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Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B

Elinor K Karlsson12*, Snaevar Sigurdsson13, Emma Ivansson13, Rachael Thomas4, Ingegerd Elvers13, Jason Wright1, Cedric Howald1, Noriko Tonomura15, Michele Perloski1, Ross Swofford1, Tara Biagi1, Sarah Fryc1, Nathan Anderson1, Celine Courtay-Cahen6, Lisa Youell6, Sally L Ricketts7, Sarah Mandlebaum8, Patricio Rivera9, Henrik von Euler10, William C Kisseberth11, Cheryl A London12, Eric S Lander1, Guillermo Couto1113, Kenine Comstock8, Mike P Starkey6, Jaime F Modiano1415, Matthew Breen164 and Kerstin Lindblad-Toh13*

Author Affiliations

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

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Genome Biology 2013, 14:R132  doi:10.1186/gb-2013-14-12-r132

Published: 12 December 2013

Abstract

Background

Canine osteosarcoma is clinically nearly identical to the human disease, but is common and highly heritable, making genetic dissection feasible.

Results

Through 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.

Conclusions

Mapping a complex cancer in multiple dog breeds reveals a polygenic spectrum of germline risk factors pointing to specific pathways as drivers of disease.