Deciphering Polyomavirus-Mediated Carcinogenesis in the Genitourinary Tract

Human polyomaviruses, particularly BK polyomavirus (BKPyV) and JC polyomavirus (JCPyV), establish persistent infections within the genitourinary tract and undergo reactivation under conditions of immunosuppression. Although their clinical relevance is well established in transplant-associated nephropathy and haemorrhagic cystitis, accumulating molecular, pathological, and epidemiological evidence suggests that these viruses may also contribute to genitourinary carcinogenesis. This review examines the emerging role of BKPyV and JCPyV in urothelial, upper urinary tract, renal, and prostate malignancies, with particular emphasis on the molecular mechanisms underlying viral oncogenicity. Polyomavirus large and small T antigens disrupt the p53 and pRb tumour-suppressor pathways, activate MAPK and PI3K/Akt signalling, interfere with DNA damage responses, and promote genomic instability. Viral genome integration and a potential hit-and-run mechanism involving APOBEC3-mediated mutagenesis provide complementary models for persistent or transient oncogenic effects. The review further explores viral microRNAs as regulators of viral persistence, immune evasion, and inter-polyomavirus competition, including JCPyV-mediated suppression of BKPyV replication. Clinically, polyomavirus-associated urothelial carcinomas demonstrate aggressive pathological features and are particularly relevant in kidney transplant recipients. Current diagnostic strategies integrating viral DNA quantification, urinary cytology, viral microRNA detection, immunohistochemistry, and RNA in situ hybridisation may facilitate risk stratification and tissue-level confirmation. Finally, therapeutic management remains challenging because effective oncological control must be balanced against preservation of graft function and restoration of antiviral immunity. Collectively, these findings position BKPyV and JCPyV as important, but mechanistically heterogeneous, candidates in genitourinary tumourigenesis and highlight critical priorities for establishing causal relationships and clinically actionable biomarkers.