Angiosarcoma is a highly aggressive cancer of blood vessel-forming cells with few effective treatment options and high patient mortality. It is both rare and heterogenous, making large, well-powered genomic studies nearly impossible. Dogs commonly suffer from a similar cancer, called hemangiosarcoma, with breeds like the golden retriever carrying heritable genetic factors that put them at high risk. If the clinical similarity of canine hemangiosarcoma and human angiosarcoma reflects shared genomic etiology, dogs could be a critically needed model for advancing angiosarcoma research. We assessed the genomic landscape of canine hemangiosarcoma via whole-exome sequencing (47 golden retriever hemangiosarcomas) and RNA sequencing (74 hemangiosarcomas from multiple breeds). Somatic coding mutations occurred most frequently in the tumor suppressor TP53 (59.6% of cases) as well as two genes in the PI3K pathway: The oncogene PIK3CA (29.8%) and its regulatory subunit PIK3R1 (8.5%). The predominant mutational signature was the age-associated deamination of cytosine to thymine. As reported in human angiosarcoma, CDKN2A/B was recurrently deleted and VEGFA, KDR, and KIT recurrently gained. We compared the canine data to human data recently released by The Angiosarcoma Project, and found many of the same genes and pathways significantly enriched for somatic mutations, particularly in breast and visceral angiosarcomas. Canine hemangiosarcoma closely models the genomic landscape of human angiosarcoma of the breast and viscera, and is a powerful tool for investigating the pathogenesis of this devastating disease.
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The authors would like to thank all of the dogs and owners who participated in our research, as well as the veterinarians who collected samples. The results included here include the use of data from The Angiosarcoma Project (https:// ascproject.org/), a project of Count Me In (https://joincountmein.org/), downloaded March 2019. We would also like to thank Dr. Scott Moroff, Vice-President and Chief Scientific Officer of Antech Diagnostics, for contributing tumor and paired blood samples to our research. This work was funded by American Kennel Club (AKC) Canine Health Foundation (CHF) grants #422 (to J.F. Modiano), 1131 (to J.F. Modiano), and 1889-G (to J.F. Modiano, M. Breen, K. Lindblad-Toh, E.K. Karlsson), NIH grants R03CA191713 (to J.F. Modiano), P30CA077598 (NIH Comprehensive Cancer Center Support Grant to the Masonic Cancer Center, University of Minnesota), R37CA218570 (to E.K. Karlsson, C. Painter), and R24OD018250 (to E.K. Karlsson), Cancerfonden (K. Lindblad-Toh), National Canine Cancer Foundation (NCCF) grants DM06CO-003 (to J.F. Modiano) and JHK15MN-004 (to J.-H. Kim), and Morris Animal Foundation grant D10CA-501 (to J.F. Modiano, M. Breen, K. Lindblad-Toh). K. Lindblad-Toh is the recipient of a Distinguished Professor award from the Swedish Research Council. I. Elvers is supported by a postdoctoral fellowship from the Swedish Medical Research Council, SSMF. J.F. Modiano is supported by the Alvin and June Perlman Chair in Animal Oncology at the University of Minnesota. M. Breen is supported in part by the Oscar J. Fletcher Distinguished Professorship in Comparative Oncology Genetics at NC State University. A.L. Sarver is supported by NCI R50 CA211249.