title: Genomic profiling of canine mast cell tumors identifies DNA copy number aberrations associated with KIT mutations and high histological grade.
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.
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC, 27607, USA.|Comparative Medicine Institute, North Carolina State University, Raleigh, NC, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mochizuki
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC, 27607, USA.|Comparative Medicine Institute, North Carolina State University, Raleigh, NC, USA.
authors.forename: Rachael
authors.initials: R
authors.lastname: Thomas
authors.affiliation: Antech Diagnostics Inc., 1111 Marcus Ave. Suite M28, New Hyde Park, NY, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Moroff
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC, 27607, USA. Matthew_Breen@ncsu.edu.|Comparative Medicine Institute, North Carolina State University, Raleigh, NC, USA. Matthew_Breen@ncsu.edu.|Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, 27695, USA. Matthew_Breen@ncsu.edu.|Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. Matthew_Breen@ncsu.edu.
authors.forename: Matthew
authors.initials: M
authors.lastname: Breen
mesh_terms: D000818:Animals; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics*; D004285:Dogs; D016678:Genome / Q000235:genetics*; D034701:Mastocytosis, Cutaneous / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D011237:Predictive Value of Tests; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D012680:Sensitivity and Specificity
chemical_list: D019009:Proto-Oncogene Proteins c-kit
keywords: Cancer; Comparative genomic hybridization; Digital PCR; Dog; Mastocytosis; Pug