Abstract 1176: Genomic profiling of canine glioma: Comparative analyses with respect to drivers of human glioma
Authors: Samirkumar B. Amin, Juan Emmanuel Martinez-Ledesma, Beth Boudreau, Hoon Kim, Kevin C. Johnson, Peter V. Dickinson, Rebecca Packer, Amanda R. Taylor, John H. Rossmeisl, Amy Heimberger, Jonathan Levine, Roel Verhaak
Journal: Cancer Research (2018)

Abstract Sporadic glioma occurs in companion dogs at frequencies comparable to humans, despite differences in environmental exposures and age at time of diagnosis. Despite advances in molecular and phenotypic characterization of adult gliomas, accurate prognostication and curative treatment modalities are often limited by lack of animal translational models that can faithfully recapitulate underlying oncogenic processes and treatment response to newer therapies. Studying canine glioma at molecular level has several merits: First, it has a distinct advantage over genetically modified animal models to study natural course of glioma in dogs. Second, breed-specific elevated cancer risk, e.g., short-nosed breeds have higher risk for gliomas and smaller effective population size compared to humans potentially allow better characterization driver elements in the evolving canine glioma. Finally, dogs with the natural mammalian immune system have spontaneous occurrence of glioma, making it an ideal model for preclinical immunotherapy testing. Based on these merits, we performed whole genome, exome, transcriptome and methylation (reduced bisulfite) sequencing on 178 canine tumor and germline samples. As in humans, we show frequently occurring mutations and copy number alterations in canine gliomas in p53 pathway, cell cycle pathway (CDK4, CDKN2A), and receptor tyrosine kinases (EGFR, PDGFRA). We identified R132 mutations in the IDH1 gene reflecting a remarkable and species-agnostic but cancer-specific driving effect. Frequent whole chromosome gains were observed of syntenic region of chromosome 13, harboring human glioma oncogenes PDGFRA and MYC, but human glioma specific changes such as 1p/19q co-deletion and whole chromosome 10 loss/whole chromosome 7 gain were absent. We calculate mutational processes and highlight ones related to DNA damage repair and transcriptional strand bias in driving glioma in both species. Based on recent study, we also estimate relative timing of mutations in driver genes and copy number gains in canine glioma and compare those to human glioma in mapping life history of glioma, i.e., are canine glioma more similar to adult or pediatric human glioma cohort? In addition, transcriptional profiling delineated tumor-associated cell fractions from 22 immune cell types. The monocyte gene signature scored highest among canine glioma transcriptomes, in contrast to macrophages/microglia in human disease. Our results suggest similarities between the canine and human glioma microenvironment and we are validating those using canine immunohistochemistry. In bringing together a large canine glioma genomic and transcriptomic sequencing dataset and comparing to human glioma, our study provides unique new insights into glioma etiology and the chronology of glioma-causing somatic alterations. Citation Format: Samirkumar B. Amin, Juan Emmanuel Martinez-Ledesma, Beth Boudreau, Hoon Kim, Kevin C. Johnson, Peter V. Dickinson, Rebecca Packer, Amanda R. Taylor, John H. Rossmeisl, Amy Heimberger, Jonathan Levine, Roel Verhaak. Genomic profiling of canine glioma: Comparative analyses with respect to drivers of human glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1176.