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Canine urothelial carcinoma: genomically aberrant and comparatively relevant

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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.

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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

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Acknowledgments

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.

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Authors and Affiliations

  1. Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC, 27607, USA

    S. G. Shapiro, S. Raghunath, C. Williams & M. Breen

  2. Department of Pediatrics and Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA

    S. Raghunath & J. D. Schiffman

  3. Department of Statistics, College of Sciences, North Carolina State University, Raleigh, NC, USA

    A. A. Motsinger-Reif

  4. Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA

    J. M. Cullen

  5. Anatomic Pathology Division Department of Pathology, University of Utah, 1950 Circle of Hope, RM N3105, Salt Lake City, UT, 84112, USA

    T. Liu & D. Albertson

  6. Agilent Technologies, 5301 Stevens Creek Blvd., Santa Clara, CA, 95051, USA

    M. Ruvolo, A. Bergstrom Lucas & J. Jin

  7. Department of Veterinary Clinical Sciences, Purdue University, School of Veterinary Medicine, West Lafayette, IN, USA

    D. W. Knapp

  8. Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, NC, USA

    A. A. Motsinger-Reif, J. M. Cullen & M. Breen

  9. Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, USA

    M. Breen

  10. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

    M. Breen

Authors
  1. S. G. Shapiro
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  2. S. Raghunath
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  3. C. Williams
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  4. A. A. Motsinger-Reif
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  5. J. M. Cullen
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  6. T. Liu
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  7. D. Albertson
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  8. M. Ruvolo
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  9. A. Bergstrom Lucas
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  10. J. Jin
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  11. D. W. Knapp
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  12. J. D. Schiffman
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  13. M. Breen
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Corresponding author

Correspondence to M. Breen.

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Responsible Editor: Conly Rieder.

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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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Shapiro, S.G., Raghunath, S., Williams, C. et al. Canine urothelial carcinoma: genomically aberrant and comparatively relevant. Chromosome Res 23, 311–331 (2015). https://doi.org/10.1007/s10577-015-9471-y

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  • DOI: https://doi.org/10.1007/s10577-015-9471-y

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