Induction of APOBEC3-mediated genomic damage in urothelium implicates BK polyomavirus (BKPyV) as a hit-and-run driver for bladder cancer

Abstract

Limited understanding of bladder cancer aetiopathology hampers progress in reducing incidence. Mutational signatures show the anti-viral apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC) enzymes are responsible for the preponderance of mutations in bladder tumour genomes, but no causative viral agent has been identified. BK polyomavirus (BKPyV) is a common childhood infection that remains latent in the adult kidney, where reactivation leads to viruria. This study provides missing mechanistic evidence linking reactivated BKPyV-infection to bladder cancer risk. We used a mitotically-quiescent, functionally-differentiated model of normal human urothelium to examine BKPyV-infection. BKPyV-infection led to significantly elevated APOBEC3A and APOBEC3B protein, increased deaminase activity and greater numbers of apurinic/apyrimidinic sites in the host urothelial genome. BKPyV Large T antigen (LT-Ag) stimulated re-entry from G0 into the cell cycle through inhibition of retinoblastoma protein and activation of EZH2, E2F1 and FOXM1, with cells arresting in G2. The single-stranded DNA displacement loops formed in urothelial cells during BKPyV-infection interacted with LT-Ag to provide a substrate for APOBEC3-activity. Addition of interferon gamma (IFNγ) to infected urothelium suppressed expression of the viral genome. These results support reactivated BKPyV infections in adults as a risk factor for bladder cancer in immune-insufficient populations.

The APOBEC3B cytidine deaminase is an adenovirus restriction factor

“…For instance, HPV-16 and -18 infections cause cervical cancer and head and neck squamous cell carcinoma, tumors that bear a high level of A3-induced mutations, resulting from the upregulation of both A3A and A3B via the oncoproteins E6 and E7 [ 39 , 43 ]. Involvement of PyVs in bladder cancer has long been suspected and the A3 mutational signature found in bladder tumors has been proposed to be the result of a hit-and-run mechanism where PyV triggers a strong A3B expression [ 44 ]. It must be stated clearly that the present study does not bring evidence that adenoviruses cause cancer in Human.…”

The Urothelial Transcriptomic Response to Interferon Gamma: Implications for Bladder Cancer Prognosis and Immunotherapy

“…Our finding that IFNγ induced urothelial expression of the CXCL9 , CXCL10 and CXCL11 chemokine genes is pertinent, as the CXCL9/10/11-CXCR3 axis is a critical regulator of leukocyte migration, differentiation and activation, including recruitment of effector T cells [ 18 ]. We have shown previously that CXCL10/11 are highly induced following exposure of normal urothelium to BK polyomavirus, where they were the only genes to be further upregulated, rather than repressed, by exogenous IFNγ [ 19 ]. This demonstrates a virally initiated positive feedback to the recruitment of further IFNγ-producing cells and suggests that attenuated BK virus could be used to generate a pro-inflammatory, IFNγ-rich local environment akin to that induced by BCG.…”

BK and JC polyomaviruses and risk of urothelial bladder carcinoma: a preliminary study in the northern shores of Persian Gulf, Iran

“…A recent study proposed the role of BKPyV in the development of bladder cancer via the anti-viral apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC)-mediated damage of the urothelial genome. In this hit-and-run mode of carcinogenesis, despite inducing APOBEC3B expression by LTAg of BKPyV, the causative viral agent is absent in the tumoral tissue probably due to immune clearance of BKPyV [ 23 ]. The present study, despite identifying BKPyV and JCPyV in a number of bladder cancer biopsy specimens in the South of Iran, suggests that these viruses are unlikely to be effective causative factors in bladder cancer in this region.…”