title: Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B.
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.
authors: Elinor K
authors: EK
authors: Karlsson
authors: Snaevar
authors: S
authors: Sigurdsson
authors: Emma
authors: E
authors: Ivansson
authors: Rachael
authors: R
authors: Thomas
authors: Ingegerd
authors: I
authors: Elvers
authors: Jason
authors: J
authors: Wright
authors: Cedric
authors: C
authors: Howald
authors: Noriko
authors: N
authors: Tonomura
authors: Michele
authors: M
authors: Perloski
authors: Ross
authors: R
authors: Swofford
authors: Tara
authors: T
authors: Biagi
authors: Sarah
authors: S
authors: Fryc
authors: Nathan
authors: N
authors: Anderson
authors: Celine
authors: C
authors: Courtay-Cahen
authors: Lisa
authors: L
authors: Youell
authors: Sally L
authors: SL
authors: Ricketts
authors: Sarah
authors: S
authors: Mandlebaum
authors: Patricio
authors: P
authors: Rivera
authors: Henrik
authors: H
authors: von Euler
authors: William C
authors: WC
authors: Kisseberth
authors: Cheryl A
authors: CA
authors: London
authors: Eric S
authors: ES
authors: Lander
authors: Guillermo
authors: G
authors: Couto
authors: Kenine
authors: K
authors: Comstock
authors: Mike P
authors: MP
authors: Starkey
authors: Jaime F
authors: JF
authors: Modiano
authors: Matthew
authors: M
authors: Breen
authors: Kerstin
authors: K
authors: Lindblad-Toh
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000662:veterinary*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D056915:DNA Copy Number Variations; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D019143:Evolution, Molecular; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D016678:Genome; D055106:Genome-Wide Association Study; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D012516:Osteosarcoma / Q000235:genetics / Q000662:veterinary*
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D035683:MicroRNAs