Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B.
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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
Genome Biol. 14 (12) R132 [2013-12-12; online 2013-12-12]
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.
PubMed 24330828
DOI 10.1186/gb-2013-14-12-r132
Crossref 10.1186/gb-2013-14-12-r132
pii: gb-2013-14-12-r132
pmc: PMC4053774
GEO: GSE52147