Sex and smoking bias in the selection of somatic mutations in human bladder

Bladder cancer is one of the most common cancers worldwide. Men are around four times more likely to develop it than women, and smoking is the main known environmental risk factor. However, the biological mechanisms behind these risk factors remain unclear. Since cancer can take decades to develop, it is important to look at healthy tissues to understand the very first steps of the disease, with the goal of improving risk prediction, prevention, and early diagnosis.Our group, in collaboration with Dr. Rosana Risques (University of Washington), have now shown that smoking and biological sex influence how normal cells evolve in healthy bladder tissue, favouring the expansion of some mutated cells, which may be key in the development of cancer. Using ultradeep duplex DNA sequencing, we identified thousands of clonal driver mutations in 16 genes across 79 normal bladder samples from 45 people. The work could provide insights into why men and smokers are at higher risk of bladder cancer. The research was delivered in part through team PROMINENT, as part of the prestigious Cancer Grand Challenges initiative, to answer fundamental questions surrounding early tumour development and identify new opportunities for intervention and routes to cancer prevention.