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

Elinor K. Karlsson, Snaevar Sigurdsson, Emma Ivansson, Rachael Thomas, Ingegerd Elvers, Jason Wright, Cedric Howald, Noriko Tonomura, Michele Perloski, Ross Swofford, Tara Biagi, Sarah Fryc, Nathan Anderson, Celine Courtay-Cahen, Lisa Youell, Sally L. Ricketts, Sarah Mandlebaum, Patricio Rivera, Henrik von Euler, William C. Kisseberth & 8 others Cheryl A. London, Eric S. Lander, Guillermo Couto, Kenine Comstock, Mike P. Starkey, Jaime F. Modiano, Matthew Breen, Kerstin Lindblad-Toh

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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.

Original languageEnglish (US)
Article numberR132
JournalGenome biology
Volume14
Issue number12
DOIs
StatePublished - Dec 12 2013

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osteosarcoma
Osteosarcoma
genome
Genome
Dogs
Rottweiler
tumor
Greyhound
loci
gene
dogs
breeds
neoplasms
Canidae
germ cells
dissection
p16 Genes
risk factor
heterozygosity
genes

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Karlsson, E. K., Sigurdsson, S., Ivansson, E., Thomas, R., Elvers, I., Wright, J., ... Lindblad-Toh, K. (2013). Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B. Genome biology, 14(12), [R132]. https://doi.org/10.1186/gb-2013-14-12-r132

Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B. / Karlsson, Elinor K.; Sigurdsson, Snaevar; Ivansson, Emma; Thomas, Rachael; Elvers, Ingegerd; Wright, Jason; Howald, Cedric; Tonomura, Noriko; Perloski, Michele; Swofford, Ross; Biagi, Tara; Fryc, Sarah; Anderson, Nathan; Courtay-Cahen, Celine; Youell, Lisa; Ricketts, Sally L.; Mandlebaum, Sarah; Rivera, Patricio; von Euler, Henrik; Kisseberth, William C.; London, Cheryl A.; Lander, Eric S.; Couto, Guillermo; Comstock, Kenine; Starkey, Mike P.; Modiano, Jaime F.; Breen, Matthew; Lindblad-Toh, Kerstin.

In: Genome biology, Vol. 14, No. 12, R132, 12.12.2013.

Research output: Contribution to journalArticle

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 2013, 'Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B', Genome biology, vol. 14, no. 12, R132. https://doi.org/10.1186/gb-2013-14-12-r132
Karlsson, Elinor K. ; Sigurdsson, Snaevar ; Ivansson, Emma ; Thomas, Rachael ; Elvers, Ingegerd ; Wright, Jason ; Howald, Cedric ; Tonomura, Noriko ; Perloski, Michele ; Swofford, Ross ; Biagi, Tara ; Fryc, Sarah ; Anderson, Nathan ; Courtay-Cahen, Celine ; Youell, Lisa ; Ricketts, Sally L. ; Mandlebaum, Sarah ; Rivera, Patricio ; von Euler, Henrik ; Kisseberth, William C. ; London, Cheryl A. ; Lander, Eric S. ; Couto, Guillermo ; Comstock, Kenine ; Starkey, Mike P. ; Modiano, Jaime F. ; Breen, Matthew ; Lindblad-Toh, Kerstin. / Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B. In: Genome biology. 2013 ; Vol. 14, No. 12.
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AU - Karlsson, Elinor K.

AU - Sigurdsson, Snaevar

AU - Ivansson, Emma

AU - Thomas, Rachael

AU - Elvers, Ingegerd

AU - Wright, Jason

AU - Howald, Cedric

AU - Tonomura, Noriko

AU - Perloski, Michele

AU - Swofford, Ross

AU - Biagi, Tara

AU - Fryc, Sarah

AU - Anderson, Nathan

AU - Courtay-Cahen, Celine

AU - Youell, Lisa

AU - Ricketts, Sally L.

AU - Mandlebaum, Sarah

AU - Rivera, Patricio

AU - von Euler, Henrik

AU - Kisseberth, William C.

AU - London, Cheryl A.

AU - Lander, Eric S.

AU - Couto, Guillermo

AU - Comstock, Kenine

AU - Starkey, Mike P.

AU - Modiano, Jaime F.

AU - Breen, Matthew

AU - Lindblad-Toh, Kerstin

PY - 2013/12/12

Y1 - 2013/12/12

N2 - 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.

AB - 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.

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