Comparative oncology analysis using genomic profiling of canine cancers by tissue and liquid biopsy testing reveals actionable somatic alterations with orthologs in human cancers.
Authors: Tsui Dana , Chorny Ilya , Kruglyak Kristina M , Tynan John A. , Hernandez Gilberto E , Nakashe Prachi , Hicks Susan Cho , Motalli-Pepio Rita , McLennan Lisa M. , Holtvoigt Lauren E. , Rafalko Jill M. , Chibuk Jason , McCleary-Wheeler Angela L. , Flory Andi , Grosu Daniel S. 
Published: June 2022

e15012 Background: Targeted therapies offer great potential for cancer treatment in humans; however, enrollment in clinical trials may be slow, particularly for rare cancer types. The high homology between human and canine cancer genomes provides an opportunity for comparative oncology analyses that can inform the development of therapeutics for the benefit of both species. Currently, there is no well-established canine cancer genomic database. This study presents preliminary findings from an ongoing initiative aimed at building a foundational database of canine cancer genomic variants and their human orthologs via tissue and liquid biopsy profiling of multiple cancer types. Methods: Matched blood and tissue samples were collected from an all-comers cohort of over 150 cancer-diagnosed, client-owned dogs undergoing surgical resection or tissue sampling by biopsy. Cancer types included those found in both humans and dogs, such as lymphoma, osteosarcoma, mammary gland tumors and melanoma. Blood samples were processed to obtain plasma and white blood cells, and all samples were subjected to DNA extraction, library preparation, and next-generation sequencing. Somatic variants detected by liquid biopsy and tissue testing were mapped to human orthologs targeted by therapeutic agents approved by the FDA or listed in NCCN guidelines, and to orthologs with therapeutic or prognostic levels of evidence annotated in human oncology databases. Results: Somatic alterations were identified in over half of the tissue and/or liquid biopsy samples tested. Results from tissue and liquid biopsy showed high concordance, and liquid biopsy revealed additional alterations that may have been missed in single-site tissue biopsies due to tumor heterogeneity. Of the mutations identified in plasma and/or tissue but absent in matched white blood cells, 10% mapped to a human ortholog listed as a biomarker targeted by either an approved therapeutic agent or a therapeutic currently undergoing clinical trials; examples include NRAS, HRAS and AKT1 mutations. Over 10% of canine cancer patients also harbored orthologs of somatic TP53 mutations reported to be prognostic in multiple human cancers. In particular, TP53 mutations were found in > 20% of canine osteosarcoma patients, which aligns with prior findings in human osteosarcoma and highlights the potential of comparative oncology for cancer types that are rare in humans but common in dogs. Conclusions: The results confirm the homology between canine and human cancers and emphasize the potential to translate genomic knowledge for biomarker discovery and therapeutic development between species. The high concordance between tumor and liquid biopsy findings support the prospect of using a noninvasive blood test to expand the genomic characterization effort to much larger cohorts of cancer-diagnosed dogs.