Finding Genes in Animal Models of Histiocytic Sarcoma. E. A. Ostrander1, J. L. Rowell1, G. R. Rutteman2, H. G. Parker1 1) Cancer Genetics Branch, Bldg 50, NHGRI/NIH, Bethesda, MD; 2) Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, The Netherlands.

   Histiocytic sarcoma (HS) is a rare but extremely aggressive cancer arising from antigen-processing phagocytes (histiocytes). Though the disease can appear at any age, ~15% of the diagnoses published in the last ten years were in children. HS does not respond well to treatment and nearly 50% of those diagnosed die of the disease. This number approaches 100% for those presenting with disseminated disease. Because the human disease is poorly defined, and may furthermore represent multiple related disorders, a reliable model system would inform the human condition and aid in the development of treatment and diagnostics. Dogs offer such an opportunity. Much like the human disease, canine HS is a highly aggressive and lethal dendritic cell neoplasm with survival times of 2-15 months. Commonly, HS is divided into two subtypes: localized and disseminated. Recent work has questioned whether the two subtypes of HS represent the same disease, are two different diseases, or operate on a continuum (disseminated being a metastatic version of localized). While HS is relatively uncommon among dog breeds, it is present at high frequency within Flat-Coated Retrievers (FCR). Here, we performed a genomewide association analysis on 204 FCR samples. Strikingly, we have discovered one locus associated with disseminated HS and a second novel locus for localized HS in FCR. For disseminated HS, the most prominent signal was located on canine chromosome 7 within a 200kb region highly conserved between human and dog, but with low conservation with mouse and chicken. We also identified a signal for localized HS on canine chromosome 5, interestingly demonstrating two peeks; one that overlaps TP53 and the second that represents a gene regulator of TP53. This work presents the first identification of two novel loci for localized and disseminated HS in FCR and will hopefully lead to clear therapeutic targets in humans and companion animals.

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