Collaborative project: Human glioblastoma

“Glioma” is a general way to refer to a tumor arising from the glial cells in the brain. Glioblastoma multiforme is a grade IV glioma, a very aggressive form of cancer which has the potential to spread rapidly. Gliomas are the most common form of malignant primary brain tumors in humans and second most common in dogs, occurring with similar frequencies in both species. Several brachycephalic breeds such as Boxer, Bulldog and Boston Terrier have an elevated risk of developing glioma, but others, including Pug and Pekingese, are not at higher risk. We have identified three candidate genes that were highly associated with glioma susceptibility in dogs: CAMKK2P2RX7 and DENRCAMKK2 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

Common genetic alterations in human glioblastoma include loss of the chromosome arm 10q, alterations in TP53, RB, amplifications of EGFR and PDGFR, and aberrations in RTK/Ras/PI3K signaling pathways, all of which are major known drivers of glioblastoma pathology. Other frequent mutations include alterations in NF1, PTEN, and MDM2. Glioblastomas are continually evolving, and within a single patient, could display multiple subtypes, gene profiles, transcriptome patterns, and methylation phenotypes, all features that could favor sub-clonal selection. In our latest study, we have performed whole genome sequencing of 38 matched tumor tissue and corresponding blood samples from glioblastoma patients, to identify novel somatic variants in regulatory regions in and around glioblastoma genes.

The project is co-led by Professor Karin Forsberg-Nilsson and Professor Kerstin Lindblad-Toh.

Scientific publications:

Truve, K., Dickinson, P., Xiong, A., York, D., Jayashankar, K., Pielberg, G., Koltookian, M., Murén, E., Fuxelius, H.-H., Weishaupt, H., Swartling, F.J., Andersson, G., Hedhammar, Å., Bongcam-Rudloff, E., Forsberg-Nilsson, K., Bannasch, D., Lindblad-Toh, K., 2016. 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. PLoS Genet 12, e1006000.

Dog breeds predisposed to glioma:

Boxer

Photo by Michael Anfang on Unsplash

Pit bull

Bulldog