Chromosome Research

, Volume 23, Issue 2, pp 311–331 | Cite as

Canine urothelial carcinoma: genomically aberrant and comparatively relevant

  • S. G. Shapiro
  • S. Raghunath
  • C. Williams
  • A. A. Motsinger-Reif
  • J. M. Cullen
  • T. Liu
  • D. Albertson
  • M. Ruvolo
  • A. Bergstrom Lucas
  • J. Jin
  • D. W. Knapp
  • J. D. Schiffman
  • M. Breen


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.


Canine Urothelial carcinoma Transitional cell carcinoma Cytogenetics Chromosome aberration Array comparative genomic hybridization Comparative oncology 



Agilent MicroArray Design Identifier


Bacterial artificial chromosome


Cyclin-dependent kinase inhibitor 2A


Canis familiaris (also used as a prefix to canine chromosome numbers)


Copy number aberration


Deoxyribonucleic acid


Evolutionarily conserved chromosome segment


Fast Adaptive States Segmentation Technique 2


Formalin-fixed paraffin embedded


Fluorescence in situ hybridization


Gene ontology


Hematoxylin and eosin


Homo sapiens (also used as a prefix to human chromosome numbers)


Oligo-array comparative genomic hybridization


Odds ratio


Protein Analysis Through Evolutionary Relationships


Phosphate-buffered saline


Relative risk


Urothelial carcinoma


Transitional cell carcinoma



The canine oaCGH and FISH data generated in this study were funded by the NCSU-CVM Cancer Genomics Fund (MB). SS was supported in part by a Graduate Fellowship from the NCSU Comparative Biomedical Sciences Graduate Program, an NIH-T35 grant, a Triangle Community Foundation award, a George Hitchings New Investigator Award in Health Research, and the NCSU-CVM Cancer Genomics Fund (MB). We gratefully acknowledge support of Skippy Frank Fund for Life Sciences and Translational Research/ Rockefeller Philanthropy Advisors (awarded to MB/JS), whose funding supported SR as a Skippy Frank Translational Postdoctoral Fellow. J.D.S. holds the Edward B. Clark, MD Chair in Pediatric Research, and is supported through the Primary Children’s Hospital (PCH) Pediatric Cancer Program funded by the Intermountain Healthcare Foundation and the Primary Children’s Hospital Foundation. We thank Rachael Thomas for assistance with humanization of canine CGH data and Clint Mason for valuable informatics advice.

Supplementary material

10577_2015_9471_MOESM1_ESM.pdf (803 kb)
SOM Fig. 1 Gene ontology analysis highlighted gene function categories frequency affected by shared copy number aberration in human and canine UC. A GO analysis was performed as a part of the pathway analysis done in PANTHER. Conserved copy number gains and losses are shown as the inner and outer donut plots, respectively, with number of genes affected shown in each category. These data indicated that genes associated with metabolic processes (GO:0008152), cell processes (GO:0009987), and biological regulation (GO:0065007) were the most prominent among human and canine UC. Each of these three processes is highlighted in the corresponding donut plot. (PDF 802 kb)


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Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • S. G. Shapiro
    • 1
  • S. Raghunath
    • 1
    • 2
  • C. Williams
    • 1
  • A. A. Motsinger-Reif
    • 3
    • 8
  • J. M. Cullen
    • 4
    • 8
  • T. Liu
    • 5
  • D. Albertson
    • 5
  • M. Ruvolo
    • 6
  • A. Bergstrom Lucas
    • 6
  • J. Jin
    • 6
  • D. W. Knapp
    • 7
  • J. D. Schiffman
    • 2
  • M. Breen
    • 1
    • 8
    • 9
    • 10
  1. 1.Department of Molecular Biomedical Sciences, College of Veterinary MedicineNorth Carolina State UniversityRaleighUSA
  2. 2.Department of Pediatrics and Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA
  3. 3.Department of Statistics, College of SciencesNorth Carolina State UniversityRaleighUSA
  4. 4.Department of Population Health and Pathobiology, College of Veterinary MedicineNorth Carolina State UniversityRaleighUSA
  5. 5.Anatomic Pathology Division Department of PathologyUniversity of UtahSalt Lake CityUSA
  6. 6.Agilent TechnologiesSanta ClaraUSA
  7. 7.Department of Veterinary Clinical SciencesPurdue University, School of Veterinary MedicineWest LafayetteUSA
  8. 8.Center for Comparative Medicine and Translational ResearchNorth Carolina State UniversityRaleighUSA
  9. 9.Center for Human Health and the EnvironmentNorth Carolina State UniversityRaleighUSA
  10. 10.Lineberger Comprehensive Cancer CenterUniversity of North CarolinaChapel HillUSA

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