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

Human polyomaviruses are ubiquitous, with primary infections that typically occur 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. We present deep sequencing data from a high-grade BK virus-associated tumor expressing large T antigen. The carcinoma arose in a kidney allograft 6 years after transplantation. We identified a novel genotype 1a BK polyomavirus, called Chapel Hill BK polyomavirus 2 (CH-2), that was integrated into the BRE gene in chromosome 2 of tumor cells. At the chromosomal integration site, viral break points 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 overexpression 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.