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Cancer Clues Gleaned from Somatic Mutation Patterns in Normal Bladders

NEW YORK – With sequence data from bladder samples collected in individuals with or without bladder cancer, an international team has uncovered somatic mutations, clonal selection patterns, and mutational signatures that accumulate in normal bladder urothelium samples in aging or diseased individuals.

"This study reveals an unexpectedly rich landscape of mutation and selection in normal bladder, with large differences across individuals driven to some extent by our daily exposures," senior author Iñigo Martincorena, a cancer, aging, and somatic mutation researcher at the Wellcome Sanger Institute, said in a statement.

Using a combination of targeted sequencing, exome sequencing, and whole-genome sequencing, the researchers tracked somatic mutations in nearly 2,100 bladder microbiopsy samples collected from 15 healthy individuals with histologically normal bladder urothelia and five individuals with bladder cancer. Their findings, published in Science on Thursday, revealed genes that are recurrently mutated in the bladder over time, while providing a look at clonal selection and mutational signatures.

"This study reveals a rich landscape of mutational processes and selection in normal urothelium with large heterogeneity across clones and individuals," the authors reported.

Based on insights from 1,914 samples assessed by targeted sequencing, 655 exome-sequenced samples and 88 samples assessed by whole-genome sequencing, the team highlighted alterations in 17 genes that appeared to be under positive selection in the bladder. Genes in that set, which included genes contributing to chromatin remodeling pathways, were mutated more frequently in those with bladder cancer compared to normal bladder samples from middle-aged or elderly participants.

"In addition to shedding light on the origins of cancer and informing early detection efforts, these observations raise questions about the possible role of these widespread mutations in aging and other diseases," Martincorena said.

The investigators found that the specific driver genes under selection in the normal bladder urothelium samples varied from one individual to the next, to some extent, as did mutational signatures. They suggested that these differences may reflect distinct environmental exposures, particularly via mutagenic or carcinogenic compounds that make their way into the urine.

Still, the results did reveal mutation patterns that were over-represented across the bladder samples, including a mutational signature stemming from APOBEC mutagenesis. And, the team explained, more fully characterizing the somatic alterations found in normal and bladder cancer samples may offer an opportunity to find individuals with bladders that are edging toward disease. 

"The presence of mutations in key cancer genes in bladder tumors that are usually absent in normal tissue opens up the possibility of looking for these changes in fragments of DNA that are present in urine," co-author Thomas Mitchell, a cancer, aging, mutation, and urology researcher affiliated with the Sanger Institute and Cambridge University Hospitals, said in a statement. "These 'liquid biopsies' could be a non-invasive way to screen for bladder cancer earlier, which could help reduce the number of people who die from this disease."