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Thomas Flaig, MD


Finding Genetic Clues in Cats, Dogs, and Cows to Treat Human Bladder Cancer

By: Celeste L. Dixon
Posted: Friday, September 8, 2023

Expanding research beyond humans has begun to enhance our understanding of muscle-invasive bladder cancer in people as well in other species that also develop urothelial carcinoma—including dogs, cats, and cows. In Genome Biology, Louise van der Weyden, BSc (Hons), PhD, of Wellcome Sanger Institute, Cambridge, United Kingdom, and colleagues discussed their work, which showed canine and feline urinary bladder urothelial carcinomas have histologic and clinical similarities to human muscle-invasive bladder cancer. Additionally, they found that mutational signatures in bovine urothelial carcinoma seem to be associated with exposure to ptaquiloside (a norsesquiterpene glucoside produced by bracken ferns), which has been linked to cancer in humans as well.

Cross-species analysis may identify evolutionarily conserved driver genes, the team noted. This finding, they continued, may be of benefit because in human muscle-invasive bladder cancer, “with a high mutation load and large number of altered genes, strategies to delineate key driver events are necessary.” In canine and feline urothelial carcinomas, the investigators discovered a convergence of driver genes—ARID1A, KDM6A, TP53, FAT1, and NRAS—as well as “common focally amplified and deleted genes involved in regulation of the cell cycle and chromatin remodeling.” They also identified mismatch-repair deficiency in a subset of these urothelial carcinomas with biallelic inactivation of MSH2.

Performing whole-exome sequencing of domestic canine (n = 87) and feline (n = 23) urothelial carcinomas, followed by comparative analysis with human muscle-invasive bladder cancer, revealed a lower mutation rate in animal cases; APOBEC mutational signatures were also absent. However, bovine urothelial carcinoma (n = 8) was “distinctly different,” they noted. It had “novel mutational signatures…recapitulated in vitro in human urinary bladder urothelial carcinoma cells treated with…ptaquiloside.”

The team included an international group of veterinary pathologists. The tissue sample diversity suggests “we can be confident about the generalizability of our research,” Dr. van der Weyden said in an institutional news release. In practical terms, the cross-species comparison approach may help researchers prioritize the top driver gene candidates in future pharmaceutical research.

Disclosure: The study authors reported no conflicts of interest.

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