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Genome-wide analysis of heritable dog osteosarcoma in 3 breeds

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Canis lupus familiaris

PROVIDER: GSE52147 | GEO | 2013/11/12

SECONDARY ACCESSION(S): PRJNA227152

REPOSITORIES: GEO

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Genome-wide analysis of heritable dog osteosarcoma in 3 breeds

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Dataset #3 for genome-wide analysis of heritable dog osteosarcoma in 3 breeds

Project description:Osteosarcoma in dogs is a spontaneously occurring disease with a global tumor gene expression signature indistinguishable from human pediatric tumors and clinical progression is remarkably similar. Unlike human OS, canine OS is a highly heritable disease with some large and giant dog breeds at >10x increased risk. We did a genome wide association study of osteosarcoma using the Illumina CanineHD genotyping array in three breeds: greyhound (mortality from OS = 26%), rottweiler (17%) and Irish wolfhound (IWH, 21%) and identified 33 inherited risk loci explaining 55 to 85% of phenotype variance in each breed. Data created for a genome-wide association studio of heritable osteosarcoma risk factors in dogs, including 267 racing greyhounds (153 affected (A) + 114 unaffected (U)), 135 rottweilers (80 A + 55 U), 141 IWH (76 A + 65 U) and 19 AKC greyhounds using the Illumina CanineHD array (~170,000 SNPs genomewide)

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Genome-wide gene expression profiling of mesenchymal stem cells, osteosarcoma cells, and osteosarcoma cell lines.

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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Genome-wide gene expression profiling of mesenchymal stem cells, osteosarcoma cells, and osteosarcoma cell lines.

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Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B.

Project description:Canine osteosarcoma is clinically nearly identical to the human disease, but is common and highly heritable, making genetic dissection feasible.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.Mapping a complex cancer in multiple dog breeds reveals a polygenic spectrum of germline risk factors pointing to specific pathways as drivers of disease.

| S-EPMC4053774 | biostudies-literature

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