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Key cross-species genes offer insight into human bladder cancer development

Muscle invasive bladder cancer (MIBC) is an aggressive form of human bladder cancer. Little is currently known about the genetic basis for this disease and few therapeutic options are available, resulting in a poor prognosis in most cases. A new study published in Genome Biology has established several key genes involved in the development of urothelial carcinoma (UC), the equivalent of MIBC in dogs and cats, which may translate into new therapeutic targets for the treatment of this disease in humans.   

Poor prognosis

Over 100,000 people are currently living with bladder cancer in the UK, of which around 25% of cases will develop into MIBC. Unfortunately, the current understanding of MIBC is limited, resulting in a lack of treatment options and a 5-year survival rate of just 6%. Therefore, there is an urgent need to improve the understanding of this disease to improve patient outcomes.

Current research has established over 60 genes which may be responsible for bladder cancer development. However, to date, no significant treatment breakthroughs have been made. To establish new potential therapeutic targets, researchers at the University of Guelph, Canada, and the Wellcome Sanger Institute, UK, have sequenced samples from dogs and cats diagnosed with UC to establish key driver genes and mutations. As UC closely resembles MIBC in humans, the group hoped that the results could help to identify key UC driver genes that are also responsible for MIBC development in humans.

Animal models

Pet dogs and cats are thought to be particularly relevant for this kind of cross-species study as they are likely to be exposed to the same potential carcinogens as their owners, such as water supply and environmental factors. UC can also develop in cattle that graze on bracken fern, which produces the carcinogen ptaquiloside during digestion. Therefore, these animals may represent relevant models of spontaneous and carcinogen-induced UC, which could translate into useful targets for human MIBC.

“If the same mutation is found across species, it is more likely to be important and should be studied,” said Dr Geoff Wood, professor in Ontario Veterinary College’s Department of Pathobiology and co-author of the study. “This allows us to narrow in on the genes that are biologically relevant for disease.”   

Driver genes

Comparison of the 60 driver genes already known to be mutated in human MIBC against the sequencing data of dog and cat UC found some similarities. Three key genes were identified in both the human and cat samples – TP53, FAT1 and NRAS – and two were found in both the human and dog samples – ARID1A and KDM6A. Other genes involved in cell cycle regulation and chromatin remodelling were also found to be amplified or deleted in the same way between species. Of note, the most frequently mutated gene in cats was TP53, which is also the most frequently mutated gene in human MIBC.

Genetic events such as mismatch repair deficiency and chromothripsis, which leads to major changes in DNA structure, were also found to be similar in all three species and may highlight a common genetic basis for these diseases. However, a number of differences were also noted between the species, including differences in recurrent somatic copy number and a lower overall mutation rate in animals compared to humans (Figure 1). Further, the most frequently mutated gene in dog UC was found to be BRAF, which is only found in around 3% of human MIBC cases.

Figure 1. Genomic regions with recurrent somatic copy number alterations in human, feline and canine bladder cancer. Outer track represents chromosomes (data for human chromosome X was not available). Inner track shows frequencies of copy number gain (purple, blue, and green) and losses (orange, red, and yellow) in human, canine and feline, respectively. Links between chromosomes show syntenic regions within recurrently amplified/deleted chromosomes (feline and canine) or chromosome arms (human). Red links represent deletions, purple links represent amplifications. Orange and purple text are genes in syntenic regions in chromosomes or chromosome arms that were recurrently deleted or amplified, respectively, in all 3 species. Red and blue text are genes that were focally amplified or deleted in 2 or more species. Black text shows other genes of interest. Adapted from Wong et al. 2023.

One Medicine, One Health

This study identifies canine and feline UC as relevant models of human MIBC and has highlighted some evolutionarily conserved driver genes across the species. This approach may help further the understanding of the similarities and differences in this disease between humans and animals, providing new opportunities for therapeutic intervention in MIBC. This also demonstrates the relevance of the ‘One Medicine, One Health’ concept, where information gained from one species can be used to benefit others, bridging the gap between human and animal research to improve outcomes for all.

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Bladder Cancer / Cancer / Sequencing