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Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B |
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| Authors: | Elinor K Karlsson Snaevar Sigurdsson Emma Ivansson Rachael Thomas Ingegerd Elvers Jason Wright Cedric Howald Noriko Tonomura Michele Perloski Ross Swofford Tara Biagi Sarah Fryc Nathan Anderson Celine Courtay-Cahen Lisa Youell Sally L Ricketts Sarah Mandlebaum Patricio Rivera Henrik von Euler William C Kisseberth Cheryl A London Eric S Lander Guillermo Couto Kenine Comstock Mike P Starkey Jaime F Modiano Matthew Breen Kerstin Lindblad-Toh |
| Institution: | 1. Broad Institute of MIT and Harvard, Cambridge, MA, USA 2. FAS Center for Systems Biology, Harvard University, Cambridge, MA, USA 3. Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden 4. Department of Molecular Biomedical Sciences, College of Veterinary Medicine & Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, NC, USA 5. Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, MA, USA 6. Oncology Research Group, Animal Health Trust, Newmarket, Suffolk, UK 7. Canine Genetics Research Group, Animal Health Trust, Newmarket, Suffolk, UK 8. Department of Urology, University of Michigan, Ann Arbor, MI, USA 9. Department of Animal Breeding and Genetics, Uppsala University, Uppsala, Sweden 10. Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden 11. Department of Veterinary Clinical Sciences and Veterinary Medical Center, The Ohio State University, Columbus, OH, USA 12. Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA 13. Couto Veterinary Consultants, Hilliard, OH, USA 14. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA 15. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, USA 16. Cancer Genetics Program, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA |
| Abstract: | BackgroundCanine osteosarcoma is clinically nearly identical to the human disease, but is common and highly heritable, making genetic dissection feasible.ResultsThrough genome-wide association analyses in three breeds (greyhounds, Rottweilers, and Irish wolfhounds), we identify 33 inherited risk loci explaining 55% to 85% of phenotype variance in each breed. The greyhound locus exhibiting the strongest association, located 150 kilobases upstream of the genes CDKN2A/B, is also the most rearranged locus in canine osteosarcoma tumors. The top germline candidate variant is found at a >90% frequency in Rottweilers and Irish wolfhounds, and alters an evolutionarily constrained element that we show has strong enhancer activity in human osteosarcoma cells. In all three breeds, osteosarcoma-associated loci and regions of reduced heterozygosity are enriched for genes in pathways connected to bone differentiation and growth. Several pathways, including one of genes regulated by miR124, are also enriched for somatic copy-number changes in tumors.ConclusionsMapping a complex cancer in multiple dog breeds reveals a polygenic spectrum of germline risk factors pointing to specific pathways as drivers of disease. |
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