The investigators collected data for 2,816 patients with bladder cancer from seven previous studies and reported that 47% of tumors had at least one mutation in FGFR3 or PIK3CA. Specific genetic alterations were linked to smoking history. For instance, FGFR3-Y375C (TAT>TGT) was more common in tumors from ever-smokers than never-smokers when compared to tumors with other FGFR3 mutations (OR, 1.84; 95% CI, 1.17-2.91; p = 0.009) and FGFR3-WT tumors (OR, 1.86; 95% CI, 1.19-2.92; p = 0.007). The common mutations identified were not associated with other known risk factors for bladder cancer, such as male sex, age, and having a high-risk occupation. In never-smokers, three specific FGFR3 mutations that have previously been linked to APOBEC3A/B enzyme activity were found to be enriched. APOBEC3A/B genes are stimulated by the interferon-gamma pathway, leading researchers to question whether viral infections may be linked to this enrichment. RNA-sequencing data revealed several viruses in bladder tumors, with the BK polyomavirus (BKPyV) being the most common, particularly in NMIBC tumors. In NMIBC tumors with FGFR3 or PIK3CA mutations, BKPyV was associated with a higher risk of progression to MIBC (p = 0.019). Furthermore, among NMIBC tumors with FGFR3 or PIK3CA mutations, 94.7% of PyV-positive tumors carried at least one APOBEC-type driver mutation versus 68.3% of PyV-negative tumors (p = 0.011). The link between these mutations and viral infection was further elucidated using in vitro experiments in which uroepithelial cells exhibited increased APOBEC3B expression after infection with BKPyV.
The model proposed by this study is that BKPyV (infection or reactivation) could lead to the increased expression of APOBEC enzymes, resulting in the generation of APOBEC-type driver mutations that can contribute to the initiation or progression of bladder cancer. Enhanced understanding of underlying molecular mechanisms and pathways can uncover novel therapeutic targets and allow for risk stratification based on tumor genomics.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
References
- Rao N, Starrett GJ, Piaskowski ML, et al. Analysis of Several Common APOBEC-type Mutations in Bladder Tumors Suggests Links to Viral Infection. Cancer Prev Res (Phila). 2023;16(10):561-570. doi:10.1158/1940-6207.CAPR-23-0112