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
Article

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)

References

  1. American Cancer Society (2014) Cancer facts and figures 2014. Society AC, AtlantaGoogle Scholar
  2. American Joint Committee on Cancer (2002) Urinary bladder. In: Greene F, Page D, Fleming I et al (eds) Cancer staging manual. Springer-Verlag, New York, pp 335–338CrossRefGoogle Scholar
  3. Anderson W, Dunham B, King J et al (1989) Presumptive subcutaneous transplation of a urinary bladder transitional cell carcinoma of the urinary bladder in a dog. Cornell Vet 79:263–266PubMedGoogle Scholar
  4. Angstadt AY, Motsinger-Reif A, Thomas R et al (2011) Characterization of canine osteosarcoma by array comparative genomic hybridization and RT-qPCR: signatures of genomic imbalance in canine osteosarcoma parallel the human counterpart. Genes Chromosom Cancer 50(11):859–874CrossRefPubMedGoogle Scholar
  5. Angstadt AY, Thayanithy V, Subramanian S, Modiano JF, Breen M (2012) A genome-wide approach to comparative oncology: high-resolution oligonucleotide aCGH of canine and human osteosarcoma pinpoints shared microaberrations. Cancer Genet 205(11):572–587CrossRefPubMedGoogle Scholar
  6. Bansal N, Gupta A, Sankhwar SN, Mahdi AA (2014) Low- and high-grade bladder cancer appraisal via serum-based proteomics approach. Clin Chim Acta 436:97–103CrossRefPubMedGoogle Scholar
  7. Bhatlekar S, Fields JZ, Boman BM (2014) HOX genes and their role in the development of human cancers. J Mol Med (1432–1440 (Electronic))Google Scholar
  8. Cai H, Kumar N, Bagheri H, von Mering C, Robinson M, Baudis M (2014) Chromothripsis-like patterns are recurring but heterogenously distributed features in a survery of 22,347 cancer genome screens. BMC Genomics 15:82CrossRefPubMedCentralPubMedGoogle Scholar
  9. Calin GA, Dumitru CS et al (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci 101(9):2999–3004CrossRefPubMedCentralPubMedGoogle Scholar
  10. Castillo-Martin M, Domingo-Domenech J, Karni-Schmidt O, Matos T, Cordon-Cardo C (2010) Molecular pathways of urothelial development and bladder tumorigenesis. Urol Oncol 28(4):401–408CrossRefPubMedGoogle Scholar
  11. Chekaluk Y, Wu CL, Rosenberg J et al (2013) Identification of nine genomic regions of amplification in urothelial carcinoma, correlation with stage, and potential prognostic and therapeutic value. PLoS One 8(4):e60927CrossRefPubMedCentralPubMedGoogle Scholar
  12. Chen R, Feng C, Xu Y (2011) Cyclin-dependent kinase-associated protein Cks2 is associated with bladder cancer progression. J Int Med Res 39(2):533–540CrossRefPubMedGoogle Scholar
  13. Development Team R (2010) R: a language and environment for statistical computing. R Foundation for Statistical Computing, ViennaGoogle Scholar
  14. Dhawan D, Ramos-Vara JA, Stewart JC, Zheng R, Knapp DW (2009) Canine invasive transitional cell carcinoma cell lines: in vitro tools to complement a relevant animal model of invasive urinary bladder cancer. Urol Oncol 27(3):284–292CrossRefPubMedGoogle Scholar
  15. Dobson JM (2013) Breed-predispositions to cancer in pedigree dogs. ISRN Veterinary Science 2013Google Scholar
  16. Ebbing J, Mathia S, Seibert F et al (2013) Urinary calprotectin: a new diagnostic marker in urothelial carcinoma of the bladder. World J Urol 1–8Google Scholar
  17. Eliseeva IA, Lyabin DN, Ovchinnikov LP (2013) Poly(A)-binding proteins: structure, domain organization, and activity regulation. Biochemistry Moscow 78(13):1377–1391CrossRefPubMedGoogle Scholar
  18. Fadl-Elmula I (2005) Chromosomal changes in uroepithelial carcinomas. Cell Chromosom 4:1CrossRefGoogle Scholar
  19. Goebell PJ, Knowles MA (2010) Bladder cancer or bladder cancers? Genetically distinct malignant conditions of the urothelium. Urol Oncol 28(4):409–428CrossRefPubMedGoogle Scholar
  20. Hall M, Frank E, Holmes G, Pfahringer B, Reutemann P, Witten IH (2009) The WEKA Data Mining Software: an update. SIGKDD Explorations 11(1)Google Scholar
  21. Hedan B, Thomas R, Motsinger-Reif A et al (2011) Molecular cytogenetic characterization of canine histiocytic sarcoma: a spontaneous model for human histiocytic cancer identifies deletion of tumor suppressor genes and highlights influence of genetic background on tumor behavior. BMC Cancer (in revision)Google Scholar
  22. Heidenblad M, Lindgren D, Jonson T et al (2008) Tiling resolution array CGH and high density expression profiling of urothelial carcinomas delineate genomic amplicons and candidate target genes specific for advanced tumors. BMC Med Genomics 1:3CrossRefPubMedCentralPubMedGoogle Scholar
  23. Hosseini SA, Horton S, Saldivar JC et al (2013) Common chromosome fragile sites in human and murine epithelial cells and FHIT/FRA3B loss-induced global genome instability. Genes Chromosom Cancer 52(11):1017–1029CrossRefPubMedCentralPubMedGoogle Scholar
  24. Karolchik D, Hinrichs AS, Furey TS et al (2004) The UCSC Table Browser data retrieval tool. Nucleic Acids Res 32(suppl 1):D493–D496CrossRefPubMedCentralPubMedGoogle Scholar
  25. Kim WJ, Kim SK, Jeong P et al (2011) A four-gene signature predicts disease progression in muscle invasive bladder cancer. Mol Med 17(5–6):478–485PubMedCentralPubMedGoogle Scholar
  26. Kim WT, Kim J, Yan C et al (2014) S100A9 and EGFR gene signatures predict disease progression in muscle invasive bladder cancer patients after chemotherapy. Ann Oncol 25(5):974–979CrossRefPubMedGoogle Scholar
  27. Knapp DW, Glickman NW, Denicola DB, Bonney PL, Lin TL, Glickman LT (2000) Naturally-occurring canine transitional cell carcinoma of the urinary bladder A relevant model of human invasive bladder cancer. Urol Oncol 5(2):47–59CrossRefPubMedGoogle Scholar
  28. Knapp D, Ramos-Vara J, Moore G, Dhawan D, Bonney P, Young K (2014) Urinary bladder cancer in dogs, a naturally occurring model for cancer biology and drug development. ILAR J 55(1):100–118CrossRefPubMedGoogle Scholar
  29. Langbein S, Szakacs O, Wilhelm M et al (2002) Alteration of the LRP1B gene region is associated with high grade of urothelial cancer. Lab Investig 82(5):639–643CrossRefPubMedGoogle Scholar
  30. Ma K, Qiu L, Mrasek K et al (2012) Common fragile sites: genomic hotspots of DNA damage and carcinogenesis. Int J Mol Sci 13(9):11974–11999CrossRefPubMedCentralPubMedGoogle Scholar
  31. Mutsaers AJ, Widmer WR, Knapp DW (2003) Canine transitional cell carcinoma. J Vet Intern Med 17(2):136–144CrossRefPubMedGoogle Scholar
  32. Oliveira PA, Arantes-Rodrigues R, Vasconcelos-Nóbrega C (2014) Animal models of urinary bladder cancer and their application to novel drug discovery. Expert Opin Drug Discov 9(5):485–503CrossRefPubMedGoogle Scholar
  33. Panani A, Roussos C (2006) Sex chromosome abnormalities in bladder cancer: Y polysomies are linked to PT1-grade III transitional cell carcinoma. Anticancer Res 26(1):319–323PubMedGoogle Scholar
  34. Poorman K, Borst L, Moroff S et al (2014) Comparative cytogenetic characterization of primary canine melanocytic lesions using array CGH and fluorescence in situ hybridization. Chromosom Res (in press)Google Scholar
  35. Prazeres H, Torres J, Rodrigues F, Pinto M (2011) Chromosomal, epigenetic and microRNA-mediated inactivation of LRP1B, a modulator of the extracellular envrionemnt of thyroid cancer cells. Oncogene 30:1302–1317CrossRefPubMedGoogle Scholar
  36. Quinlan AR, Hall IM (2010) BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26(6):841–842CrossRefPubMedCentralPubMedGoogle Scholar
  37. Richards R (2001) Fragile and unstable chromosomes in cancer: causes and consequences. Trends Genet 17(6):339–345CrossRefPubMedGoogle Scholar
  38. Richter J, Beffa L, Wagner U et al (1998) Patterns of chromosomal imbalances in advanced urinary bladder cancer detected by comparative genomic hybridization. Am J Pathol 153(5):1615–1621CrossRefPubMedCentralPubMedGoogle Scholar
  39. Sahrief Y, Reich C, Bonar R (1980) Polyploidy in mammalian urothelial cells. Urol Res 8:153–161Google Scholar
  40. Schulz W (2006) Understanding urothelial carcinoma through cancer pathways. Int J Cancer 119:1513–1518CrossRefPubMedGoogle Scholar
  41. Shearin AL, Ostrander EA (2010) Leading the way: canine models of genomics and disease. Dis Model Mech 3(1–2):27–34CrossRefPubMedCentralPubMedGoogle Scholar
  42. Simoneau M, LaRue H, Aboulkassim T, Meyer F, Moore L, Fradet Y (2000) Chromosome 9 deletions and recurrence of superficial bladder cancer: identification of four regions of prognostic interest. Oncogene 19(54):6317–6323CrossRefPubMedGoogle Scholar
  43. Stephens P, Greenman C, Fu B, Yang F et al (2011) Massive genomic rearrangement required in a single catastrophic event during cancer development. Cell 144(1):27–40CrossRefPubMedCentralPubMedGoogle Scholar
  44. The Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507(7492):315–322CrossRefPubMedCentralGoogle Scholar
  45. Thomas PD, Campbell MJ, Kejariwal A et al (2003a) PANTHER: a library of protein families and subfamilies indexed by function. Genome Res 13(9):2129–2141CrossRefPubMedCentralPubMedGoogle Scholar
  46. Thomas PD, Kejariwal A, Campbell MJ et al (2003b) PANTHER: a browsable database of gene products organized by biological function, using curated protein family and subfamily classification. Nucleic Acids Res 31(1):334–341CrossRefPubMedCentralPubMedGoogle Scholar
  47. Thomas R, Smith KC, Ostrander EA, Galibert F, Breen M (2003c) Chromosome aberrations in canine multicentric lymphomas detected with comparative genomic hybridisation and a panel of single locus probes. Br J Cancer 89(8):1530–1537CrossRefPubMedCentralPubMedGoogle Scholar
  48. Thomas R, Seiser EL, Motsinger-Reif A et al (2011) Refining tumor-associated aneuploidy through 'genomic recoding' of recurrent DNA copy number aberrations in 150 canine non-Hodgkin lymphomas. Leuk Lymphoma 52(7):1321–1335CrossRefPubMedCentralPubMedGoogle Scholar
  49. Thomas R, Borst L, Rotroff D et al (2014) Genomic profiling reveals extensive heterogeneity in somatic DNA copy number aberrations of canine hemangiosarcoma. Chromosom Res 1–15Google Scholar
  50. van Duin M, van Marion R, Vissers K et al (2005) High-resolution array comparative genomic hybridization of chromosome arm 8q: evaluation of genetic progression markers for prostate cancer. Genes Chromosom Cancer 44(4):438–449CrossRefPubMedGoogle Scholar
  51. Xiao H, Li H, Yu G et al (2014) MicroRNA-10b promotes migration and invasion through KLF4 and HOXD10 in human bladder cancer. Oncol Rep 31(4):1832–1838PubMedGoogle Scholar

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

Personalised recommendations