Differential gene expression analysis in French bulldog high grade oligodendroglioma: breed-associated differences in tumor and tumor microenvironment gene expression.

Abstract

Several canine breeds, including boxers, Boston terriers, and French bulldogs, belong to the same phylogenetic clade and have a higher risk for high-grade oligodendroglioma (HGO) than the general canine population. Despite their shared increased risk for HGO, French bulldogs treated with immunotherapy have experienced worse survival outcomes compared to boxers and Boston terriers. We hypothesized that the French bulldog HGO transcriptome differs from those of boxers and Boston terriers, which might account for the disparity in survival. We performed RNA sequencing on formalin-fixed, paraffin-embedded tissue from French bulldogs, boxers, and Boston terriers to identify differentially expressed genes (DEGs) between French bulldogs and the other evaluated breeds. There were 31 DEGs in HGO samples from French bulldogs compared to boxers and Boston terriers. Gene set enrichment analysis revealed activated enrichment of 15 cell cycle progression, oncogene, and immune pathways, including E2F targets, mTOR signaling, IL2-STAT 5 signaling, and allograft rejection. These data confirm the presence of breed-specific canine HGO transcriptomes that can be used to advance our understanding of canine glioma, its translational capacity for human glioma, and precision-based therapies for individual canine patients. High-grade glioma is a deadly brain cancer that affects pet dogs, especially three related breeds: the French bulldog, boxer, and Boston terrier. Treatment options for pet dogs that develop this devastating brain cancer are limited, and none has yet led to widespread prolonged survival or cure. Thus, a variety of new treatment options are currently being investigated. One of the most promising treatment options is immunotherapy. Immunotherapy recruits the patient’s immune system to fight against the tumor. This treatment has shown promise in other cancers. It has also been investigated in pet dogs with high-grade glioma. However, response to immunotherapy was discovered to be very different between dog breeds. While boxers and Boston terriers respond favorably, French bulldogs responded poorly. We hypothesized that the genetic makeup of French bulldog high-grade glioma tumors differs from those of boxers and Boston terriers and might explain their poor response to immunotherapy. To investigate this hypothesis, we compared gene levels in high-grade glioma brain tumors from French bulldogs relative to those from boxers and Boston terriers. We found 31 genes with different expression levels in French bulldogs compared to in boxers and Boston terriers. These genes play key roles in processes that promote tumor growth and impact immune function. These findings support our hypothesis that French bulldog high-grade glioma is genetically distinct from the tumors of other related breeds. The results of this study increase our understanding of canine brain cancer genetics and might also guide development of more effective therapy.