Journal
GENOME BIOLOGY
Volume 14, Issue 12, Pages -Publisher
BMC
DOI: 10.1186/gb-2013-14-12-r132
Keywords
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Funding
- AKC/CFH [2254, 947, 373A, 757, 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
- Uppsala University
- Swedish Medical Research Council
- Research Council FORMAS
- European Commission [FP7-LUPA, GA-201370]
- Morris Animal Foundation
- Barncancerfonden
- Swedish Society for Medical Research
- American Cancer Society
- Swedish Research Council
- Swiss National Research Foundation
- EURYI
- NATIONAL CANCER INSTITUTE [P30CA016058] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR000090] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [U54HG003067] Funding Source: NIH RePORTER
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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.
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