The Same, but Different: Shared Hallmarks and Divergent Drivers in Adult, Pediatric and Canine Glioma

Malignant gliomas are the most common primary brain tumors, with dismal outcomes. Pet dogs have been proposed as a valuable model for studying gliomas. Here, we compare spontaneously occurring gliomas from adult and pediatric human and canine patients, focusing on the tumor microenvironment (TME) and the canonical pathways of human glioma dysregulation (RTK/RAS/PI(3)K, p53 and Rb). Transcriptomic, genomic, and methylation data from adult, pediatric, and canine samples were evaluated. Across cohorts, aberrant signaling in the three canonical pathways correlated with increasing tumor grade. Canine high-grade glioma (HGG) showed extensive pathway dysregulation, especially when incorporating differentially expressed genes such as TP53. PDGFRA was a key driver of glioma in purebred brachycephalic ("short-skulled") dogs. IDH1 mutations and hypermethylation were concentrated in adult tumors. Both species exhibited increased neutrophils, M2 macrophages, and regulatory T cells, coupled with depletion of key antitumor effectors. PD-1 and PD-L1 immune checkpoint biology was similarly preserved. Canine glioma seems to occupy a "middle ground" between pediatric and adult. Methylation patterns mirrored pediatric glioma, yet immune infiltration and pathway activation resembled adult HGG. Complex heterogeneity between patients was a major similarity between species. Despite different driver mutations, dogs and humans converge on a similar malignant, immune-suppressed TME.