title: Canine urothelial carcinoma: genomically aberrant and comparatively relevant.
abstract: Urothelial carcinoma (UC), also referred to as transitional cell carcinoma (TCC), is the most common bladder malignancy in both human and canine populations. In human UC, numerous studies have demonstrated the prevalence of chromosomal imbalances. Although the histopathology of the disease is similar in both species, studies evaluating the genomic profile of canine UC are lacking, limiting the discovery of key comparative molecular markers associated with driving UC pathogenesis. In the present study, we evaluated 31 primary canine UC biopsies by oligonucleotide array comparative genomic hybridization (oaCGH). Results highlighted the presence of three highly recurrent numerical aberrations: gain of dog chromosome (CFA) 13 and 36 and loss of CFA 19. Regional gains of CFA 13 and 36 were present in 97 % and 84 % of cases, respectively, and losses on CFA 19 were present in 77 % of cases. Fluorescence in situ hybridization (FISH), using targeted bacterial artificial chromosome (BAC) clones and custom Agilent SureFISH probes, was performed to detect and quantify these regions in paraffin-embedded biopsy sections and urine-derived urothelial cells. The data indicate that these three aberrations are potentially diagnostic of UC. Comparison of our canine oaCGH data with that of 285 human cases identified a series of shared copy number aberrations. Using an informatics approach to interrogate the frequency of copy number aberrations across both species, we identified those that had the highest joint probability of association with UC. The most significant joint region contained the gene PABPC1, which should be considered further for its role in UC progression. In addition, cross-species filtering of genome-wide copy number data highlighted several genes as high-profile candidates for further analysis, including CDKN2A, S100A8/9, and LRP1B. We propose that these common aberrations are indicative of an evolutionarily conserved mechanism of pathogenesis and harbor genes key to urothelial neoplasia, warranting investigation for diagnostic, prognostic, and therapeutic applications.
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC, 27607, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Shapiro
authors.forename: S
authors.initials: S
authors.lastname: Raghunath
authors.forename: C
authors.initials: C
authors.lastname: Williams
authors.forename: A A
authors.initials: AA
authors.lastname: Motsinger-Reif
authors.forename: J M
authors.initials: JM
authors.lastname: Cullen
authors.forename: T
authors.initials: T
authors.lastname: Liu
authors.forename: D
authors.initials: D
authors.lastname: Albertson
authors.forename: M
authors.initials: M
authors.lastname: Ruvolo
authors.forename: A
authors.initials: A
authors.lastname: Bergstrom Lucas
authors.forename: J
authors.initials: J
authors.lastname: Jin
authors.forename: D W
authors.initials: DW
authors.lastname: Knapp
authors.forename: J D
authors.initials: JD
authors.lastname: Schiffman
authors.forename: M
authors.initials: M
authors.lastname: Breen
mesh_terms: D000818:Animals; D001706:Biopsy; D002277:Carcinoma / Q000662:veterinary*; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D019295:Computational Biology / Q000379:methods; D056915:DNA Copy Number Variations; D004285:Dogs; D005260:Female; D056426:Genetic Loci; D023281:Genomics / Q000379:methods; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D014571:Urologic Neoplasms / Q000662:veterinary*