Mining the Dog Genome for Novel Glioma Drug Targets

Gliomas are the most common malignant brain tumors in humans, constituting about 30% of all brain and central nervous system tumors and 80% of all malignant brain tumors. Gliomas are very severe human brain tumors that are rarely curable. Interestingly, these tumors are strikingly similar in dogs and humans. Moreover, gliomas occur in a variety of brachycephalic (broad, short skull) dog breeds, such as Boxers and Bulldogs—which have a considerably elevated risk for this type of cancer.

Now, researchers from Uppsala University and Swedish University of Agricultural Sciences have employed genome-wide association studies (GWAS) for different dog breeds, in order to identify genes that could have a role in the development of brain tumors—in both dogs and human.

“In our study we hypothesized that since the brachycephalic dog breeds with elevated risk are closely related we would be able to identify a genomic region shared by those breeds,” explained lead study author Katarina Truvé, Ph.D., who performed the work while she was a doctoral student at the Swedish University of Agricultural Sciences. “The same risk factors for glioma could also be present in other breeds and the way to identify the genomic region would be to compare genetic markers from dogs diagnosed with glioma from several breeds to healthy controls. Based on this we then performed several genetic analyses to narrow down the region in the genome.”

The GWAS was performed using 25 different dog breeds, allowing the researchers to identify an area in the genome that differed between diseased and healthy dogs. This region also showed signs of selection in the brachycephalic dog breeds at high risk of developing glioma—suggesting that genes essential for glioma development could be located in the same locus as genes that have been promoted in the breeding for specific traits for these brachycephalic breeds. In this genomic region, researchers also identified three particular genes as the most associated with the development of glioma in dogs— CAMKK2, P2RX7, and DENR.

“CAMKK2 showed reduced expression in both canine and human brain tumors, and a non-synonymous variant in P2RX7—previously demonstrated to have a 50% decrease in receptor function—was also associated with disease. Thus, one or more of these genes appear to affect glioma susceptibility,” the authors wrote.

The findings from this study were published recently in PLOS Genetics through an article entitled “Utilizing the Dog Genome in the Search for Novel Candidate Genes Involved in Glioma Development—Genome Wide Association Mapping followed by Targeted Massive Parallel Sequencing Identifies a Strongly Associated Locus.”

“We compared for instance how active the genes were in tumor tissues and normal brain tissue,” noted co-author Karin Forsberg Nilsson, professor in the department of immunology, genetics and pathology at Uppsala University. “We found that especially one of the genes showed reduced activity in tumor tissue. These results indicate that further investigations of the role of these three genes in glioma development would be of interest, with potential benefit to both dog and human.”