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

Abstract

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.

Donor‐derived, metastatic urothelial cancer after kidney transplantation associated with a potentially oncogenic BK polyomavirus

“…Although our analyses provide evidence of both NCCR rearrangement and genomic integration, our functional studies challenge the view that integration of polyomaviruses is a necessary condition for tumourigenesis. The 17‐bp deletion in the NCCR P‐block in the non‐integrated BKPyV genome may lead to the same early versus late gene expression imbalance as an LVGR genomic disruption . We have demonstrated that the 17‐bp deletion NCCR constitutively activated LTag and sTag EVGR expression, while impairing LVGR expression and the replicative capacity of isogenic derivatives.…”

Treatment for presumed BK polyomavirus nephropathy and risk of urinary tract cancers among kidney transplant recipients in the United States

“…13 Over the last few years, Merkel cell polyomavirus has been demonstrated to be the causative agent for the majority of Merkel cell carcinomas in humans. 15 Notably, BKV has been linked to aggressive urinary tract cancers in kidney transplant recipients in a large number of recent case reports, [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] as summarized by Papadimitriou et al 35 These reports provide evidence of BKV in the tumors as demonstrated by immunohistochemical staining for BKV proteins, polymerase chain reaction (PCR) testing for BKV DNA, or detection of chromosomally integrated BKV through whole-genome shotgun sequencing of the tumor.…”

High grade infiltrative adenocarcinomas of renal cell origin: New insights into classification, morphology, and molecular pathogenesis

“…However, recent genomic studies have suggested, or at least produced findings consistent with, the idea that BK polyomavirus may contribute to tumorigenesis through viral integration into the host genome and expression of viral oncoproteins (e.g. polyoma T‐antigen) . From the standpoint of the differential diagnosis with bona fide CDC, our experience with ongoing studies of a cohort of these tumors is that they most frequently are urothelial carcinomas; however, they often show variant differentiation, which can include glandular patterns entering the differential diagnosis with CDC (Fig.…”

“…polyoma T-antigen). [95][96][97] From the standpoint of the differential diagnosis with bona fide CDC, our experience with ongoing studies of a cohort of these tumors 98 is that they most frequently are urothelial carcinomas; however, they often show variant differentiation, which can include glandular patterns entering the differential diagnosis with CDC ( Fig. 4).…”