Virus-induced APOBEC3 transmutagenesis in bladder cancer initiation.

Area of Science:

• Oncology
• Virology
• Genetics

Background:

• Carcinogenesis in human urothelium involves a high mutation burden from APOBEC3 enzymes, but a viral cause is not established.
• BK polyomavirus (BKPyV) is a common virus persisting in kidneys and detected in urine, potentially linked to urothelial changes.

Purpose of the Study:

• To investigate the role of BKPyV infection in inducing APOBEC3 expression and subsequent urothelial carcinogenesis.
• To explore the mechanism of "transmutagenesis" where bystander cells acquire mutations due to nearby viral infections.

Main Methods:

• Induction of chronic BKPyV infections in normal human urothelium models.
• Analysis of innate immune responses, including cell extrusion and interferon signaling.
• Assessment of APOBEC3 expression and mutational signatures in infected and bystander cells.

Main Results:

• BKPyV infection induced an innate response with cell extrusion and paracrine interferon signaling, increasing APOBEC3 expression.
• APOBEC3 activity in infected and bystander cells generated mutational signatures mirroring those in muscle-invasive bladder cancer.
• Uninfected bystander cells near BKPyV infection acquired APOBEC3-driven mutations, gaining a hypermutable advantage.

Conclusions:

• BKPyV infection can initiate urothelial carcinogenesis by inducing APOBEC3-mediated mutations in both infected and bystander cells via "transmutagenesis".
• This mechanism explains virus-negative, APOBEC3-rich urothelial carcinomas, suggesting a potential for prevention through antiviral intervention.