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

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.

Sigurdsson, SnaevarUppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för medicinsk biokemi och mikrobiologi (author)
Ivansson, EmmaUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)emfra062 (author)
Thomas, Rachael (author)
Elvers, IngegerdUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)ingel569 (author)
Wright, Jason (author)
Howald, Cedric (author)
Tonomura, Noriko (author)
Perloski, Michele (author)
Swofford, Ross (author)
Biagi, Tara (author)
Fryc, Sarah (author)
Anderson, Nathan (author)
Courtay-Cahen, Celine (author)
Youell, Lisa (author)
Ricketts, Sally L (author)
Mandlebaum, Sarah (author)
Rivera, Patricio (author)
von Euler, Henrik (author)
Kisseberth, William C (author)
London, Cheryl A (author)
Lander, Eric S (author)
Couto, Guillermo (author)
Comstock, Kenine (author)
Starkey, Mike P (author)
Modiano, Jaime F (author)
Breen, Matthew (author)
Lindblad-Toh, KerstinUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)kerli865 (author)
Rönnberg, HenrikSwedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för kliniska vetenskaper (KV),Department of Clinical Sciences(Swepub:slu)49018 (author)
Uppsala universitetScience for Life Laboratory, SciLifeLab (creator_code:org_t)
Sveriges lantbruksuniversitet

In:Genome Biology: Springer Science and Business Media LLC14:121465-69061474-760X1474-7596

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Medical Genetics

By the university: Uppsala University; Swedish University of Agricultural Sciences

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