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With a high mutation load and large number of altered genes, strategies to delineate key driver events are necessary. Dogs and cats develop urothelial carcinoma (UC) with histological and clinical similarities to human MIBC. Cattle that graze on bracken fern also develop UC, associated with exposure to the carcinogen ptaquiloside. These species may represent relevant animal models of spontaneous and carcinogen-induced UC that can provide insight into human MIBC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Whole-exome sequencing of domestic canine (<jats:italic>n<\/jats:italic>\u2009=\u200987) and feline (<jats:italic>n<\/jats:italic>\u2009=\u200923) UC, and comparative analysis with human MIBC reveals a lower mutation rate in animal cases and the absence of APOBEC mutational signatures. A convergence of driver genes (<jats:italic>ARID1A, KDM6A, TP53<\/jats:italic>,<jats:italic>FAT1<\/jats:italic>, and<jats:italic>NRAS<\/jats:italic>) is discovered, along with common focally amplified and deleted genes involved in regulation of the cell cycle and chromatin remodelling. We identify mismatch repair deficiency in a subset of canine and feline UCs with biallelic inactivation of<jats:italic>MSH2<\/jats:italic>. Bovine UC (<jats:italic>n<\/jats:italic>\u2009=\u20098) is distinctly different; we identify novel mutational signatures which are recapitulated in vitro in human urinary bladder UC cells treated with bracken fern extracts or purified ptaquiloside.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Canine and feline urinary bladder UC represent relevant models of MIBC in humans, and cross-species analysis can identify evolutionarily conserved driver genes. We characterize mutational signatures in bovine UC associated with bracken fern and ptaquiloside exposure, a human-linked cancer exposure. Our work demonstrates the relevance of cross-species comparative analysis in understanding both human and animal UC.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s13059-023-03026-4","type":"journal-article","created":{"date-parts":[[2023,8,27]],"date-time":"2023-08-27T23:02:23Z","timestamp":1693177343000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer"],"prefix":"10.1186","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0984-1477","authenticated-orcid":false,"given":"Kim","family":"Wong","sequence":"first","affiliation":[]},{"given":"Federico","family":"Abascal","sequence":"additional","affiliation":[]},{"given":"Latasha","family":"Ludwig","sequence":"additional","affiliation":[]},{"given":"Heike","family":"Aupperle-Lellbach","sequence":"additional","affiliation":[]},{"given":"Julia","family":"Grassinger","sequence":"additional","affiliation":[]},{"given":"Colin W.","family":"Wright","sequence":"additional","affiliation":[]},{"given":"Simon J.","family":"Allison","sequence":"additional","affiliation":[]},{"given":"Emma","family":"Pinder","sequence":"additional","affiliation":[]},{"given":"Roger M.","family":"Phillips","sequence":"additional","affiliation":[]},{"given":"Laura P.","family":"Romero","sequence":"additional","affiliation":[]},{"given":"Arnon","family":"Gal","sequence":"additional","affiliation":[]},{"given":"Patrick J.","family":"Roady","sequence":"additional","affiliation":[]},{"given":"Isabel","family":"Pires","sequence":"additional","affiliation":[]},{"given":"Franco","family":"Guscetti","sequence":"additional","affiliation":[]},{"given":"John S.","family":"Munday","sequence":"additional","affiliation":[]},{"given":"Maria C.","family":"Peleteiro","sequence":"additional","affiliation":[]},{"given":"Carlos A.","family":"Pinto","sequence":"additional","affiliation":[]},{"given":"T\u00e2nia","family":"Carvalho","sequence":"additional","affiliation":[]},{"given":"Jo\u00e3o","family":"Cota","sequence":"additional","affiliation":[]},{"given":"Elizabeth C.","family":"Du Plessis","sequence":"additional","affiliation":[]},{"given":"Fernando","family":"Constantino-Casas","sequence":"additional","affiliation":[]},{"given":"Stephanie","family":"Plog","sequence":"additional","affiliation":[]},{"given":"Lars","family":"Moe","sequence":"additional","affiliation":[]},{"given":"Simone","family":"de Brot","sequence":"additional","affiliation":[]},{"given":"Ingrid","family":"Bemelmans","sequence":"additional","affiliation":[]},{"given":"Ren\u00e9e Laufer","family":"Amorim","sequence":"additional","affiliation":[]},{"given":"Smitha R.","family":"Georgy","sequence":"additional","affiliation":[]},{"given":"Justina","family":"Prada","sequence":"additional","affiliation":[]},{"given":"Jorge","family":"del Pozo","sequence":"additional","affiliation":[]},{"given":"Marianne","family":"Heimann","sequence":"additional","affiliation":[]},{"given":"Louisiane","family":"de Carvalho Nunes","sequence":"additional","affiliation":[]},{"given":"Outi","family":"Simola","sequence":"additional","affiliation":[]},{"given":"Paolo","family":"Pazzi","sequence":"additional","affiliation":[]},{"given":"Johan","family":"Steyl","sequence":"additional","affiliation":[]},{"given":"Rodrigo","family":"Ubukata","sequence":"additional","affiliation":[]},{"given":"Peter","family":"Vajdovich","sequence":"additional","affiliation":[]},{"given":"Simon L.","family":"Priestnall","sequence":"additional","affiliation":[]},{"given":"Alejandro","family":"Su\u00e1rez-Bonnet","sequence":"additional","affiliation":[]},{"given":"Franco","family":"Roperto","sequence":"additional","affiliation":[]},{"given":"Francesca","family":"Millanta","sequence":"additional","affiliation":[]},{"given":"Chiara","family":"Palmieri","sequence":"additional","affiliation":[]},{"given":"Ana L.","family":"Ortiz","sequence":"additional","affiliation":[]},{"given":"Claudio S. 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All tissue samples were sent from veterinary pathologists that confirmed they were collected from animals with the owner\u2019s consent, and the sampling was performed for diagnostic purposes with the primary aim of benefiting the animal. If the samples were taken post-mortem, the animal was euthanized for purposes relating to its welfare; in the case of the cows, they were sacrificed using a captive bolt that was performed by a veterinarian at an officially registered\/regulated abattoir or veterinary center.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing or financial interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"191"}}