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.
Highlights
Canine osteosarcoma is clinically nearly identical to the human disease, but is common and highly heritable, making genetic dissection feasible
While linkage disequilibrium in all breeds is long, as compared to human populations, it varies markedly by breed, with average r2 dropping below 0.2 at 196 kb in the greyhounds, 632 kb in the Rottweilers, and 1,533 kb in the IWH, suggesting genome-wide association study (GWAS) regions will be shortest in greyhound, facilitating identification of associated functional elements in this breed (Figure 1c)
Using the GISTIC algorithm [57], we identified discrete regions that had statistically high copy number aberrations (CNAs) frequency in canine tumors relative to the globally chaotic genomic background of OS, suggestive of specific gene targets strongly associated with disease pathogenesis
Summary
Canine osteosarcoma is clinically nearly identical to the human disease, but is common and highly heritable, making genetic dissection feasible. The only genome-wide association study (GWAS) of OS in OS in dogs is a spontaneously occurring disease with a global tumor gene expression signature indistinguishable from human pediatric tumors [6,7] and, while relative age of onset is higher in dogs, their clinical progression is remarkably similar [8]. Both human and canine OS most commonly arise at the ends of the long bones of the limbs and metastasize readily, usually to the lungs [9].
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