title: Genomic profiling reveals extensive heterogeneity in somatic DNA copy number aberrations of canine hemangiosarcoma.
abstract: Canine hemangiosarcoma is a highly aggressive vascular neoplasm associated with extensive clinical and anatomical heterogeneity and a grave prognosis. Comprehensive molecular characterization of hemangiosarcoma may identify novel therapeutic targets and advanced clinical management strategies, but there are no published reports of tumor-associated genome instability and disrupted gene dosage in this cancer. We performed genome-wide microarray-based somatic DNA copy number profiling of 75 primary intra-abdominal hemangiosarcomas from five popular dog breeds that are highly predisposed to this disease. The cohort exhibited limited global genomic instability, compared to other canine sarcomas studied to date, and DNA copy number aberrations (CNAs) were predominantly of low amplitude. Recurrent imbalances of several key cancer-associated genes were evident; however, the global penetrance of any single CNA was low and no distinct hallmark aberrations were evident. Copy number gains of dog chromosomes 13, 24, and 31, and loss of chromosome 16, were the most recurrent CNAs involving large chromosome regions, but their relative distribution within and between cases suggests they most likely represent passenger aberrations. CNAs involving CDKN2A, VEGFA, and the SKI oncogene were identified as potential driver aberrations of hemangiosarcoma development, highlighting potential targets for therapeutic modulation. CNA profiles were broadly conserved between the five breeds, although subregional variation was evident, including a near twofold lower incidence of VEGFA gain in Golden Retrievers versus other breeds (22 versus 40 %). These observations support prior transcriptional studies suggesting that the clinical heterogeneity of this cancer may reflect the existence of multiple, molecularly distinct subtypes of canine hemangiosarcoma.
authors.affiliation: Department of Molecular Biomedical Sciences, North Carolina State University College of Veterinary Medicine, 1060 William Moore Drive, Raleigh, NC, 27607, USA.
authors.forename: Rachael
authors.initials: R
authors.lastname: Thomas
authors.forename: Luke
authors.initials: L
authors.lastname: Borst
authors.forename: Daniel
authors.initials: D
authors.lastname: Rotroff
authors.forename: Alison
authors.initials: A
authors.lastname: Motsinger-Reif
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lindblad-Toh
authors.forename: Jaime F
authors.initials: JF
authors.lastname: Modiano
authors.forename: Matthew
authors.initials: M
authors.lastname: Breen
mesh_terms: D000818:Animals; D001947:Breeding; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics*; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D005784:Gene Amplification; D020869:Gene Expression Profiling; D018740:Genetic Heterogeneity; D016678:Genome; D006394:Hemangiosarcoma / Q000235:genetics* / Q000662:veterinary*; D019683:Penetrance; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D042461:Vascular Endothelial Growth Factor A