Genomic profiling reveals extensive heterogeneity in somatic DNA copy number aberrations of canine hemangiosarcoma

Rachael Thomas, Luke Borst, Daniel Rotroff, Alison Motsinger-Reif, Kerstin Lindblad-Toh, Jaime F. Modiano, Matthew Breen

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)305-319
Number of pages15
JournalChromosome Research
Volume22
Issue number3
DOIs
StatePublished - Jan 1 2014

Fingerprint

Hemangiosarcoma
Canidae
DNA
Genomic Instability
Vascular Neoplasms
Dogs
Chromosomes, Human, Pair 16
Chromosomes, Human, Pair 13
Neoplasms
Gene Dosage
Penetrance
Neoplasm Genes
Oncogenes
Sarcoma
Chromosomes
Genome
Incidence
Therapeutics

Keywords

  • canine
  • chromosome
  • comparative genomic hybridization (CGH)
  • hemangiosarcoma

Cite this

Genomic profiling reveals extensive heterogeneity in somatic DNA copy number aberrations of canine hemangiosarcoma. / Thomas, Rachael; Borst, Luke; Rotroff, Daniel; Motsinger-Reif, Alison; Lindblad-Toh, Kerstin; Modiano, Jaime F.; Breen, Matthew.

In: Chromosome Research, Vol. 22, No. 3, 01.01.2014, p. 305-319.

Research output: Contribution to journalArticle

Thomas, Rachael ; Borst, Luke ; Rotroff, Daniel ; Motsinger-Reif, Alison ; Lindblad-Toh, Kerstin ; Modiano, Jaime F. ; Breen, Matthew. / Genomic profiling reveals extensive heterogeneity in somatic DNA copy number aberrations of canine hemangiosarcoma. In: Chromosome Research. 2014 ; Vol. 22, No. 3. pp. 305-319.
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