Comparative genomics reveals shared mutational landscape in canine hemangiosarcoma and human angiosarcoma

Kate Megquier, Jason Turner-Maier, Ross Swofford, Jong Hyuk Kim, Aaron L. Sarver, Chao Wang, Sharadha Sakthikumar, Jeremy Johnson, Michele Koltookian, Mitzi Lewellen, Milcah C. Scott, Ashley J. Schulte, Luke Borst, Noriko Tonomura, Jessica Alfoldi, Corrie Painter, Rachael Thomas, Elinor K. Karlsson, Matthew Breen, Jaime F. ModianoIngegerd Elvers, Kerstin Lindblad-Toh

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2410-2421
Number of pages12
JournalMolecular Cancer Research
Volume17
Issue number12
DOIs
StatePublished - Jan 1 2019

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Megquier, K., Turner-Maier, J., Swofford, R., Kim, J. H., Sarver, A. L., Wang, C., Sakthikumar, S., Johnson, J., Koltookian, M., Lewellen, M., Scott, M. C., Schulte, A. J., Borst, L., Tonomura, N., Alfoldi, J., Painter, C., Thomas, R., Karlsson, E. K., Breen, M., ... Lindblad-Toh, K. (2019). Comparative genomics reveals shared mutational landscape in canine hemangiosarcoma and human angiosarcoma. Molecular Cancer Research, 17(12), 2410-2421. https://doi.org/10.1158/1541-7786.MCR-19-0221