Common Molecular Alterations in Canine Oligodendroglioma and Human Malignant Gliomas and Potential Novel Therapeutic Targets

Abstract

Spontaneous canine ( Canis lupus ) oligodendroglioma (ODG) holds tremendous potential as an immunocompetent large animal model of human malignant gliomas (MG). However, the feasibility of utilizing this model in pre-clinical studies depends on a thorough understanding of the similarities and differences of the molecular pathways associated with gliomas between the two species. We have previously shown that canine ODG has an immune landscape and expression pattern of commonly described oncogenes similar to that of human MG. In the current study, we performed a comprehensive analysis of canine ODG RNAseq data from 4 dogs with ODG and 2 normal controls to identify highly dysregulated genes in canine tumors. We then evaluated the expression of these genes in human MG using Xena Browser, a publicly available database. STRING-database inquiry was used in order to determine the suggested protein associations of these differentially expressed genes as well as the dysregulated pathways commonly enriched by the protein products of these genes in both canine ODG and human MG. Our results revealed that 3,712 (23%) of the 15,895 differentially expressed genes demonstrated significant up- or downregulation (log2-fold change > 2.0). Of the 3,712 altered genes, ~50% were upregulated ( n = 1858) and ~50% were downregulated ( n = 1854). Most of these genes were also found to have altered expression in human MG. Protein association and pathway analysis revealed common pathways enriched by members of the up- and downregulated gene categories in both species. In summary, we demonstrate that a similar pattern of gene dysregulation characterizes both human MG and canine ODG and provide additional support for the use of the canine model in order to therapeutically target these common genes. The results of such therapeutic targeting in the canine model can serve to more accurately predict the efficacy of anti-glioma therapies in human patients.

Integrative Analysis of Dna Methylation and Gene Expression Profiles to Explore Potential Biomarkers of Glioblastoma

“…Other genes like C1QB and C1QC which are involved in complement cascade, KIAA0101 (or PCALF) in cell proliferation, and PARP9 performing in DNA damage repair have been known in literature to be up-regulated in GBM and promote tumorigenesis in consistent with our results (34)(35)(36)(37) while no witness was found for NUP37 as an encoding gene for Nucleoporin 37; a member of nuclear pore complex (NPC) which also was shown to be upregulated in the signature. On the other side, CLDN10 encoding claudin 10 in Tight junction interactions and RAB11FIP4 located on chromosome 17q11.2 and encodes for Rab11 family-interacting protein 4 which plays role in the regulation of endocytic tra c, both were shown to be down-regulated in the signature in consistent with the past ndings (38)(39)(40), although a controversial result also has been reported for the latter (41).…”

Safety and interim survival data after intracranial administration of M032, a genetically engineered oncolytic HSV-1 expressing IL-12, in pet dogs with sporadic gliomas

“…27 It has been shown that canine oligodendrogliomas are more genetically similar to human glioblastomas than human oligodendrogliomas, particularly in terms of upregulated genes. 28 Favorable IDH1 mutations and 1p/19q codeletions are rare in canine tumors. 28 Due to differences in arrangement of the dog and human genome, it may be that canine oligodendrogliomas possess sufficient genetic information to behave as aggressively as WHO grade IV glioblastomas in humans, as evidenced by similar patterns of resistance to antitumoral agents and systemic immune interference.…”

“…28 Favorable IDH1 mutations and 1p/19q codeletions are rare in canine tumors. 28 Due to differences in arrangement of the dog and human genome, it may be that canine oligodendrogliomas possess sufficient genetic information to behave as aggressively as WHO grade IV glioblastomas in humans, as evidenced by similar patterns of resistance to antitumoral agents and systemic immune interference. 29 Overall, survival in our cohort has been favorable and is clearly superior to that in published data on outcomes in palliated dogs with gliomas.…”

Immunohistochemical evaluation of immune cell infiltration in canine gliomas

“…Gliomas are a group of devastating brain tumors that affect both dogs and humans. 1,3,11,50,64,69,72 They represent approximately 35% of primary intracranial tumors in the dog and are overrepresented in brachycephalic breeds such as the boxer, Boston terrier, and English and French bulldog. 49,64,73 Glioma subtypes in humans include oligodendroglioma, astrocytoma, and glioblastoma, and in dogs are oligodendroglioma, astrocytoma, and undefined glioma.…”