Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer

Kim Wong, Federico Abascal, Latasha Ludwig, Heike Aupperle-Lellbach, Julia Grassinger, Colin W. Wright, Simon J. Allison, Emma Pinder, Roger Phillips, Laura P. Romero, Arnon Gal, Patrick J. Roady, Isabel Pires, Franco Guscetti, John S. Munday, Maria C. Peleteiro, Carlos A. Pinto, Tânia Carvalho, João Cota, Elizabeth C. Du PlessisFernando Constantino-Casas, Stephanie Plog, Lars Moe, Simone de Brot, Ingrid Bemelmans, Renée Laufer Amorim, Smitha R. Georgy, Justina Prada, Jorge del Pozo, Marianne Heimann, Louisiane de Carvalho Nunes, Outi Simola, Paolo Pazzi, Johan Steyl, Rodrigo Ubukata, Peter Vajdovich, Simon L. Priestnall, Alejandro Suárez-Bonnet, Franco Roperto, Francesca Millanta, Chiara Palmieri, Ana L. Ortiz, Claudio S. L. Barros, Aldo Gava, Minna E. Söderström, Marie O’Donnell, Robert Klopfleisch, Andrea Manrique-Rincón, Inigo Martincorena, Ingrid Ferreira, Mark J. Arends, Geoffrey A. Wood, David J. Adams, Louise van der Weyden

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Abstract

Background: In humans, muscle-invasive bladder cancer (MIBC) is highly aggressive and associated with a poor prognosis. 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. Results: Whole-exome sequencing of domestic canine (n = 87) and feline (n = 23) 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 (ARID1A, KDM6A, TP53, FAT1, and NRAS) 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 MSH2. Bovine UC (n = 8) 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. Conclusion: 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.

Original languageEnglish
Article number191
Number of pages29
JournalGenome Biology
Volume24
Issue number1
Early online date28 Aug 2023
DOIs
Publication statusPublished - 1 Dec 2023

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