BK Polyomavirus Genomic Integration and Large T Antigen Expression: Evolving Paradigms in Human Oncogenesis

Human polyomaviruses are ubiquitous, with primary infections typically occurring during childhood and subsequent latency that may last a lifetime. Polyomavirus-mediated disease has been described in immunocompromised patients; its relationship to oncogenesis is poorly understood. Here we present deep sequencing data from a high grade BK virus-associated tumor expressing large T antigen. The carcinoma arose in a kidney allograft six years after transplantation. We identified a novel genotype-1a BK polyomavirus (termed “Chapel Hill BK polyomavirus-2″) that was integrated into the BRE gene in chromosome 2 of tumor cells. At the chromosomal integration site, viral breakpoints were found, disrupting late BK gene sequences encoding capsid proteins VP1 and VP2/3. Immunohistochemistry and in situ hybridization studies demonstrated that the integrated BK-virus was replication incompetent. We propose that the BK virus CH-2 was integrated into the human genome as a concatemer resulting in alterations of feedback loops and over expression of large T antigen. Collectively, these findings support the emerging understanding that viral integration is a nearly ubiquitous feature in polyomavirus-associated malignancy, and that unregulated large T antigen expression drives a proliferative state that is conducive to oncogenesis. Based on the current observations we present an updated model of polyomavirus-mediated oncogenesis. This article is protected by copyright. All rights reserved.