Genomic profiling of canine mast cell tumors identifies DNA copy number aberrations associated with KIT mutations and high histological grade
- 529 Downloads
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.
KeywordsCancer Comparative genomic hybridization Digital PCR Dog Mastocytosis Pug
Canis familiaris (also used as a prefix to chromosome numbers)
Copy number aberration
Droplet digital PCR
Formalin fixed paraffin embedded
Genomic Identification of Significant Targets in Cancer
Internal tandem duplication
Mast cell tumor
Oligonucleotide array comparative genomic hybridization
Receiver operating characteristic
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
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.
- 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 11(201)Google Scholar
- London CA, Malpas PB, Wood-Follis SL et al (2009) Multi-center, placebo-controlled, double-blind, randomized study of oral toceranib phosphate (SU11654), a receptor tyrosine kinase inhibitor, for the treatment of dogs with recurrent (either local or distant) mast cell tumor following surgical excision. Clin Cancer Res 15:3856–3865CrossRefPubMedGoogle Scholar
- Mochizuki, H, Motsinger-Reif, A, Bettini, C, Moroff, S, Breen, M (2016a) Association of breed and histopathological grade in canine mast cell tumours. Veterinary and Comparative Oncology. Google Scholar
- Roode, SC, Rotroff, D, Avery, AC, et al. (2015) Genome-wide assessment of recurrent genomic imbalances in canine leukemia identifies evolutionarily conserved regions for subtype differentiation. Chromosome Res.Google Scholar
- Stefanello D, Buracco P, Sabattini S et al (2015) Comparison of 2-and 3-category histologic grading systems for predicting the presence of metastasis at the time of initial evaluation in dogs with cutaneous mast cell tumors: 386 cases (2009–2014). J Am Vet Med Assoc 246:765–769CrossRefPubMedGoogle Scholar