
    6. Leigheb G
    7. Weissenborn SJ
    8. Pfister H
    9. Michael KM
    10. Waterboer T
    11. Pawlita M
    12. Amantea A
    13. Landolfo S
    14. Gariglio M

    (2009) High beta-HPV DNA loads and strong seroreactivity are present in epidermodysplasia verruciformis

    The Journal of Investigative Dermatology 129:1026–1034.

    https://doi.org/10.1038/jid.2008.317

    • PubMed
    • Google Scholar
25. 1. de Martel C
    2. Georges D
    3. Bray F
    4. Ferlay J
    5. Clifford GM

    (2020) Global burden of cancer attributable to infections in 2018: a worldwide incidence analysis

    The Lancet. Global Health 8:e180–e190.

    https://doi.org/10.1016/S2214-109X(19)30488-7

    • PubMed
    • Google Scholar
26. 1. De Vlaminck I
    2. Khush KK
    3. Strehl C
    4. Kohli B
    5. Luikart H
    6. Neff NF
    7. Okamoto J
    8. Snyder TM
    9. Cornfield DN
    10. Nicolls MR
    11. Weill D
    12. Bernstein D
    13. Valantine HA
    14. Quake SR

    (2013) Temporal response of the human virome to immunosuppression and antiviral therapy

    Cell 155:1178–1187.

    https://doi.org/10.1016/j.cell.2013.10.034

    • PubMed
    • Google Scholar
27. 1. Dobin A
    2. Davis CA
    3. Schlesinger F
    4. Drenkow J
    5. Zaleski C
    6. Jha S
    7. Batut P
    8. Chaisson M
    9. Gingeras TR

    (2013) Star: ultrafast universal RNA-seq aligner

    Bioinformatics 29:15–21.

    https://doi.org/10.1093/bioinformatics/bts635

    • PubMed
    • Google Scholar
28. 1. Dooley KE
    2. Warburton A
    3. McBride AA

    (2016) Tandemly integrated HPV16 can form a BRD4-dependent super-enhancer-like element that drives transcription of viral oncogenes

    MBio 7:e01446-16.

    https://doi.org/10.1128/mBio.01446-16

    • PubMed
    • Google Scholar
29. 1. Fang LT
    2. Afshar PT
    3. Chhibber A
    4. Mohiyuddin M
    5. Fan Y
    6. Mu JC
    7. Gibeling G
    8. Barr S
    9. Asadi NB
    10. Gerstein MB
    11. Koboldt DC
    12. Wang W
    13. Wong WH
    14. Lam HYK

    (2015) An ensemble approach to accurately detect somatic mutations using somaticseq

    Genome Biology 16:197.

    https://doi.org/10.1186/s13059-015-0758-2

    • PubMed
    • Google Scholar
30. 1. Feng H
    2. Shuda M
    3. Chang Y
    4. Moore PS

    (2008) Clonal integration of a polyomavirus in human Merkel cell carcinoma

    Science 319:1096–1100.

    https://doi.org/10.1126/science.1152586

    • PubMed
    • Google Scholar
31. 1. Fischer M
    2. Müller GA

    (2017) Cell cycle transcription control: DREAM/muvb and Rb-E2F complexes

    Critical Reviews in Biochemistry and Molecular Biology 52:638–662.

    https://doi.org/10.1080/10409238.2017.1360836

    • PubMed
    • Google Scholar
32. 1. Fu F
    2. Deng W
    3. Yu S
    4. Liu Y
    5. Yu L
    6. Liu R
    7. Lang J
    8. Geng D
    9. Geng J
    10. Li J
    11. Huang G
    12. Luo M
    13. Xiong F
    14. Wu C-L
    15. Miao Y

    (2018) Occurrence and regression of BK polyomavirus associated carcinoma: a clinical and next-generation sequencing study

    Clinical Science 132:1753–1763.

    https://doi.org/10.1042/CS20180443

    • PubMed
    • Google Scholar
33. 1. Graham SV

    (2017) The human papillomavirus replication cycle, and its links to cancer progression: a comprehensive review

    Clinical Science 131:2201–2221.

    https://doi.org/10.1042/CS20160786

    • PubMed
    • Google Scholar
34. 1. Guma S
    2. Maglantay R
    3. Lau R
    4. Wieczorek R
    5. Melamed J
    6. Deng F-M
    7. Zhou M
    8. Makarov D
    9. Lee P
    10. Pincus MR
    11. Pei Z-H

    (2016)

    Papillary urothelial carcinoma with squamous differentiation in association with human papilloma virus: case report and literature review

    American Journal of Clinical and Experimental Urology 4:12–16.

    • PubMed
    • Google Scholar
35. 1. Gupta G
    2. Kuppachi S
    3. Kalil RS
    4. Buck CB
    5. Lynch CF
    6. Engels EA

    (2018) Treatment for presumed BK polyomavirus nephropathy and risk of urinary tract cancers among kidney transplant recipients in the United States

    American Journal of Transplantation 18:245–252.

    https://doi.org/10.1111/ajt.14530

    • PubMed
    • Google Scholar
36. 1. Harris KF
    2. Christensen JB
    3. Imperiale MJ

    (1996) Bk virus large T antigen: interactions with the retinoblastoma family of tumor suppressor proteins and effects on cellular growth control

    Journal of Virology 70:2378–2386.

    https://doi.org/10.1128/JVI.70.4.2378-2386.1996

    • PubMed
    • Google Scholar
37. 1. Jeannot E
    2. Harlé A
    3. Holmes A
    4. Sastre-Garau X

    (2018) Nuclear factor I X is a recurrent target for HPV16 insertions in anal carcinomas

    Genes, Chromosomes & Cancer 57:638–644.

    https://doi.org/10.1002/gcc.22675

    • PubMed
    • Google Scholar
38. 1. Jin Y
    2. Zhou Y
    3. Deng W
    4. Wang Y
    5. Lee RJ
    6. Liu Y
    7. Elias N
    8. Hu Y
    9. Luo M-H
    10. Liu R
    11. Guan B
    12. Geng J
    13. Xu J
    14. Ma J
    15. Zhou J
    16. Liu N
    17. Blute ML
    18. Colvin RB
    19. Wu C-L
    20. Miao Y

    (2021) 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.

    https://doi.org/10.1038/s41388-020-01502-w

    • PubMed
    • Google Scholar
39. 1. Kassem A
    2. Schöpflin A
    3. Diaz C
    4. Weyers W
    5. Stickeler E
    6. Werner M
    7. Zur Hausen A

    (2008) Frequent detection of Merkel cell polyomavirus in human Merkel cell carcinomas and identification of a unique deletion in the VP1 gene

    Cancer Research 68:5009–5013.

    https://doi.org/10.1158/0008-5472.CAN-08-0949

    • PubMed
    • Google Scholar
40. 1. Kenan DJ
    2. Mieczkowski PA
    3. Burger-Calderon R
    4. Singh HK
    5. Nickeleit V

    (2015) The oncogenic potential of BK-polyomavirus is linked to viral integration into the human genome

    The Journal of Pathology 237:379–389.

    https://doi.org/10.1002/path.4584

    • PubMed
    • Google Scholar
41. 1. Kenan DJ
    2. Mieczkowski PA
    3. Latulippe E
    4. Côté I
    5. Singh HK
    6. Nickeleit V

    (2017) Bk polyomavirus genomic integration and large T antigen expression: evolving paradigms in human oncogenesis

    American Journal of Transplantation 17:1674–1680.

    https://doi.org/10.1111/ajt.14191

    • PubMed
    • Google Scholar
42. 1. Koboldt DC
    2. Zhang Q
    3. Larson DE
    4. Shen D
    5. McLellan MD
    6. Lin L
    7. Miller CA
    8. Mardis ER
    9. Ding L
    10. Wilson RK

    (2012) VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing

    Genome Research 22:568–576.

    https://doi.org/10.1101/gr.129684.111

    • PubMed
    • Google Scholar
43. 1. Kuleshov MV
    2. Jones MR
    3. Rouillard AD
    4. Fernandez NF
    5. Duan Q
    6. Wang Z
    7. Koplev S
    8. Jenkins SL
    9. Jagodnik KM
    10. Lachmann A
    11. McDermott MG
    12. Monteiro CD
    13. Gundersen GW
    14. Ma’ayan A

    (2016) Enrichr: a comprehensive gene set enrichment analysis web server 2016 update

    Nucleic Acids Research 44:W90–W97.

    https://doi.org/10.1093/nar/gkw377

    • PubMed
    • Google Scholar
44. 1. Langmead B
    2. Salzberg SL

    (2012) Fast gapped-read alignment with bowtie 2

    Nature Methods 9:357–359.

    https://doi.org/10.1038/nmeth.1923

    • PubMed
    • Google Scholar
45. 1. Li D
    2. Liu CM
    3. Luo R
    4. Sadakane K
    5. Lam TW

    (2015) MEGAHIT: an ultra-fast single-node solution for large and complex metagenomics assembly via succinct de bruijn graph

    Bioinformatics 31:1674–1676.

    https://doi.org/10.1093/bioinformatics/btv033

    • PubMed
    • Google Scholar
46. 1. Li Y-J
    2. Wu H-H
    3. Chen C-H
    4. Wang H-H
    5. Chiang Y-J
    6. Hsu H-H
    7. Pang S-T
    8. Wang RYL
    9. Tian Y-C

    (2021) High incidence and early onset of urinary tract cancers in patients with BK polyomavirus associated nephropathy

    Viruses 13:476.

    https://doi.org/10.3390/v13030476

    • PubMed
    • Google Scholar
47. 1. Llewellyn MA
    2. Gordon NS
    3. Abbotts B
    4. James ND
    5. Zeegers MP
    6. Cheng KK
    7. Macdonald A
    8. Roberts S
    9. Parish JL
    10. Ward DG
    11. Bryan RT

    (2018) Defining the frequency of human papillomavirus and polyomavirus infection in urothelial bladder tumours

    Scientific Reports 8:11290.

    https://doi.org/10.1038/s41598-018-29438-y

    • PubMed
    • Google Scholar
48. 1. Love MI
    2. Huber W
    3. Anders S

    (2014) Moderated estimation of fold change and dispersion for RNA-seq data with deseq2

    Genome Biology 15:550.

    https://doi.org/10.1186/s13059-014-0550-8

    • PubMed
    • Google Scholar
49. 1. Martí-Carreras J
    2. Mineeva-Sangwo O
    3. Topalis D
    4. Snoeck R
    5. Andrei G
    6. Maes P

    (2020) BKTyper: free online tool for polyoma BK virus VP1 and NCCR typing

    Viruses 12:837.

    https://doi.org/10.3390/v12080837

    • PubMed
    • Google Scholar
50. 1. Meier RPH
    2. Muller YD
    3. Dietrich P-Y
    4. Tille J-C
    5. Nikolaev S
    6. Sartori A
    7. Labidi-Galy I
    8. Ernandez T
    9. Kaur A
    10. Hirsch HH
    11. McKee TA
    12. Toso C
    13. Villard J
    14. Berney T

    (2021) Immunologic clearance of a BK virus-associated metastatic renal allograft carcinoma

    Transplantation 105:423–429.

    https://doi.org/10.1097/TP.0000000000003193

    • PubMed
    • Google Scholar
51. 1. Michel A
    2. Kopp-Schneider A
    3. Zentgraf H
    4. Gruber AD
    5. de Villiers E-M

    (2006) E6/E7 expression of human papillomavirus type 20 (HPV-20) and HPV-27 influences proliferation and differentiation of the skin in UV-irradiated SKH-hr1 transgenic mice

    Journal of Virology 80:11153–11164.

    https://doi.org/10.1128/JVI.00954-06

    • PubMed
    • Google Scholar
52. 1. Mirabello L
    2. Yeager M
    3. Yu K
    4. Clifford GM
    5. Xiao Y
    6. Zhu B
    7. Cullen M
    8. Boland JF
    9. Wentzensen N
    10. Nelson CW
    11. Raine-Bennett T
    12. Chen Z
    13. Bass S
    14. Song L
    15. Yang Q
    16. Steinberg M
    17. Burdett L
    18. Dean M
    19. Roberson D
    20. Mitchell J
    21. Lorey T
    22. Franceschi S
    23. Castle PE
    24. Walker J
    25. Zuna R
    26. Kreimer AR
    27. Beachler DC
    28. Hildesheim A
    29. Gonzalez P
    30. Porras C
    31. Burk RD
    32. Schiffman M

    (2017) Hpv16 E7 genetic conservation is critical to carcinogenesis

    Cell 170:1164–1174.

    https://doi.org/10.1016/j.cell.2017.08.001

    • PubMed
    • Google Scholar
53. 1. Moens U
    2. Macdonald A

    (2019) Effect of the large and small T-antigens of human polyomaviruses on signaling pathways

    International Journal of Molecular Sciences 20:3914.

    https://doi.org/10.3390/ijms20163914

    • PubMed
    • Google Scholar
54. 1. Mori S
    2. Takeuchi T
    3. Ishii Y
    4. Yugawa T
    5. Kiyono T
    6. Nishina H
    7. Kukimoto I

    (2017) Human papillomavirus 16 E6 upregulates APOBEC3B via the TeaD transcription factor

    Journal of Virology 91:e02413-16.

    https://doi.org/10.1128/JVI.02413-16

    • PubMed
    • Google Scholar
55. 1. Müller DC
    2. Rämö M
    3. Naegele K
    4. Ribi S
    5. Wetterauer C
    6. Perrina V
    7. Quagliata L
    8. Vlajnic T
    9. Ruiz C
    10. Balitzki B
    11. Grobholz R
    12. Gosert R
    13. Ajuh ET
    14. Hirsch HH
    15. Bubendorf L
    16. Rentsch CA

    (2018) Donor-Derived, metastatic urothelial cancer after kidney transplantation associated with a potentially oncogenic BK polyomavirus

    The Journal of Pathology 244:265–270.

    https://doi.org/10.1002/path.5012

    • PubMed
    • Google Scholar
56. 1. Nassar AH
    2. Umeton R
    3. Kim J
    4. Lundgren K
    5. Harshman L
    6. Van Allen EM
    7. Preston M
    8. Dong F
    9. Bellmunt J
    10. Mouw KW
    11. Choueiri TK
    12. Sonpavde G
    13. Kwiatkowski DJ

    (2019) Mutational analysis of 472 urothelial carcinoma across grades and anatomic sites

    Clinical Cancer Research 25:2458–2470.

    https://doi.org/10.1158/1078-0432.CCR-18-3147

    • PubMed
    • Google Scholar
57. 1. Nguyen DTT
    2. Richter D
    3. Michel G
    4. Mitschka S
    5. Kolanus W
    6. Cuevas E
    7. Wulczyn FG

    (2017) The ubiquitin ligase LIN41/TRIM71 targets p53 to antagonize cell death and differentiation pathways during stem cell differentiation

    Cell Death and Differentiation 24:1063–1078.

    https://doi.org/10.1038/cdd.2017.54

    • PubMed
    • Google Scholar
58. 1. Nickeleit V
    2. Singh HK
    3. Kenan DJ
    4. Mieczkowski PA

    (2018) The two-faced nature of BK polyomavirus: lytic infection or non-lytic large-T-positive carcinoma

    The Journal of Pathology 246:7–11.

    https://doi.org/10.1002/path.5127

    • PubMed
    • Google Scholar
59. 1. Papadimitriou JC
    2. Randhawa P
    3. Rinaldo CH
    4. Drachenberg CB
    5. Alexiev B
    6. Hirsch HH

    (2016) Bk polyomavirus infection and renourinary tumorigenesis

    American Journal of Transplantation 16:398–406.

    https://doi.org/10.1111/ajt.13550

    • PubMed
    • Google Scholar
60. 1. Peretti A
    2. Geoghegan EM
    3. Pastrana DV
    4. Smola S
    5. Feld P
    6. Sauter M
    7. Lohse S
    8. Ramesh M
    9. Lim ES
    10. Wang D
    11. Borgogna C
    12. FitzGerald PC
    13. Bliskovsky V
    14. Starrett GJ
    15. Law EK
    16. Harris RS
    17. Killian JK
    18. Zhu J
    19. Pineda M
    20. Meltzer PS
    21. Boldorini R
    22. Gariglio M
    23. Buck CB

    (2018) Characterization of BK polyomaviruses from kidney transplant recipients suggests a role for APOBEC3 in driving in-host virus evolution

    Cell Host & Microbe 23:628–635.

    https://doi.org/10.1016/j.chom.2018.04.005

    • PubMed
    • Google Scholar
61. 1. Poon SL
    2. Huang MN
    3. Choo Y
    4. McPherson JR
    5. Yu W
    6. Heng HL
    7. Gan A
    8. Myint SS
    9. Siew EY
    10. Ler LD
    11. Ng LG
    12. Weng W-H
    13. Chuang C-K
    14. Yuen JS
    15. Pang S-T
    16. Tan P
    17. Teh BT
    18. Rozen SG

    (2015) Mutation signatures implicate aristolochic acid in bladder cancer development

    Genome Medicine 7:38.

    https://doi.org/10.1186/s13073-015-0161-3

    • PubMed
    • Google Scholar
62. 1. Poulain F
    2. Lejeune N
    3. Willemart K
    4. Gillet NA

    (2020) Footprint of the host restriction factors APOBEC3 on the genome of human viruses

    PLOS Pathogens 16:e1008718.

    https://doi.org/10.1371/journal.ppat.1008718

    • PubMed
    • Google Scholar
63. 1. Querido S
    2. Fernandes I
    3. Weigert A
    4. Casimiro S
    5. Albuquerque C
    6. Ramos S
    7. Adragão T
    8. Luz I
    9. Paixão P
    10. Chasqueira M
    11. Santos M
    12. Machado D

    (2020) High-grade urothelial carcinoma in a kidney transplant recipient after JC virus nephropathy: the first evidence of JC virus as a potential oncovirus in bladder cancer

    American Journal of Transplantation 20:1188–1191.

    https://doi.org/10.1111/ajt.15663

    • PubMed
    • Google Scholar
64. 1. Robbe P
    2. Popitsch N
    3. Knight SJL
    4. Antoniou P
    5. Becq J
    6. He M
    7. Kanapin A
    8. Samsonova A
    9. Vavoulis DV
    10. Ross MT
    11. Kingsbury Z
    12. Cabes M
    13. Ramos SDC
    14. Page S
    15. Dreau H
    16. Ridout K
    17. Jones LJ
    18. Tuff-Lacey A
    19. Henderson S
    20. Mason J
    21. Buffa FM
    22. Verrill C
    23. Maldonado-Perez D
    24. Roxanis I
    25. Collantes E
    26. Browning L
    27. Dhar S
    28. Damato S
    29. Davies S
    30. Caulfield M
    31. Bentley DR
    32. Taylor JC
    33. Turnbull C
    34. Schuh A
    35. 100,000 Genomes Project

    (2018) Clinical whole-genome sequencing from routine formalin-fixed, paraffin-embedded specimens: pilot study for the 100,000 genomes project

    Genetics in Medicine 20:1196–1205.

    https://doi.org/10.1038/gim.2017.241

    • PubMed
    • Google Scholar
65. 1. Roberts SA
    2. Lawrence MS
    3. Klimczak LJ
    4. Grimm SA
    5. Fargo D
    6. Stojanov P
    7. Kiezun A
    8. Kryukov GV
    9. Carter SL
    10. Saksena G
    11. Harris S
    12. Shah RR
    13. Resnick MA
    14. Getz G
    15. Gordenin DA

    (2013) An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers

    Nature Genetics 45:970–976.

    https://doi.org/10.1038/ng.2702

    • PubMed
    • Google Scholar
66. 1. Robertson AG
    2. Kim J
    3. Al-Ahmadie H
    4. Bellmunt J
    5. Guo G
    6. Cherniack AD
    7. Hinoue T
    8. Laird PW
    9. Hoadley KA
    10. Akbani R
    11. Castro MAA
    12. Gibb EA
    13. Kanchi RS
    14. Gordenin DA
    15. Shukla SA
    16. Sanchez-Vega F
    17. Hansel DE
    18. Czerniak BA
    19. Reuter VE
    20. Su X
    21. de Sa Carvalho B
    22. Chagas VS
    23. Mungall KL
    24. Sadeghi S
    25. Pedamallu CS
    26. Lu Y
    27. Klimczak LJ
    28. Zhang J
    29. Choo C
    30. Ojesina AI
    31. Bullman S
    32. Leraas KM
    33. Lichtenberg TM
    34. Wu CJ
    35. Schultz N
    36. Getz G
    37. Meyerson M
    38. Mills GB
    39. McConkey DJ
    40. TCGA Research Network
    41. Weinstein JN
    42. Kwiatkowski DJ
    43. Lerner SP

    (2017) Comprehensive molecular characterization of muscle-invasive bladder cancer

    Cell 171:540–556.

    https://doi.org/10.1016/j.cell.2017.09.007

    • PubMed
    • Google Scholar
67. 1. Rosty C
    2. Sheffer M
    3. Tsafrir D
    4. Stransky N
    5. Tsafrir I
    6. Peter M
    7. de Crémoux P
    8. de La Rochefordière A
    9. Salmon R
    10. Dorval T
    11. Thiery JP
    12. Couturier J
    13. Radvanyi F
    14. Domany E
    15. Sastre-Garau X

    (2005) Identification of a proliferation gene cluster associated with HPV E6/E7 expression level and viral DNA load in invasive cervical carcinoma

    Oncogene 24:7094–7104.

    https://doi.org/10.1038/sj.onc.1208854

    • PubMed
    • Google Scholar
68. 1. Sadasivam S
    2. Duan S
    3. DeCaprio JA

    (2012) The muvb complex sequentially recruits B-Myb and FoxM1 to promote mitotic gene expression

    Genes & Development 26:474–489.

    https://doi.org/10.1101/gad.181933.111

    • PubMed
    • Google Scholar
69. 1. Schade AE
    2. Oser MG
    3. Nicholson HE
    4. DeCaprio JA

    (2019) Cyclin D-Cdk4 relieves cooperative repression of proliferation and cell cycle gene expression by DREAM and Rb

    Oncogene 38:4962–4976.

    https://doi.org/10.1038/s41388-019-0767-9

    • PubMed
    • Google Scholar
70. 1. Schneidewind L
    2. Neumann T
    3. Plis A
    4. Brückmann S
    5. Keiser M
    6. Krüger W
    7. Schmidt CA

    (2020) Novel 3D organotypic urothelial cell culture model for identification of new therapeutic approaches in urological infections

    Journal of Clinical Virology 124:104283.

    https://doi.org/10.1016/j.jcv.2020.104283

    • PubMed
    • Google Scholar
71. 1. Serebrenik AA
    2. Starrett GJ
    3. Leenen S
    4. Jarvis MC
    5. Shaban NM
    6. Salamango DJ
    7. Nilsen H
    8. Brown WL
    9. Harris RS

    (2019) The deaminase APOBEC3B triggers the death of cells lacking uracil DNA glycosylase

    PNAS 116:22158–22163.

    https://doi.org/10.1073/pnas.1904024116

    • PubMed
    • Google Scholar
72. 1. Shuda M
    2. Feng H
    3. Kwun HJ
    4. Rosen ST
    5. Gjoerup O
    6. Moore PS
    7. Chang Y

    (2008) T antigen mutations are a human tumor-specific signature for merkel cell polyomavirus

    PNAS 105:16272–16277.

    https://doi.org/10.1073/pnas.0806526105

    • PubMed
    • Google Scholar
73. 1. Sirohi D
    2. Vaske C
    3. Sanborn Z
    4. Smith SC
    5. Don MD
    6. Lindsey KG
    7. Federman S
    8. Vankalakunti M
    9. Koo J
    10. Bose S
    11. Peralta-Venturina M de
    12. Ziffle J
    13. Grenert JP
    14. Miller S
    15. Chiu C
    16. Amin MB
    17. Simko JP
    18. Stohr BA
    19. Luthringer DJ

    (2018) Polyoma virus-associated carcinomas of the urologic tract: a clinicopathologic and molecular study

    Modern Pathology 31:1429–1441.

    https://doi.org/10.1038/s41379-018-0065-z

    • PubMed
    • Google Scholar
74. 1. Solis M
    2. Velay A
    3. Porcher R
    4. Domingo-Calap P
    5. Soulier E
    6. Joly M
    7. Meddeb M
    8. Kack-Kack W
    9. Moulin B
    10. Bahram S
    11. Stoll-Keller F
    12. Barth H
    13. Caillard S
    14. Fafi-Kremer S

    (2018) Neutralizing antibody-mediated response and risk of BK virus-associated nephropathy

    Journal of the American Society of Nephrology 29:326–334.

    https://doi.org/10.1681/ASN.2017050532

    • PubMed
    • Google Scholar
75. 1. Starrett GJ
    2. Marcelus C
    3. Cantalupo PG
    4. Katz JP
    5. Cheng J
    6. Akagi K
    7. Thakuria M
    8. Rabinowits G
    9. Wang LC
    10. Symer DE
    11. Pipas JM
    12. Harris RS
    13. DeCaprio JA

    (2017) Merkel cell polyomavirus exhibits dominant control of the tumor genome and transcriptome in virus-associated Merkel cell carcinoma

    MBio 8:e02079-16.

    https://doi.org/10.1128/mBio.02079-16

    • PubMed
    • Google Scholar
76. 1. Starrett GJ
    2. Serebrenik AA
    3. Roelofs PA
    4. McCann JL
    5. Verhalen B
    6. Jarvis MC
    7. Stewart TA
    8. Law EK
    9. Krupp A
    10. Jiang M
    11. Martens JWM
    12. Cahir-McFarland E
    13. Span PN
    14. Harris RS

    (2019) Polyomavirus T antigen induces APOBEC3B expression using an LXCXE-dependent and TP53-independent mechanism

    MBio 10:e02690-18.

    https://doi.org/10.1128/mBio.02690-18

    • PubMed
    • Google Scholar
77. Software

    1. Starrett GJ

    (2020) Oncovirus tools, version 99c8707

    GitHub.

    https://github.com/gstarrett/oncovirus_tools
78. 1. Starrett GJ
    2. Thakuria M
    3. Chen T
    4. Marcelus C
    5. Cheng J
    6. Nomburg J
    7. Thorner AR
    8. Slevin MK
    9. Powers W
    10. Burns RT
    11. Perry C
    12. Piris A
    13. Kuo FC
    14. Rabinowits G
    15. Giobbie-Hurder A
    16. MacConaill LE
    17. DeCaprio JA

    (2020) Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma

    Genome Medicine 12:30.

    https://doi.org/10.1186/s13073-020-00727-4

    • PubMed
    • Google Scholar
79. 1. Su X
    2. Lu X
    3. Bazai SK
    4. Compérat E
    5. Mouawad R
    6. Yao H
    7. Rouprêt M
    8. Spano J-P
    9. Khayat D
    10. Davidson I
    11. Tannir NN
    12. Yan F
    13. Malouf GG

    (2021) Comprehensive integrative profiling of upper tract urothelial carcinomas

    Genome Biology 22:7.

    https://doi.org/10.1186/s13059-020-02230-w

    • PubMed
    • Google Scholar
80. 1. Swanton C
    2. McGranahan N
    3. Starrett GJ
    4. Harris RS

    (2015) Apobec enzymes: mutagenic fuel for cancer evolution and heterogeneity

    Cancer Discovery 5:704–712.

    https://doi.org/10.1158/2159-8290.CD-15-0344

    • PubMed
    • Google Scholar
81. 1. Tisza MJ
    2. Pastrana DV
    3. Welch NL
    4. Stewart B
    5. Peretti A
    6. Starrett GJ
    7. Pang Y-YS
    8. Krishnamurthy SR
    9. Pesavento PA
    10. McDermott DH
    11. Murphy PM
    12. Whited JL
    13. Miller B
    14. Brenchley J
    15. Rosshart SP
    16. Rehermann B
    17. Doorbar J
    18. Ta’ala BA
    19. Pletnikova O
    20. Troncoso JC
    21. Resnick SM
    22. Bolduc B
    23. Sullivan MB
    24. Varsani A
    25. Segall AM
    26. Buck CB

    (2020) Discovery of several thousand highly diverse circular DNA viruses

    eLife 9:e51971.

    https://doi.org/10.7554/eLife.51971

    • PubMed
    • Google Scholar
82. Software

    1. Tisza M

    (2021) Cenote-taker 2, version 2.1.2

    GitHub.

    https://github.com/mtisza1/Cenote-Taker2
83. 1. Tisza MJ
    2. Belford AK
    3. Domínguez-Huerta G
    4. Bolduc B
    5. Buck CB

    (2021) Cenote-taker 2 democratizes virus discovery and sequence annotation

    Virus Evolution 7:veaa100.

    https://doi.org/10.1093/ve/veaa100

    • PubMed
    • Google Scholar
84. 1. Toptan T
    2. Yousem SA
    3. Ho J
    4. Matsushima Y
    5. Stabile LP
    6. Fernández-Figueras M-T
    7. Bhargava R
    8. Ryo A
    9. Moore PS
    10. Chang Y

    (2016) Survey for human polyomaviruses in cancer

    JCI Insight 1:e85562.

    https://doi.org/10.1172/jci.insight.85562

    • PubMed
    • Google Scholar
85. 1. Tye S
    2. Ronson GE
    3. Morris JR

    (2021) A fork in the road: where homologous recombination and stalled replication fork protection part ways

    Seminars in Cell & Developmental Biology 113:14–26.

    https://doi.org/10.1016/j.semcdb.2020.07.004

    • PubMed
    • Google Scholar
86. 1. Vajdic CM
    2. van Leeuwen MT

    (2009) Cancer incidence and risk factors after solid organ transplantation

    International Journal of Cancer 125:1747–1754.

    https://doi.org/10.1002/ijc.24439

    • PubMed
    • Google Scholar
87. 1. Van Doorslaer K
    2. Li Z
    3. Xirasagar S
    4. Maes P
    5. Kaminsky D
    6. Liou D
    7. Sun Q
    8. Kaur R
    9. Huyen Y
    10. McBride AA

    (2017) The papillomavirus episteme: a major update to the papillomavirus sequence database

    Nucleic Acids Research 45:D499–D506.

    https://doi.org/10.1093/nar/gkw879

    • PubMed
    • Google Scholar
88. 1. Verhalen B
    2. Starrett GJ
    3. Harris RS
    4. Jiang M

    (2016) Functional upregulation of the DNA cytosine deaminase APOBEC3B by polyomaviruses

    Journal of Virology 90:6379–6386.

    https://doi.org/10.1128/JVI.00771-16

    • PubMed
    • Google Scholar
89. 1. Viarisio D
    2. Müller-Decker K
    3. Zanna P
    4. Kloz U
    5. Aengeneyndt B
    6. Accardi R
    7. Flechtenmacher C
    8. Gissmann L
    9. Tommasino M

    (2016) Novel ß-HPV49 transgenic mouse model of upper digestive tract cancer

    Cancer Research 76:4216–4225.

    https://doi.org/10.1158/0008-5472.CAN-16-0370

    • Google Scholar
90. 1. Viarisio D
    2. Müller-Decker K
    3. Accardi R
    4. Robitaille A
    5. Dürst M
    6. Beer K
    7. Jansen L
    8. Flechtenmacher C
    9. Bozza M
    10. Harbottle R
    11. Voegele C
    12. Ardin M
    13. Zavadil J
    14. Caldeira S
    15. Gissmann L
    16. Tommasino M

    (2018) Beta HPV38 oncoproteins act with a hit-and-run mechanism in ultraviolet radiation-induced skin carcinogenesis in mice

    PLOS Pathogens 14:e1006783.

    https://doi.org/10.1371/journal.ppat.1006783

    • PubMed
    • Google Scholar
91. 1. Vieira VC
    2. Leonard B
    3. White EA
    4. Starrett GJ
    5. Temiz NA
    6. Lorenz LD
    7. Lee D
    8. Soares MA
    9. Lambert PF
    10. Howley PM
    11. Harris RS

    (2014) Human papillomavirus E6 triggers upregulation of the antiviral and cancer genomic DNA deaminase APOBEC3B

    MBio 5:e02234-14.

    https://doi.org/10.1128/mBio.02234-14

    • PubMed
    • Google Scholar
92. 1. Wallez Y
    2. Riedl SJ
    3. Pasquale EB

    (2014) Association of the breast cancer antiestrogen resistance protein 1 (BCAR1) and BCAR3 scaffolding proteins in cell signaling and antiestrogen resistance

    The Journal of Biological Chemistry 289:10431–10444.

    https://doi.org/10.1074/jbc.M113.541839

    • PubMed
    • Google Scholar
93. 1. Wang Y
    2. Liu Y
    3. Deng W
    4. Fu F
    5. Yan S
    6. Yang H
    7. Liu R
    8. Geng J
    9. Xu J
    10. Wu Y
    11. Ma J
    12. Zhou J
    13. Liu N
    14. Jin Y
    15. Xia R
    16. Elias N
    17. Lee RJ
    18. Feldman AS
    19. Blute ML
    20. Colvin RB
    21. Wu C-L
    22. Miao Y

    (2020) Viral integration in BK polyomavirus-associated urothelial carcinoma in renal transplant recipients: multistage carcinogenesis revealed by next-generation virome capture sequencing

    Oncogene 39:5734–5742.

    https://doi.org/10.1038/s41388-020-01398-6

    • Google Scholar
94. 1. Warburton A
    2. Redmond CJ
    3. Dooley KE
    4. Fu H
    5. Gillison ML
    6. Akagi K
    7. Symer DE
    8. Aladjem MI
    9. McBride AA

    (2018) HPV integration hijacks and multimerizes a cellular enhancer to generate a viral-cellular super-enhancer that drives high viral oncogene expression

    PLOS Genetics 14:e1007179.

    https://doi.org/10.1371/journal.pgen.1007179

    • PubMed
    • Google Scholar
95. 1. Warren CJ
    2. Van Doorslaer K
    3. Pandey A
    4. Espinosa JM
    5. Pyeon D

    (2015a) Role of the host restriction factor APOBEC3 on papillomavirus evolution

    Virus Evolution 1:vev015.

    https://doi.org/10.1093/ve/vev015

    • PubMed
    • Google Scholar
96. 1. Warren CJ
    2. Xu T
    3. Guo K
    4. Griffin LM
    5. Westrich JA
    6. Lee D
    7. Lambert PF
    8. Santiago ML
    9. Pyeon D

    (2015b) Apobec3A functions as a restriction factor of human papillomavirus

    Journal of Virology 89:688–702.

    https://doi.org/10.1128/JVI.02383-14

    • PubMed
    • Google Scholar
97. 1. Warren C.J
    2. Westrich JA
    3. Doorslaer KV
    4. Pyeon D

    (2017) Roles of APOBEC3A and APOBEC3B in human papillomavirus infection and disease progression

    Viruses 9:233.

    https://doi.org/10.3390/v9080233

    • PubMed
    • Google Scholar
98. 1. Wilm A
    2. Aw PPK
    3. Bertrand D
    4. Yeo GHT
    5. Ong SH
    6. Wong CH
    7. Khor CC
    8. Petric R
    9. Hibberd ML
    10. Nagarajan N

    (2012) LoFreq: a sequence-quality aware, ultra-sensitive variant caller for uncovering cell-population heterogeneity from high-throughput sequencing datasets

    Nucleic Acids Research 40:11189–11201.

    https://doi.org/10.1093/nar/gks918

    • PubMed
    • Google Scholar
99. 1. Wilson AL
    2. Schrecengost RS
    3. Guerrero MS
    4. Thomas KS
    5. Bouton AH

    (2013) Breast cancer antiestrogen resistance 3 (BCAR3) promotes cell motility by regulating actin cytoskeletal and adhesion remodeling in invasive breast cancer cells

    PLOS ONE 8:e65678.

    https://doi.org/10.1371/journal.pone.0065678

    • PubMed
    • Google Scholar
100. 1. Zapatka M
     2. Borozan I
     3. Brewer DS
     4. Iskar M
     5. Grundhoff A
     6. Alawi M
     7. Desai N
     8. Sültmann H
     9. Moch H
     10. PCAWG Pathogens
     11. Cooper CS
     12. Eils R
     13. Ferretti V
     14. Lichter P
     15. PCAWG Consortium

     (2020) The landscape of viral associations in human cancers

     Nature Genetics 52:320–330.

     https://doi.org/10.1038/s41588-019-0558-9

     • PubMed
     • Google Scholar
101. 1. Zhang J
     2. Fujimoto J
     3. Zhang J
     4. Wedge DC
     5. Song X
     6. Zhang J
     7. Seth S
     8. Chow C-W
     9. Cao Y
     10. Gumbs C
     11. Gold KA
     12. Kalhor N
     13. Little L
     14. Mahadeshwar H
     15. Moran C
     16. Protopopov A
     17. Sun H
     18. Tang J
     19. Wu X
     20. Ye Y
     21. William WN
     22. Lee JJ
     23. Heymach JV
     24. Hong WK
     25. Swisher S
     26. Wistuba II
     27. Futreal PA

     (2014) Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing

     Science 346:256–259.

     https://doi.org/10.1126/science.1256930

     • PubMed
     • Google Scholar

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

• 980

  views

• 208

  downloads

• 7

  citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.