Genome-wide association study identifies three candidate genes linked to glioma development.
A new study of the genetic factors underlying glioma formation in dogs may hold clues to how these common and often untreatable tumors form in humans. The genome study, which was conducted across 25 dog breeds, identified three genes associated with the tumor. The results from this research, led by Katarina Truvé of the Swedish University of Agricultural Sciences and Kerstin Lindblad-Toh of Uppsala University, were published on May 12 in PLOS Genetics.
Gliomas are the most common form of malignant primary brain tumors in humans and the second most common in dogs. Several dog breeds such as Boxer, Bulldog and Boston Terrier have an elevated risk of developing glioma, while certain related breeds do not, suggesting that a mix of genes may impact glioma formation. Dr Truvé says: “Researchers in the consortium are now continuing the analysis of the genes identified, and their functional roles in development and progression of glioma in both dogs and humans.”
To identify genetic variations that contribute to the tumor’s development, scientists performed a genome-wide association study (GWAS) using blood samples from 39 dogs diagnosed with glioma and 141 control dogs. By screening for variations commonly found in dogs that developed gliomas, they pinpointed three genes highly associated with susceptibility to the tumor: CAMKK2, P2RX7 and DENR.
Two of these genes have additional links to cancer. Further experiments by the scientists showed that both human and canine gliomas express CAMKK2 at lower levels than normal brain tissue, and previous studies have shown that a variation of P2RX7 reduces protein function in dogs while other variations have been identified in cancer patients. Future investigation of all three genes may yield a better understanding of the causes and potential treatments of glioma in both dogs and humans.
Funding: This study was partially funded by the Swedish Kennel Club, Agria Insurance Company, the Swedish Research Council, Swedish Cancer Society, the Swedish Childhood Cancer Foundation, the EMBRACE project funded by the European Commission within its FP6 Programme, under the thematic area “Life sciences, genomics and biotechnology for health”, contract number LHSG-CT-2004-512092, The University of California Cancer Research Coordinating Committee, The Center for Companion Animal Health, UC Davis School of Veterinary Medicine and by the Paul C. and Borghild T. Petersen Foundation. KLT is the recipient of a European Young Investigator Award (EURYI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Source: Amy Yau – PLOS
Image Source: The image is credited to Katarina Sundberg.
Original Research: Full open access research for “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” by Katarina Truvé, Peter Dickinson, Anqi Xiong, Daniel York, Kartika Jayashankar, Gerli Pielberg, Michele Koltookian, Eva Murén, Hans-Henrik Fuxelius, Holger Weishaupt, Fredrik J. Swartling, Göran Andersson, Åke Hedhammar, Erik Bongcam-Rudloff, Karin Forsberg-Nilsson, Danika Bannasch, and Kerstin Lindblad-Toh in PLOS Genetics. Published online May 12 2016 doi:10.1371/journal.pgen.1006000
Abstract
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
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. Dogs are valuable spontaneous models of human complex diseases including cancers and may provide insight into disease susceptibility and oncogenesis. 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. To identify glioma-associated genetic susceptibility factors, an across-breed genome-wide association study (GWAS) was performed on 39 dog glioma cases and 141 controls from 25 dog breeds, identifying a genome-wide significant locus on canine chromosome (CFA) 26 (p = 2.8 x 10−8). Targeted re-sequencing of the 3.4 Mb candidate region was performed, followed by genotyping of the 56 SNVs that best fit the association pattern between the re-sequenced cases and controls. We identified three candidate genes that were highly associated with glioma susceptibility: 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.
“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” by Katarina Truvé, Peter Dickinson, Anqi Xiong, Daniel York, Kartika Jayashankar, Gerli Pielberg, Michele Koltookian, Eva Murén, Hans-Henrik Fuxelius, Holger Weishaupt, Fredrik J. Swartling, Göran Andersson, Åke Hedhammar, Erik Bongcam-Rudloff, Karin Forsberg-Nilsson, Danika Bannasch, and Kerstin Lindblad-Toh in PLOS Genetics. Published online May 12 2016 doi:10.1371/journal.pgen.1006000
