New clues to understanding why bladder cancer affects men four times more often

BarcelonaThe bladder is one of the organs that accumulates the most mutations due to its function – it stores urine and conducts toxins and chemicals – and its biology, since the cells that line it renew themselves very quickly. Cancer that affects this type of muscular and membranous globe of the human body is one of the most common worldwide, and it is known to affect men more than women and smokers more than non-smokers. In fact, men are four times more likely than women to have this tumor. The cause is a mystery, partly because the studies carried out until now are mostly based on organs with a developed tumor.

Now a study published in the journalNatureLed by researcher Núria López-Bigas of the Institute for Research in Biomedicine (IRB) and in collaboration with the University of Washington, the study has shifted its focus from counting mutations to identifying which ones thrive. It has observed in healthy tissue—in other words, in people without the disease—how cells evolve until they convert. "Studying healthy tissue is essential for understanding the early stages of the disease and, therefore, improving risk prediction, prevention, and early diagnosis," explains López-Bigas.

The main conclusion of this basic science study—which generates knowledge without direct application to patients—is that being male and smoking have a direct influence on the behavior of mutations in the bladder, to the point of favoring the development of cancer. "Throughout life, healthy tissues accumulate many mutations, but what is relevant is not only how many there are, but which ones manage to expand and form clones, that is, copies of the same cell that share the same mutations," explains Núria López-Bigas, Icrea researcher and the leader.

The accumulation of mutations is normal for all human cells, but some of them give cancer a selective advantage and are present in completely healthy tissue. This research focuses on finding detectable somatic mutations, that is, changes in the genetic material (DNA) in all cells of the body except eggs and sperm, which are experienced by healthy tissues. "With techniques that we have developed and improved [ultrafine sequencing called duplex DNA sequencing] we are now able to detect them in tissues that have not yet developed it. With this information, we can begin to calculate which ones can lead to clonal expansions, that is, a cell duplicating and repeating itself," the expert summarizes to the ARA. 45 deceased donors who had never suffered from bladder cancer. Thanks to the new approach, they were able to detect and quantify 64,000 mutations that are invisible to current sequencing techniques. This technique is like going from using a home telescope to using the James Webb Space Telescope: suddenly, multiple mutations become visible in healthy bladder tissue long before a tumor appears," compares Risques, senior co-author of the study.

Unprecedented discovery

The researchers observed clear differences in the clonal architecture of bladder tissue between men and women: in men, certain mutations in cancer-related genes showed an evolutionary advantage, meaning that clones carrying these mutations tended to expand even in healthy tissue. The team also observed that donors over 55 who had smoked had a high frequency of mutations in the promoter of the TERT gene, a DNA element that allows cells to avoid aging and continue dividing. In this sense, the study provides evidence that tobacco not only acts as a mutagen (causing new mutations) but also as a clonal promoter, that is, it facilitates the expansion of cells with existing mutations.

Both findings (sex bias and smoking) are unprecedented: it is the first time that these effects have been directly observed in healthy bladder tissue rather than in tumors, providing new insights into the earliest stages of cancer development. In fact, it could help explain why men and smokers are more likely to develop bladder cancer, and open the door to future applications, such as measuring expanding clones in the bladder, to develop risk prediction and early detection tools using a simple urine test.

López-Bigas points out that this finding does not have immediate implications for people, but it does have long-term implications. "We all know that smoking is not good. What we don't know in many cases is what exactly tobacco does inside our tissues and how it modifies the risk of developing bladder cancer. That is what we now understand somewhat better at the molecular level, which can help us prevent it," he explains. González-Pérez agrees: "This study is just the tip of the iceberg. We analyzed 16 genes from the bladders of 45 people and found relevant differences. This same strategy can be applied to other tissues and risk factors."

This research is part of the Prominent project, within the framework of the prestigious Cancer Grand Challenges initiative, and has received support from the Spanish Association Against Cancer.