Histiocytic sarcoma is a rare, aggressive hematopoietic malignancy of mature tissue histiocytes with a poorly understood etiology in humans. A histologically and clinically similar counterpart in dogs affects two breeds at unusually high frequency, with 20-25% of Flatcoated Retrievers and Bernese Mountain Dogs developing histiocytic sarcoma, while the disease is extremely rare in other breeds. In this study, we leveraged the canine model system to investigate genetic risk factors for histiocytic sarcoma in the Flatcoated Retriever. Population bottlenecks and artificial selection during breed formation within last 200 years have created the unique breed structure in dogs, characterized by long linkage disequilibrium and low within-breed genetic diversity. This allows for the identification of disease-associated traits with relatively few markers and individuals. We conducted multiple genome-wide association studies in Flatcoated Retrievers in which we identified two loci conferring risk for histiocytic sarcoma (177 cases and 132 controls, total). The first locus, on canine chromosome (CFA) 5, also colocalizes with previously identified risk for hemangiosarcoma and B-cell lymphoma, two hematopoietic malignancies in the closely related golden retriever breed. The second locus is unique to the Flatcoated Retriever and increases risk for histiocytic sarcoma in combination with CFA5. There have been multiple reports of human histiocytic sarcoma diagnosis concurrent with other hematological cancers, including lymphoma, suggested to be the result of transdifferentiation or a common neoplastic progenitor. Here we link germline predisposition for histiocytic sarcoma and B-cell lymphoma to the same locus in retrievers. Subsequent whole genome, transcriptome, and ChIP sequencing, highlighted candidate genes at each locus with roles in cell migration, as well as candidate regulatory variants with predicted impact on transcription factor binding. This comprehensive, multi-omics approach has been previously largely unexplored in the canine model. Here we advance our knowledge of the biology of histiocytic sarcoma, which will have direct impact on canine health and elucidate the genetic mechanisms underlying a rare human cancer.

Citation Format: Jacquelyn M. Evans, Heidi G. Parker, Jocelyn Plassais, Gerard R. Rutteman, Elaine A. Ostrander. Genetic risk factors for histiocytic sarcoma in a canine disease model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 829.