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Common Mechanisms of Virus-Mediated Oncogenesis in Bladder Cancers Arising In Solid Organ Transplant Recipients

By Gabriel J. Starrett, Kelly Yu, Yelena Golubeva, Petra Lenz, Mary L Piaskowski, David Peterson, Michael Dean, Ajay Israni, Brenda Y Hernandez, Thomas C Tucker, Iona Cheng, Lou Gonsalves, Cyllene R Morris, Shehnaz K. Hussain, Charles F. Lynch, Reuben S Harris, Ludmila Prokunina-Olsson, Paul Meltzer, Christopher B Buck, Eric A. Engels

Posted 11 Nov 2021
medRxiv DOI: 10.1101/2021.11.11.21266080

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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