Abstract 4312: Identification of shared mutations across many parallel human and canine cancers based on comprehensive survey of canine cancer mutations and the “caninization” of human mutations from COSMIC
Authors: Sakthikumar Sharadha , Facista Salvatore , Whitley Derick , Warrier Manisha , Hendricks William , Wang Guannan 
Published: April 2023

Introduction: Vidium Insight™ is a canine cancer genomic biomarker database built from exhaustive curation of peer-reviewed literature describing genomic mutations in canine cancers. This repository catalogs the ever-increasing abundance of cancer mutations and their diagnostic, prognostic, and therapeutic biomarker associations in canine oncology. However, the design of cancer research/clinical studies in dogs and the interpretation of the data, still rely heavily on inferences from human cancers. To leverage the wealth of well-annotated human mutation data and close the canine cancer genomics knowledge gap, we recently "caninized" ~ 400K cancer mutations from the largest human mutation database, COSMIC. Here, we aim to systematically assess the cross-species conservation status of mutations found in parallel human and canine cancers.

Methods: Human mutations from the COSMIC Cancer Gene Census (CGC) dataset were “caninized”, i.e. structured analysis of protein sequence conservation and conversion of human cancer mutations to their canine homologous sites. Caninized point and indel mutations, as well as copy number alterations, were subsequently intersected with curated primary canine data in Vidium Insight™ to determine if they have been previously reported in canine cancers. Cancer-wise mutation data were also parsed and assessed for any shared mutations in equivalent human and canine cancers.

Results: Over 90% of the coding point and indel mutations in COSMIC CGC were successfully converted to the canine genome, i.e. caninized. We found 436 unique caninized mutations reported in 27 primary canine cancers across 78 studies. Of these, 410 were predicted pathogenic mutations that likely contribute to oncogenesis. Genes affected by copy number alterations in human cancers have published evidence in canine cancers as well. We then assessed concordance in putative cancer driver mutations recorded in both species. Of the 27 primary canine cancers that have mutation data to date, 26 have been shown to share somatic mutations with corresponding human cancers.

Conclusion: It has long been recognized that human and canine cancers share similar etiology, histopathology, clinical manifestations, and treatment responses. We have demonstrated high-level conservation of mutation profiles across many parallel human and canine cancers. Our work suggests that pathogenic mutations found in one species can inform the other's genomic and molecular underpinnings, guide basic/clinical research, drive drug development, facilitate clinical management, and ultimately, empower genomic-guided precision medicine across species.

Citation Format: Sharadha Sakthikumar, Salvatore Facista, Derick Whitley, Manisha Warrier, William Hendricks, Guannan Wang. Identification of shared mutations across many parallel human and canine cancers based on comprehensive survey of canine cancer mutations and the “caninization” of human mutations from COSMIC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4312.