Chromosome Research

, Volume 23, Issue 2, pp 311–331

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
Article

DOI: 10.1007/s10577-015-9471-y

Cite this article as:
Shapiro, S.G., Raghunath, S., Williams, C. et al. Chromosome Res (2015) 23: 311. doi:10.1007/s10577-015-9471-y

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.

Keywords

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

Abbreviations

AMADID

Agilent MicroArray Design Identifier

BAC

Bacterial artificial chromosome

CDKN2A

Cyclin-dependent kinase inhibitor 2A

CFA

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

CNA

Copy number aberration

DNA

Deoxyribonucleic acid

ECCS

Evolutionarily conserved chromosome segment

FASST2

Fast Adaptive States Segmentation Technique 2

FFPE

Formalin-fixed paraffin embedded

FISH

Fluorescence in situ hybridization

GO

Gene ontology

H&E

Hematoxylin and eosin

HSA

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

oaCGH

Oligo-array comparative genomic hybridization

OR

Odds ratio

PANTHER

Protein Analysis Through Evolutionary Relationships

PBS

Phosphate-buffered saline

RR

Relative risk

UC

Urothelial carcinoma

TCC

Transitional cell carcinoma

Supplementary material

10577_2015_9471_MOESM1_ESM.pdf (803 kb)
SOM Fig. 1Gene 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)

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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