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.
|Original language||English (US)|
|State||Published - Dec 12 2013|
Bibliographical noteFunding Information:
We thank pet owners and their dogs and all the breed clubs for their participation, which made this research possible. We thank Anna Blom, Susanne Björnefeldt, Susan Fosmire, Cristan Jubala, Lori Gardner, Mitzi Lewellen, Catherine Gavin, Milcah Scott, and the SciLifeLab/SLU Canine Biobank for help with sample collection. We thank Abhirami Ratnakumar, Erik Axelsson, and Matthew T. Webster for assistance with data analysis, as well as Jill Mesirov, Subbaya Subramanian, Colm O’Dushlaine, Aaron Sarver, the Broad Cancer Program, and the Sabeti group for helpful discussions. We thank the Broad Genomics Platform as well as the SNP & Seq Platform at SciLifeLab for help with sequencing and genotyping. Funding is gratefully acknowledged from AKC/CFH (2254, 947, 373A, 757, and 1317), Irish Wolfhound Foundation (USA), Irish Wolfhound Club (UK), Irish Wolfhound Society (UK), Irish Wolfhound Association of New England, Leonberger Club of America, Leonberger Health Foundation, 2 Million Dogs, Uppsala University, Swedish Medical Research Council, Research Council FORMAS, the European Commission (FP7-LUPA, GA-201370), and the Morris Animal Foundation. EI is supported by fellowships from Barncancerfonden and the Swedish Society for Medical Research, EKK by fellowships from the American Cancer Society and the Charles A. King Trust, IE by the Swedish Research Council, CH by the Swiss National Research Foundation and KLT by a EURYI from the ESF and Consolidator Award from the ERC.