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Chromosome Research

, Volume 25, Issue 2, pp 129–143 | Cite as

Genomic profiling of canine mast cell tumors identifies DNA copy number aberrations associated with KIT mutations and high histological grade

  • Hiroyuki Mochizuki
  • Rachael Thomas
  • Scott Moroff
  • Matthew Breen
Original Article

Abstract

Mast cell tumor (MCT) is the most common skin malignancy of domestic dogs and presents with a widely variable clinical behavior. Although activating KIT mutations are present in approximately 20% of canine MCTs, molecular etiology is largely unknown for the majority of this cancer. Characterization of genomic alterations in canine MCTs may identify genomic regions and/or genes responsible for their development and progression, facilitating the discovery of new therapeutic targets and improved clinical management of this heterogeneous cancer. We performed genome-wide DNA copy number analysis of 109 primary MCTs derived from three popular canine breeds (the Boxer, Labrador Retriever, and Pug) as well as nontarget breeds using oligonucleotide array comparative genomic hybridization (oaCGH). We demonstrated a stepwise accumulation of numerical DNA copy number aberrations (CNAs) as tumor grade increases. DNA sequencing analysis revealed that KIT mutations were found less frequently in the Pug tumors and were strongly associated with high histological grade. Tumors with KIT mutations showed genome-wide aberrant copy number profiles, with frequent CNAs involving genes in the p53 and RB pathways, whereas CNAs were very limited in tumors with wild-type KIT. We evaluated the presence of four CNAs to predict aggressive tumor phenotypes. This approach predicted aggressive tumors with a sensitivity of 78–94% and specificity of 88–93%, when using oaCGH and droplet digital PCR platforms. Further investigation of genome regions identified in this study may lead to the development of a molecular tool for classification and prognosis, as well as identification of therapeutic target molecules.

Keywords

Cancer Comparative genomic hybridization Digital PCR Dog Mastocytosis Pug 

Abbreviations

CFA

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

CI

Confidence interval

CNA

Copy number aberration

ddPCR

Droplet digital PCR

FFPE

Formalin fixed paraffin embedded

GISTIC

Genomic Identification of Significant Targets in Cancer

ITD

Internal tandem duplication

MCT

Mast cell tumor

mut-KIT

Mutant KIT

oaCGH

Oligonucleotide array comparative genomic hybridization

OR

Odds ratio

ROC

Receiver operating characteristic

wt-KIT

Wild-type KIT

Notes

Acknowledgements

This study was funded in part by a grant from Antech Diagnostics (awarded to MB) and by the NCSU Cancer Genomics fund (MB). HM was supported in part by a Morris Animal Foundation Fellowship (awarded to HM, study ID: D14CA-401) and a Postdoctoral Fellowship for Research Abroad, provided by the Japan Society for the Promotion of Science (HM).

Compliance with ethical standards

Ethical standards

The experiment complies with the current laws of the country, the USA, in which they were performed.

Studies of human or animal subjects

This article does not contain any studies with human or animal subjects performed by the any of the authors.

Supplementary material

10577_2016_9543_MOESM1_ESM.xls (236 kb)
ESM 1 (XLS 235 kb)

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Copyright information

© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  • Hiroyuki Mochizuki
    • 1
    • 2
  • Rachael Thomas
    • 1
    • 2
  • Scott Moroff
    • 3
  • Matthew Breen
    • 1
    • 2
    • 4
    • 5
  1. 1.Department of Molecular Biomedical Sciences, College of Veterinary MedicineNorth Carolina State UniversityRaleighUSA
  2. 2.Comparative Medicine InstituteNorth Carolina State UniversityRaleighUSA
  3. 3.Antech Diagnostics Inc.New Hyde ParkUSA
  4. 4.Center for Human Health and the EnvironmentNorth Carolina State UniversityRaleighUSA
  5. 5.Lineberger Comprehensive Cancer CenterUniversity of North CarolinaChapel HillUSA

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