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.
Subject(s)
Bone Neoplasms/veterinary , Cyclin-Dependent Kinase Inhibitor p15/genetics , Cyclin-Dependent Kinase Inhibitor p16/genetics , Dog Diseases/genetics , Genome-Wide Association Study , Osteosarcoma/veterinary , Animals , Bone Neoplasms/genetics , DNA Copy Number Variations , Dogs , Evolution, Molecular , Genetic Predisposition to Disease , Genetic Variation , Genome , Humans , MicroRNAs/genetics , Osteosarcoma/geneticsABSTRACT
Osteosarcoma (OSA) is the most common primary malignant bone tumor in children, 30% of whom develop lung metastases despite aggressive treatment. Our objective was to develop a mouse model of OSA for preclinical studies that (i) incorporates the natural history of OSA including tumor growth in bone and development of lung metastasis and (ii) is amenable to non-invasive detection methods. A human OSA cell line that expresses high levels of luciferase was created. Following subcutaneous injection, nine out of ten mice showed tumor growth. Eight out of ten mice showed tumor growth following orthotopic injection into the proximal tibia. Thirty percent of mice showed pulmonary metastasis by bioluminescent imaging eight to 10 weeks following orthotopic injection. Animals receiving cisplatin treatment showed reduced tumor volume compared to animals treated with vehicle alone. This model allows real-time detection of tumors and can be used to study mechanisms of OSA metastasis and test new therapeutic agents.