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

Wang, Yuchen; Liu, Yanna; Deng, Wen-feng; Fu, Fangxiang; Yan, Susha; Yang, Hongwei; Liu, Rumin; Geng, Jiao; Xu, Jian; Wu, Yihan; Ma, Junfeng; Zhou, Jun; Liu, Na; Jin, Yu; Xia, Renfei; Elias, Nahel; Lee, Richard J.; Feldman, Adam S.; Blute, Michael L.; Colvin, Robert B.; Wu, Chin‐Lee; Miao, Yun

doi:10.1038/s41388-020-01398-6

Cited by 20 publications

(21 citation statements)

References 29 publications

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“…In several tumors we identified heterogeneous expression of LTAg, potentially consistent with a multistage integration and carcinogenesis process proposed by other recent studies on BKPyV-positive urinary tumors from kidney transplant recipients (76,77). However, our sequencing experiments support a dominant integrated form in most BKPyV-positive tumors in this study.…”

Section: Another Difference Between Bkpyv-mediated Carcinogenesis and That Of Hpv Andsupporting

confidence: 91%

Evidence for Virus-Mediated Oncogenesis in Bladder Cancers Arising in Solid Organ Transplant Recipients

Starrett

Golubeva

et al. 2021

Preprint

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A small percentage of bladder cancers in the general population have been found to harbor polyomaviruses and papillomaviruses. In contrast, up to 25% of tumors of solid organ transplant recipients, who are at an increased risk of developing bladder cancer, have been reported to harbor BK polyomavirus (BKPyV). To better understand the biology of the tumors and the mechanisms of carcinogenesis from any potential oncovirus, we performed whole genome sequencing and transcriptomic sequencing on bladder cancer specimens from 43 transplant patients. Roughly a third of the tumors from this patient population contained viral sequences, among which the most common were from BKPyV (N=9, 21%), JC polyomavirus (N=7, 16%), carcinogenic human papillomaviruses (N=3, 7%), and torque teno viruses (N=5, 12%). BKPyV presence was validated by Large T antigen staining and revealed heterogeneous staining patterns between cases ranging from less than one percent to 100% of tumor tissue staining positive. In most cases of BKPyV-positive tumors, the viral genome was integrated into the host chromosome consistent with microhomology-mediated end joining and, in some cases, resulting in focal amplifications of the tumor genome. In BKPyV-positive tumors, significant changes in the expression of E2F- and DREAM-regulated genes amongst others were also observed consistent with the depletion of RB-family members by BKPyV Large T antigen in the tumors. We identified four mutation signatures in our cases with APOBEC3 and SBS5 mutations being the most abundant. We also identified a widespread mutation signature most similar to that caused by the antiviral, ganciclovir, and several cases harbored a high mutation burden associated with aristolochic acid, a nephrotoxic compound found in some herbal medicines. The results indicate that viruses may play a causal role in the development of bladder cancer among immunosuppressed individuals.

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Section: Another Difference Between Bkpyv-mediated Carcinogenesis and That Of Hpv Andsupporting

confidence: 91%

Evidence for Virus-Mediated Oncogenesis in Bladder Cancers Arising in Solid Organ Transplant Recipients

Starrett

Golubeva

et al. 2021

Preprint

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“…The mechanism of multistage BKPyV carcinogenesis in the development of RCC was investigated by a Harvard team of researchers: using next-generation virome capture sequencing, they detected viral integration in BKPyV-associated UCa in renal transplant recipients and concluded that the integration of BKPyV was a continuous process, occurring in both primary and metastatic tumors, generating heterogenous tumoral cell populations [ 20 ]. The hypothesis that integration of polyomaviruses is essential to tumorigenesis is sustained by other authors [ 21 , 22 , 23 ].…”

Section: Renal Cell Carcinoma: Carcinogenesis Mechanisms Of Oncogenic...mentioning

confidence: 99%

The Influence of Oncogenic Viruses in Renal Carcinogenesis: Pros and Cons

et al. 2022

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Viral infections are major contributors to the global cancer burden. Recent advances have revealed that known oncogenic viruses promote carcinogenesis through shared host cell targets and pathways. The aim of this review is to point out the connection between several oncogenic viruses from the Polyomaviridae, Herpesviridae and Flaviviridae families and renal carcinogenesis, highlighting their involvement in the carcinogenic mechanism. We performed a systematic search of the PubMed and EMBASE databases, which was carried out for all the published studies on RCC in the last 10 years, using the following search algorithm: renal cell carcinoma (RCC) and urothelial carcinoma, and oncogenic viruses (BKPyV, EBV, HCV, HPV and Kaposi Sarcoma Virus), RCC and biomarkers, immunohistochemistry (IHC). Our analysis included studies that were published in English from the 1st of January 2012 to the 1st of May 2022 and that described and analyzed the assays used for the detection of oncogenic viruses in RCC and urothelial carcinoma. The virus most frequently associated with RCC was BKPyV. This review of the literature will help to understand the pathogenic mechanism of the main type of renal malignancy and whether the viral etiology can be confirmed, at a minimum, as a co-factor. In consequence, these data can contribute to the development of new therapeutic strategies. A virus-induced tumor could be efficiently prevented by vaccination or treatment with oncolytic viral therapy and/or by targeted therapy.

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“…Although the term episome is now somewhat interchangeable with the term plasmid, episomes are larger in size and are retained for a longer period of time following transfection of host cells. Episome integration is a rare event and can occur through canonical sequence-independent, non-homologous end joining (NHEJ) or microhomology-mediated end joining (MMEJ) 32,33 . Nevertheless, episomal integration must be inhibited if episomes are to become safe vehicles for gene therapy applications.…”

Section: Recipient Cellsmentioning

confidence: 99%

“…Episome integration is a rare event and can occur through canonical sequence-independent, nonhomologous end joining or microhomology-mediated end joining. 33 , 34 Nevertheless, episomal integration must be inhibited if episomes are to become safe vehicles for gene therapy applications.…”

Section: The Development Of Nonviral Episomal Vectorsmentioning

confidence: 99%

Advances in the Development and the Applications of Nonviral, Episomal Vectors for Gene Therapy

et al. 2021

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Non-viral and non-integrating episomal vectors are reemerging as a valid, alternative technology to integrating viral vectors for gene therapy, due to their more favorable safety profile, significantly lower risk for insertional mutagenesis and a lesser potential for innate immune reactions, in addition to their low production cost. Over the past few years, attempts have been made to generate highly functional non-viral vectors that display long-term maintenance within cells and promote more sustained gene expression relative to conventional plasmids. Extensive research into the parameters that

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

Cited by 20 publications

References 29 publications

Evidence for Virus-Mediated Oncogenesis in Bladder Cancers Arising in Solid Organ Transplant Recipients

Evidence for Virus-Mediated Oncogenesis in Bladder Cancers Arising in Solid Organ Transplant Recipients

The Influence of Oncogenic Viruses in Renal Carcinogenesis: Pros and Cons

Advances in the Development and the Applications of Nonviral, Episomal Vectors for Gene Therapy

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