Impact of Smoking and Biological Sex on Healthy Bladder Tissue and Cancer Risk

Bladder cancer ranks among the most prevalent cancers worldwide, with men exhibiting approximately four times higher incidence than women. While smoking has long been identified as a major environmental risk factor, the underlying biological mechanisms have remained elusive. Understanding the earliest changes in healthy tissue can offer valuable insights into disease development, enabling better risk prediction, prevention, and early detection strategies.

Recent research led by scientists at IRB Barcelona and the University of Washington has uncovered how both smoking and biological sex influence the evolution of healthy bladder tissue. The study, published in Nature, demonstrates that these factors promote the expansion of certain mutated cells, which may pave the way for cancer formation. Dr. Núria López-Bigas and Dr. Abel González-Pérez from IRB Barcelona, along with Dr. Rosana Risques, used innovative techniques to analyze bladder samples from 45 donors. They employed a novel approach, akin to using a powerful 'microscope,' capable of detecting thousands of mutations that traditional DNA sequencing often misses. This method revealed that even in healthy tissue, there are significant differences in how cells with mutations expand and form clones.

A key finding of the study is that healthy tissues accumulate many mutations over time, but the critical factor is which mutations enable cells to outgrow others. The researchers observed that in males, specific mutations in cancer-related genes tend to have an "evolutionary advantage," leading to the expansion of these clones even before any signs of disease. Additionally, smoking was shown to significantly influence mutation patterns; among individuals over 55 who smoked, there was a high prevalence of mutations in the TERT promoter, a region involved in cell immortality. This suggests that tobacco not only introduces new mutations but also promotes the expansion of pre-existing mutated cells.

This groundbreaking research provides new perspectives on bladder cancer initiation, emphasizing that the process begins at a molecular level long before tumors develop. The findings could impact future diagnostics, such as urine tests that detect expanding mutant clones, making early intervention more feasible. Furthermore, the approach developed in this study could be adapted to explore other tissues and risk factors, broadening our understanding of cancer development and prevention.

"Our work reveals that the influence of smoking and biological sex on tissue evolution occurs early, shaping which cells become dominant," explains Dr. González-Pérez. "This shifts the focus from counting mutations to understanding which ones lead to aggressive clones, aiding in risk assessment and early detection."

In summary, this research highlights how lifestyle and biological differences influence the earliest stages of cancer, paving the way for innovative preventive strategies and personalized risk assessment tools.