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Article

Genome-Wide Analyses for Osteosarcoma in Leonberger Dogs Reveal the CDKN2A/B Gene Locus as a Major Risk Locus

1
Institute of Genetics, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
2
Institut de Génétique et Développement de Rennes (IGDR)—UMR6290, University Rennes, CNRS, 35000 Rennes, France
3
Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55108, USA
4
Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA
5
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, 75105 Uppsala, Sweden
6
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
7
Animal Health Trust, Newmarket CB8 7UU, UK
8
Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN 55113, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to the work.
Kerstin Lindblad-Toh, James R. Mickelson and Cord Drögemüller shared last author.
Academic Editor: Benjamin N. Sacks
Genes 2021, 12(12), 1964; https://doi.org/10.3390/genes12121964
Received: 7 November 2021 / Revised: 8 December 2021 / Accepted: 8 December 2021 / Published: 9 December 2021
(This article belongs to the Special Issue Canine Genetics 2)
Dogs represent a unique spontaneous cancer model. Osteosarcoma (OSA) is the most common primary bone tumor in dogs (OMIA 001441-9615), and strongly resembles human forms of OSA. Several large- to giant-sized dog breeds, including the Leonberger, have a greatly increased risk of developing OSA. We performed genome-wide association analysis with high-density imputed SNP genotype data from 273 Leonberger cases with a median age of 8.1 [3.1–13.5] years and 365 controls older than eight years. This analysis revealed significant associations at the CDKN2A/B gene locus on canine chromosome 11, mirroring previous findings in other dog breeds, such as the greyhound, that also show an elevated risk for OSA. Heritability (h2SNP) was determined to be 20.6% (SE = 0.08; p-value = 5.7 × 10−4) based on a breed prevalence of 20%. The 2563 SNPs across the genome accounted for nearly all the h2SNP of OSA, with 2183 SNPs of small effect, 316 SNPs of moderate effect, and 64 SNPs of large effect. As with many other cancers it is likely that regulatory, non-coding variants underlie the increased risk for cancer development. Our findings confirm a complex genetic basis of OSA, moderate heritability, and the crucial role of the CDKN2A/B locus leading to strong cancer predisposition in dogs. It will ultimately be interesting to study and compare the known genetic loci associated with canine OSA in human OSA. View Full-Text
Keywords: osteosarcoma; bone cancer; canis familiaris; Leonberger; animal model; CDKN2A/B osteosarcoma; bone cancer; canis familiaris; Leonberger; animal model; CDKN2A/B
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MDPI and ACS Style

Letko, A.; Minor, K.M.; Norton, E.M.; Marinescu, V.D.; Drögemüller, M.; Ivansson, E.; Megquier, K.; Noh, H.J.; Starkey, M.; Friedenberg, S.G.; Lindblad-Toh, K.; Mickelson, J.R.; Drögemüller, C. Genome-Wide Analyses for Osteosarcoma in Leonberger Dogs Reveal the CDKN2A/B Gene Locus as a Major Risk Locus. Genes 2021, 12, 1964. https://doi.org/10.3390/genes12121964

AMA Style

Letko A, Minor KM, Norton EM, Marinescu VD, Drögemüller M, Ivansson E, Megquier K, Noh HJ, Starkey M, Friedenberg SG, Lindblad-Toh K, Mickelson JR, Drögemüller C. Genome-Wide Analyses for Osteosarcoma in Leonberger Dogs Reveal the CDKN2A/B Gene Locus as a Major Risk Locus. Genes. 2021; 12(12):1964. https://doi.org/10.3390/genes12121964

Chicago/Turabian Style

Letko, Anna, Katie M. Minor, Elaine M. Norton, Voichita D. Marinescu, Michaela Drögemüller, Emma Ivansson, Kate Megquier, Hyun J. Noh, Mike Starkey, Steven G. Friedenberg, Kerstin Lindblad-Toh, James R. Mickelson, and Cord Drögemüller. 2021. "Genome-Wide Analyses for Osteosarcoma in Leonberger Dogs Reveal the CDKN2A/B Gene Locus as a Major Risk Locus" Genes 12, no. 12: 1964. https://doi.org/10.3390/genes12121964

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