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Chromosome Research

, Volume 27, Issue 3, pp 179–202 | Cite as

Genome-wide DNA copy number analysis and targeted transcriptional analysis of canine histiocytic malignancies identifies diagnostic signatures and highlights disruption of spindle assembly complex

  • Katherine Kennedy
  • Rachael Thomas
  • Jessica Durrant
  • Tao Jiang
  • Alison Motsinger-Reif
  • Matthew BreenEmail author
Original Article

Abstract

Canine histiocytic malignancies (HM) are rare across the general dog population, but overrepresented in certain breeds, such as Bernese mountain dog and flat-coated retriever. Accurate diagnosis relies on immunohistochemical staining to rule out histologically similar cancers with different prognoses and treatment strategies (e.g., lymphoma and hemangiosarcoma). HM are generally treatment refractory with overall survival of less than 6 months. A lack of understanding regarding the mechanisms of disease development and progression hinders development of novel therapeutics. While the study of human tumors can benefit veterinary medicine, the rarity of the suggested orthologous disease (dendritic cell sarcoma) precludes this. This study aims to improve the understanding of underlying disease mechanisms using genome-wide DNA copy number and gene expression analysis of spontaneous HM across several dog breeds. Extensive DNA copy number disruption was evident, with losses of segments of chromosomes 16 and 31 detected in 93% and 72% of tumors, respectively. Droplet digital PCR (ddPCR) evaluation of these regions in numerous cancer specimens effectively discriminated HM from other common round cell tumors, including lymphoma and hemangiosarcoma, resulting in a novel, rapid diagnostic aid for veterinary medicine. Transcriptional analysis demonstrated disruption of the spindle assembly complex, which is linked to genomic instability and reduced therapeutic impact in humans. A key signature detected was up-regulation of Matrix Metalloproteinase 9 (MMP9), supported by an immunohistochemistry-based assessment of MMP9 protein levels. Since MMP9 has been linked with rapid metastasis and tumor aggression in humans, the data in this study offer a possible mechanism of aggression in HM.

Keywords

Histiocytic sarcoma Chromothripsis MMP9 Aurora kinase Dendritic cell sarcoma 

Abbreviations

BAC

bacterial artificial chromosome

BMD

Bernese mountain dog

CFA

Canis familiaris

oaCGH

oligo-array comparative genomic hybridization

CNA

copy number aberration

CYT

histiocytoma

ddPCR

droplet digital polymerase chain reaction

DNA

deoxyribonucleic acid

FCR

flat-coated retriever

FFPE

formalin fixed paraffin embedded

FISH

fluorescence in situ hybridization

HEM

hemangiosarcoma

HM

histiocytic malignancy

IHC

immunohistochemistry

LSA

lymphoma

MCT

mast cell tumor

MEL

melanoma

OSA

osteosarcoma

PL

plasmacytoma

STS

soft-tissue sarcoma

TMA

tissue microarray

TVT

transmissible venereal tumor

UC

urothelial carcinoma

WCPP

whole chromosome paint probe

Notes

Acknowledgements

The authors wish to thank the North Carolina State University College of Veterinary Medicine Histopathology department for their expertise in performing immunohistochemistry evaluation of canine tumors. The authors also wish to thank the American Kennel Club Canine Health Foundation (Grant 01557) and the North Carolina State University Cancer Genomics fund for their generous financial support. We thank the Bernese Mountain Dog Club of America, Berner-L, and the Flat-Coated Retriever Foundation for continued support of HM research at NC State University.

Author contributions

M.B. conceived of the study, participated in its design and coordination, and helped to draft the manuscript. K.K. carried out molecular genetic studies and drafted the manuscript. R.T. assisted with data interpretation and manuscript preparation. J.D. reviewed tumor histopathology and immunohistochemistry. A.M.-R. supervised and performed statistical analyses with T.J. All authors read and approved the final manuscript.

Compliance with ethical standards

Declaration of competing interests

K.K. is an employee of Sentinel Biomedical, which currently holds the commercial license to the ddPCR assay described in this paper. M.B. and R.T. are founders of Sentinel Biomedical.

Supplementary material

10577_2019_9606_MOESM1_ESM.pdf (31 kb)
Supplemental Table 1 ddPCR assay sequences and locations. Sequence and location information for each set of primers and probes for the regions of interest. (PDF 30 kb)
10577_2019_9606_MOESM2_ESM.pdf (18 kb)
Supplemental Table 2 ddPCR CFA 31 assay sensitivity and specificity by disease. Results of a 100-fold cross-validation assessment of the sensitivity and specificity for the ddPCR chromosome 31 assay when comparing HM to each of 10 other tumor types individually, and when comparing HM to those tumors that would be in the top differential (hemangiosarcoma, lymphoma, mast cell tumor, extramedullary plasmacytoma, benign histiocytoma, and amelanotic melanoma). (PDF 17 kb)

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Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Molecular Biomedical Sciences, College of Veterinary MedicineNorth Carolina State UniversityRaleighUSA
  2. 2.Sentinel Biomedical Incorporated, Centennial Biomedical CampusRaleighUSA
  3. 3.Comparative Medicine InstituteNorth Carolina State UniversityRaleighUSA
  4. 4.Department of Population Health and Pathobiology, College of Veterinary MedicineNorth Carolina State UniversityRaleighUSA
  5. 5.Bioinformatics Research CenterNorth Carolina State UniversityRaleighUSA
  6. 6.Department of StatisticsNorth Carolina State UniversityRaleighUSA
  7. 7.Cancer Genetics ProgramUniversity of North Carolina Lineberger Comprehensive Cancer CenterChapel HillUSA
  8. 8.Duke Cancer InstituteDuke UniversityDurhamUSA

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