️ Episode 201: Sex, Smoking, and Somatic Selection in the Bladder
In this episode of PaperCast Base by Base, we explore how ultradeep duplex DNA sequencing of normal human bladder tissue reveals sex- and smoking-related biases in the selection of somatic mutations and cancer driver clones.

Study Highlights:
Researchers applied ultradeep duplex DNA sequencing at around 5,000× coverage to 79 normal bladder urothelium samples from 45 deceased donors, targeting 16 genes known to drive clonal expansions and bladder tumors. They identified more than 64,000 somatic mutations and thousands of clonal driver events, allowing precise estimates of positive and negative selection across genes such as TP53, RBM10, STAG2, ARID1A, CDKN1A, FGFR3, and the TERT promoter. Men showed markedly stronger positive selection for truncating driver mutations in RBM10, CDKN1A, and ARID1A than women, despite similar burdens of non-protein-affecting mutations, indicating sex-specific differences in clonal evolution of the normal urothelium. Activating TERT promoter mutations were strongly associated with older age and were far more frequent in donors with a history of smoking, suggesting that tobacco exposure promotes the expansion of telomerase-activated clones rather than simply increasing overall mutation burden. By approaching “natural saturation mutagenesis” in these genes, the study maps selection at individual residues and protein domains, providing an in vivo framework to assess the functional impact of somatic mutations directly in human tissues.

Conclusion:
These results show that sex and smoking history leave distinct imprints on the clonal architecture of the normal bladder and highlight ultradeep sequencing of normal tissues as a powerful tool for understanding cancer risk and mapping functionally important mutations in vivo.

Music:
Enjoy the music based on this article at the end of the episode.

Reference:
Calvet F, Blanco Martinez-Illescas R, Muiños F, Tretiakova M, Latorre-Esteves ES, Fredrickson J, et al. Sex and smoking bias in the selection of somatic mutations in human bladder. Nature. 2025;647:436–444. https://doi.org/10.1038/s41586-025-09521-x

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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