Mutations in normal cells may set stage for bladder cancer

Mutations that give certain cells an evolutionary advantage may help explain why men are more likely than women and smokers are more likely than nonsmokers to develop bladder cancer, according to a study by researchers at the University of Washington School of Medicine in Seattle and the Institute for Research in Biomedicine in Barcelona, Spain. 

“Our findings show that many of the mutations that drive bladder cancer can be found in the normal bladder but with some differences in males and smokers,” said Rosana Risques, associate professor of laboratory medicine and pathology and a cell and molecular biologist at UW Medicine. She co-led the study with Núria López-Bigas and Abel González-Pérez in Barcelona. 

The researchers reported their findings Oct. 8 in the journal Nature. 

The investigators used ultrasensitive sequencing technology to identify mutations in the normal bladder lining collected at autopsy from 45 individuals. This method allowed them to detect thousands of mutations in bladder cells that would be missed using standard DNA sequencing technology. 

Some mutations are fatal, but others confer a proliferative advantage that allows the cells to replicate and expand their numbers. Because the new cells are genetically identical to their parent cells, they are called clones and their proliferation is called clonal expansion. 

As a result of this evolutionary process, healthy tissues are made of mosaics of competing populations of clones. In most cases, these populations do not cause disease, but some clones harbor mutations that increase their risk of becoming cancerous.  

The researchers found that although men and women overall had a similar number of mutations, men had significantly more truncating mutations that produce a broken protein in three cancer-related genes, RBM10, CDKN1A and ARID1A.  

“For these three genes, we see more positive selection of truncating mutations in males than in females,” Risques said. “What that means is that clones with these mutations have more of an advantage in the male tissue than in the female tissue.” 

The researchers also found that clonal expansion of cells with a mutation in another cancer-related gene, called TERT, increased with age and with a history of smoking.  

Interestingly, as was seen in men, smokers did not seem to have more mutations overall, suggesting that something else — perhaps something in cigarette smoke — does not cause mutations but drives the expansion of clones with the TERT mutation and increases the risk of cancer. 

“This is a new kind of role for smoking,” Risques said. “Smoking is typically considered to be mutagenic. But the effect we’re seeing is not due to more mutations but the expansion of clones with the TERT mutation.” 

In addition to bladder cancer, ultradeep duplex DNA sequencing can be used to study the role of clonal expansion in other tissues, Risques said, and hopefully will lead to new ways to screen, predict and prevent common cancers. 

The project was conducted within the PROMINENT Cancer Grand Challenge team, which is supported by Cancer Research UK, the UW Medicine Department of Laboratory Medicine and Pathology, the National Cancer Institute (OT2CA278668), and the Spanish Association Against Cancer. Risques is a consultant and equity holder of TwinStrand Biosciences and received research funding from the company. She is the named inventor on a patent owned by the University of Washington and licensed to TwinStrand Biosciences. 

Written by Michael McCarthy.

Related: Nature published an accompanying commentary, "Ultrasensitive Methods to Map Mutations," by Jian Carrot-Zhang of the Memorial Sloan-Kettering Cancer Center in New York. 

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