dc.contributor.author
Wong, Kim
dc.contributor.author
Abascal, Federico
dc.contributor.author
Ludwig, Latasha
dc.contributor.author
Aupperle-Lellbach, Heike
dc.contributor.author
Grassinger, Julia
dc.contributor.author
Wright, Colin W.
dc.contributor.author
Allison, Simon J.
dc.contributor.author
Pinder, Emma
dc.contributor.author
Phillips, Roger M.
dc.contributor.author
Klopfleisch, Robert
dc.date.accessioned
2023-10-19T08:59:31Z
dc.date.available
2023-10-19T08:59:31Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/41197
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-40918
dc.description.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.
en
dc.format.extent
29 Seiten
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
Urinary bladder
en
dc.subject
Mutational signature
en
dc.subject
Ptaquiloside
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::630 Landwirtschaft::630 Landwirtschaft und verwandte Bereiche
dc.title
Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
191
dcterms.bibliographicCitation.doi
10.1186/s13059-023-03026-4
dcterms.bibliographicCitation.journaltitle
Genome Biology
dcterms.bibliographicCitation.volume
24
dcterms.bibliographicCitation.url
https://doi.org/10.1186/s13059-023-03026-4
refubium.affiliation
Veterinärmedizin
refubium.affiliation.other
Institut für Tierpathologie
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refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.isPartOf.eissn
1474-760X
refubium.resourceType.provider
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