|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Karlsson, EK, Sigurdsson, S, Ivansson, E, Thomas, R, Elvers, I, Wright, J, Howald, C, Tonomura, N, Perloski, M, Swofford, R, Biagi, T, Fryc, S, Anderson, N, Courtay-Cahen, C, Youell, L, Ricketts, SL, Mandlebaum, S, Rivera, P, von Euler, H, Kisseberth, WC, London, CA, Lander, ES, Couto, G, Comstock, K, Starkey, MP, Modiano, JF, Breen, M, Lindblad-Toh, K|
|Date Published||2013 Dec 12|
|Keywords||Animals, Bone Neoplasms, Cyclin-Dependent Kinase Inhibitor p15, Cyclin-Dependent Kinase Inhibitor p16, DNA Copy Number Variations, Dog Diseases, Dogs, Evolution, Molecular, Genetic Predisposition to Disease, Genetic Variation, Genome, Genome-Wide Association Study, Humans, MicroRNAs, Osteosarcoma|
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.
|Alternate Journal||Genome Biol.|
|PubMed Central ID||PMC4053774|
|Grant List||P30 CA016058 / CA / NCI NIH HHS / United States |
UL1 TR000090 / TR / NCATS NIH HHS / United States