T Antigen Dependent Oncogenic Pathways Are Active in Post-Transplant Tumors Driven By BK Polyoma Virus.

Abstract

BK Polyoma Virus (BKPyV) transforms primary cells and is homologous to the Merkel Cell Carcinoma virus, but has never been convincingly demonstrated to cause tumors in humans. There have been 18 case reports of urinary tract tumors in solid organ transplant recipients (17 kidney, 1 lung) with diffuse expression of BKPyV’s large T antigen (LTA), partial evidence that BKPyV is an oncovirus. Here we report that known binding partners and downstream effectors of the LTA and Small T Antigen (STA) of BKPyV are active in a series of 10 of these tumors (5 novel). Methods: Formalin fixed tissue was obtained from kidney and bladder tumors with diffuse LTA expression arising in solid organ transplant recipients. Control populations include kidney and bladder tumors arising in transplant recipients without diffuse large T antigen expression, and cases of polyoma virus reactivation and superinfection. Sections were stained for p53, cyclin A, and β-catenin. Results: Tumors with diffuse LTA staining showed universal nuclear staining for p53, 9/10 had high rates of cyclin A nuclear positivity, and 9/10 had at least weak membrane accumulation of β-catenin. Control tumors had variable positivity for p53, with urothelial carcinoma of the bladder showing weak membrane staining for β-catenin and low cyclin A positivity, and renal cell carcinoma showing minimal β-catenin but high levels of cyclin A. Active BKPyV infections stained similarly to tumors withdiffuse LTA, but only in the infected cells. Discussion: Cyclin A is a known target of STA signaling through PP2A. The LTA stabilizes p53 directly and β-catenin indirectly via Rac1. These proteins are involved in distinct pathways of oncogenesis. p53: DNA repair and apoptosis, β-catenin: growth and metastasis, cyclin A: cell cycle. While activation of any single pro-oncogenic pathway is non-specific, tumors with diffuse LTA are generally positive for all 3 proteins. In contrast, control tumors did not stain for the full panel. Staining in tumors and active infections are similar, suggesting that STA and LTA sequences are intact in tumors with BKPyV. This provides additional supporting evidence that BKPyV is an oncovirus in humans. DISCLOSURE:Emerson, L.: Employee, ARUP Laboratories.