Evidence for Virus-Mediated Oncogenesis in Bladder Cancers Arising in Solid Organ Transplant Recipients
Authors: Starrett Gabriel J , Yu Kelly , Golubeva Yelena , Lenz Petra , Piaskowski Mary L , Petersen David , Dean Michael , Israni Ajay , Hernandez Brenda Y , Tucker Thomas C , Cheng Iona , Gonsalves Lou , Morris Cyllene R , Hussain Shehnaz K , Lynch Charles F , Harris Reuben S , Prokunina-Olsson Ludmila , Meltzer Paul , Buck Christopher B , Engels Eric A 
Published: November 2021

A small percentage of bladder cancers in the general population have been found to harbor DNA viruses. In contrast, up to 25% of tumors of solid organ transplant recipients, who are at an increased risk of developing bladder cancer and have overall poorer outcome, harbor BK polyomavirus (BKPyV). To better understand the biology of the tumors and the mechanisms of carcinogenesis from potential oncoviruses, we performed whole genome and transcriptome sequencing on bladder cancer specimens from 43 transplant patients. Nearly half of tumors from this patient population contained viral sequences. The most common were from BKPyV (N=9, 21%), JC polyomavirus (N=7, 16%), carcinogenic human papillomaviruses (N=3, 7%), and torque teno viruses (N=5, 12%). Immunohistochemistry revealed variable Large T antigen expression in BKPyV-positive tumors ranging from 100% positive staining of tumor tissue to less than 1%. In most cases of BKPyV-positive tumors, the viral genome appeared to be clonally integrated into the host chromosome consistent with microhomology-mediated end joining and coincided with focal amplifications of the tumor genome similar to other virus-mediated cancers. Significant changes in host gene expression consistent with the functions of BKPyV Large T antigen were also observed in these tumors. Lastly, we identified four mutation signatures in our cases with those attributable to APOBEC3 and SBS5 being the most abundant. Mutation signatures associated with the antiviral drug, ganciclovir, and aristolochic acid, a nephrotoxic compound found in some herbal medicines, were also observed. The results suggest multiple pathways to carcinogenesis in solid organ transplant recipients with a large fraction being virus-associated.

Author Summary

Solid organ transplant recipients are at a significantly increases risk for developing bladder cancer compared to the general population, suggesting a potential infectious origin to these tumors. This study identifies that BK polyomavirus, JC polyomavirus, human papillomaviruses, and anelloviruses are commonly found in bladder tumors of solid organ transplant recipients. In most cases when detected, BK polyomavirus is integrated into the tumor genome and associates with genomic structural changes and distinct gene expression through the activity of viral oncogenes. Additionally, mutational signature analysis suggests that a subset of tumors of solid organ transplant recipients develop through distinct mutagenic processes compared to the general population. Together these results indicate multiple distinct mechanisms of carcinogenesis in bladder cancers of solid organ transplant recipients that may have implications for prevention, treatment, and outcome.