Virus-induced APOBEC3 transmutagenesis in bladder cancer initiation
George H Hatton1, Sally R James2, Andrew S Mason1
1Jack Birch Unit for Molecular Carcinogenesis, Department of Biology and York Biomedical Research Institute, University of York, Heslington, York, UK.
Abstract:
Carcinogenesis in human urothelium is driven by a high burden of mutations caused by the antiviral "APOBEC3" (apolipoprotein B mRNA editing enzyme, catalytic subunit-like 3) cytosine deaminase enzymes; however, there is no established viral etiology. BK polyomavirus (BKPyV) is a ubiquitous childhood infection that persists in the kidney during adulthood and is frequently detected in urine. Chronic BKPyV infections of normal human urothelium induced an innate response, including apical extrusion of infected cells. Local paracrine interferon signaling induced APOBEC3 expression in both infected and juxtaposed bystander cells, leading to acquisition of hallmark APOBEC3-mediated mutational signatures that recapitulated the variation in mutational character found in patients with muscle-invasive bladder cancer. In our model for urothelial carcinogenesis, uninfected bystander cells witnessing BKPyV infection become APOBEC3 damaged, escape extrusion, and acquire hypermutable advantage. "Transmutagenesis" explains how cells proximal to infected neighbors acquire cancer-initiating mutations. This hypothesis for how urothelial cancers can develop as APOBEC3 signature rich, while remaining virus-negative, suggests that a large proportion of urothelial carcinomas may be preventable by antiviral intervention.
Insights
BK polyomavirus (BKPyV) infection triggers APOBEC3 enzyme activity in urothelial cells, leading to mutations that drive bladder cancer. This "transmutagenesis" suggests urothelial carcinomas may be preventable with antiviral therapies.
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.
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