Journal Article

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

Immuno-Endocrinologie Cellulaire et Moléculaire (IECM) ; Institut National de la Recherche Agronomique (INRA), Cullen, John, Department of Statistics ; North Carolina State University [Raleigh] (NC State) ; University of North Carolina System (UNC)-University of North Carolina System (UNC), Hedan, Benoit, Department of Population Health and Pathobiology ; North Carolina State University [Raleigh] (NC State) ; University of North Carolina System (UNC)-University of North Carolina System (UNC)-College of Veterinary Medicine Raleigh, This study was supported by funds from the American Kennel Club Canine Health Foundation (award numbers 2667 and 760 [MB and JC] and 336b/ 337 [CA]), Motsinger-Reif, Alison, Abadie, Jérome, Institut de Génétique et Développement de Rennes (IGDR) ; Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Bioinformatics Research Center ; North Carolina State University [Raleigh] (NC State) ; University of North Carolina System (UNC)-University of North Caro

2011

Overview

UNLABELLED: ABSTRACT: BACKGROUND: Histiocytic malignancies in both humans and dogs are rare and poorly understood. While canine histiocytic sarcoma (HS) is uncommon in the general domestic dog population, there is a strikingly high incidence in a subset of breeds, suggesting heritable predisposition. Molecular cytogenetic profiling of canine HS in these breeds would serve to reveal recurrent DNA copy number aberrations (CNAs) that are breed and/or tumor associated, as well as defining those shared with human HS. This process would identify evolutionarily conserved cytogenetic changes to highlight regions of particular importance to HS biology. METHODS: Using genome wide array comparative genomic hybridization we assessed CNAs in 104 spontaneously occurring HS from two breeds of dog exhibiting a particularly elevated incidence of this tumor, the Bernese Mountain Dog and Flat-Coated Retriever. Recurrent CNAs were evaluated further by multicolor fluorescence in situ hybridization and loss of heterozygosity analyses. Statistical analyses were performed to identify CNAs associated with tumor location and breed. RESULTS: Almost all recurrent CNAs identified in this study were shared between the two breeds, suggesting that they are associated more with the cancer phenotype than with breed. A subset of recurrent genomic imbalances suggested involvement of known cancer associated genes in HS pathogenesis, including deletions of the tumor suppressor genes CDKN2A/B, RB1 and PTEN. A small number of aberrations were unique to each breed, implying that they may contribute to the major differences in tumor location evident in these two breeds. The most highly recurrent canine CNAs revealed in this study are evolutionarily conserved with those reported in human histiocytic proliferations, suggesting that human and dog HS share a conserved pathogenesis. CONCLUSIONS: The breed associated clinical features and DNA copy number aberrations exhibited by canine HS offer a valuable model for the human counterpart, providing additional evidence towards elucidation of the pathophysiological and genetic mechanisms associated with histiocytic malignancies. Extrapolation of data derived from canine histiocytic disorders to human histiocytic proliferation may help to further our understanding of the propagation and cancerization of histiocytic cells, contributing to development of new and effective therapeutic modalities for both species.

• Publisher: CCSD,BioMed Central,BioMed Central Ltd,BMC
• Subject: Animals / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Chemical properties / Comparative Genomic Hybridization / Cytogenetic Analysis / Cytogenetics / Disease Models, Animal / Diseases / DNA Copy Number Variations - genetics / Dogs / Female / Gene Deletion / Genes, p16 / Genes, Tumor Suppressor / Genetic aspects / Genetic Predisposition to Disease - genetics / Genetics / genomics and epigenetics / Health Promotion and Disease Prevention / Histiocytic Sarcoma - genetics / Histiocytic Sarcoma - physiopathology / Immunology / Life Sciences / Macrophages / Male / Medicine/Public Health / Oncology / Penetrance / Physiological aspects / PTEN Phosphohydrolase - genetics / Research Article / Risk factors / Sarcoma / Surgical Oncology
• ISBN: 0002920347000