Comparative molecular life history of spontaneous canine and human gliomas

Abstract

48Sporadic gliomas in companion dogs provide a window on the interaction between 49 tumorigenic mechanisms and host environment. We compared the molecular profiles of 50 canine gliomas with those of human pediatric and adult gliomas to characterize 51 evolutionarily conserved mammalian mutational processes in gliomagenesis. Employing 52 whole genome-, exome-, transcriptome-and methylation-sequencing of 81 canine 53 gliomas, we found alterations shared between canine and human gliomas such as the 54 receptor tyrosine kinases, p53 and cell cycle pathways, and IDH1 R132. Canine 55 gliomas showed high similarity with human pediatric gliomas per robust aneuploidy, 56 mutational rates, relative timing of mutations, and DNA methylation patterns. Our cross-57 species comparative genomic analysis provides unique insights into glioma etiology and 58 the chronology of glioma-causing somatic alterations. 59 60 Significance 61 Diffuse gliomas are the most common malignant brain tumors, with high-grade tumors 62 carrying a dismal prognosis. Preclinical models have proven themselves as poor 63 predictors of clinical efficacy. Spontaneous glioma in dogs provides an attractive 64 alternative model, because of their comparable tumor microenvironment and tumor life 65history. We determined the similarities and differences between human and canine 66 gliomas through genomic profiling, and leveraged our datasets to identify conserved 67 somatic drivers, mutational processes and temporal ordering of somatic glioma events 68 across species. We show that canine gliomas resemble human gliomas at (epi-)genetic 69 levels and are more reminiscent of pediatric than adult disease, thus rationalizing 70 sporadic canine glioma as a preclinical model tailored to measuring treatment efficacies 71 in patients with canine or human glioma. 72 73

Using the canine microbiome to bridge translation of cancer immunotherapy from pre-clinical murine models to human clinical trials

“…Canine mammary tumors and lymphomas share major gene alterations with their human counterparts in addition to having similar tumor mutation burdens (91). Gliomas have been shown to share specific alterations in receptor tyrosine kinases such as TP53 and cell cycle pathways with human pediatric gliomas (89). Overall, the incidence of these canine cancers is believed to be as high or higher than their human counterparts, although precise case numbers are not known since no national database exists for dogs.…”