Abstract IA11: Bladder cancers affecting transplant recipients harbor diverse viruses that associate with overall survival
Authors: Starrett Gabriel J. , Yu Kelly , Petersen David , Lenz Petra , Dyrskjøt Lars , Meltzer Paul , Engels Eric , Buck Christopher B. 
Published: December 2020

Abstract
BK polyomavirus (BKPyV) is a ubiquitous virus that establishes a lifelong subclinical infection in the urinary tract. In transplant recipients, BKPyV can reactivate and cause kidney and bladder damage. Recent sequencing studies of tumors from transplant recipients have revealed that BKPyV sequences are present in approximately 25% of bladder tumors. This is dramatically higher than the &lt;1% rate of BKPyV detection observed in muscle-invasive bladder cancers affecting the general population. Like cancer-causing human papillomaviruses (HPVs), BKPyV has been shown to upregulate the human cytosine deaminase APOBEC3B, which has emerged as the second most abundant source of point mutations in human cancers. Furthermore, the APOBEC3-associated mutation signature is the most abundant mutational signature in bladder cancer. To comprehensively assess the role of BKPyV and other viruses in bladder cancer from solid organ transplant recipients, we used a database linking US transplant and cancer registries to identify and collect 44 archived primary bladder tumors, 5 metastases, and 15 adjacent normal tissue specimens. Whole-genome and total RNA sequencing was performed on the samples. From these data, we detected BKPyV in 18% of primary tumors. In five cases, there is clear evidence of BKPyV integration into the host cell genome, and all cases show transcription of the viral tumor antigens. In a separate set of analyses, BKPyV transcription was detected in 3.7% of non-muscle-invasive early-stage bladder cancer cases affecting the general population. Our surveys also detected other viruses, including high- and low-risk HPVs, JC polyomavirus (JCPyV), and anelloviruses, at lower frequencies. Two primary-metastatic pairs maintained clonally integrated HPV or BKPyV and respective viral oncogene expression in the metastatic lesions. Nearly all tumors had dominant APOBEC3 signature mutations, and BKPyV-positive tumors expressed significantly more APOBEC3B compared to virus-negative tumors or normal tissues. Tumors from four kidney transplant patients showed high mutation burden consistent with exposure to aristolochic acid, a nephrotoxic carcinogen found in some herbal supplements. Clinical data indicate that BKPyV-positive tumors are predominantly high grade with invasive behavior. Strikingly, survival was significantly shorter for patients whose tumors harbored BKPyV or JCPyV (9.7 and 8.4 months, respectively) compared to patients with tumors harboring HPV or no detectable viruses (65.8 and 50.2 months, respectively). This study comprehensively characterizes the genomes and transcriptomes of tumors, revealing several distinct tumor etiologies that impact patient outcome.
Citation Format: Gabriel J. Starrett, Kelly Yu, David Petersen, Petra Lenz, Lars Dyrskjøt, Paul Meltzer, Eric Engels, Christopher B. Buck. Bladder cancers affecting transplant recipients harbor diverse viruses that associate with overall survival [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr IA11.