Comparative molecular life history of spontaneous canine and human gliomas

Abstract

Sporadic gliomas in companion dogs provide a window on the interaction between tumorigenic mechanisms and host environment. We compared the molecular profiles of canine gliomas with those of human pediatric and adult gliomas to characterize evolutionarily conserved mammalian mutational processes in gliomagenesis. Employing whole genome-, exome-, transcriptome-and methylation-sequencing of 81 canine gliomas, we found alterations shared between canine and human gliomas such as the receptor tyrosine kinases, p53 and cell cycle pathways, and IDH1 R132. Canine gliomas showed high similarity with human pediatric gliomas per robust aneuploidy, mutational rates, relative timing of mutations, and DNA methylation patterns. Our cross-species comparative genomic analysis provides unique insights into glioma etiology and the chronology of glioma-causing somatic alterations.\n\nSignificanceDiffuse gliomas are the most common malignant brain tumors, with high-grade tumors carrying a dismal prognosis. Preclinical models have proven themselves as poor predictors of clinical efficacy. Spontaneous glioma in dogs provides an attractive alternative model, because of their comparable tumor microenvironment and tumor life history. We determined the similarities and differences between human and canine gliomas through genomic profiling, and leveraged our datasets to identify conserved somatic drivers, mutational processes and temporal ordering of somatic glioma events across species. We show that canine gliomas resemble human gliomas at (epi-)genetic levels and are more reminiscent of pediatric than adult disease, thus rationalizing sporadic canine glioma as a preclinical model tailored to measuring treatment efficacies in patients with canine or human glioma.