Canine osteosarcoma genome sequencing identifies recurrent mutations in DMD and the histone methyltransferase gene SETD2

Heather L. Gardner; Karthigayini Sivaprakasam; Natalia Briones; Victoria Zismann; Nieves Perdigones; Kevin Drenner; Salvatore Facista; Ryan Richholt; Winnie Liang; Jessica Aldrich; Jeffrey M. Trent; Peter G. Shields; Nicholas Robinson; Jeremy Johnson; Susan Lana; Peter Houghton; Joelle Fenger; Gwendolen Lorch; Katherine A. Janeway; Cheryl A. London; William P.D. Hendricks

doi:10.1038/s42003-019-0487-2

Canine osteosarcoma genome sequencing identifies recurrent mutations in DMD and the histone methyltransferase gene SETD2

Heather L. Gardner, Karthigayini Sivaprakasam, Natalia Briones, Victoria Zismann, Nieves Perdigones, Kevin Drenner, Salvatore Facista, Ryan Richholt, Winnie Liang, Jessica Aldrich, Jeffrey M. Trent, Peter G. Shields, Nicholas Robinson, Jeremy Johnson, Susan Lana, Peter Houghton, Joelle Fenger, Gwendolen Lorch, Katherine A. Janeway, Cheryl A. LondonWilliam P.D. Hendricks

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76 Scopus citations

Abstract

Osteosarcoma (OS) is a rare, metastatic, human adolescent cancer that also occurs in pet dogs. To define the genomic underpinnings of canine OS, we performed multi-platform analysis of OS tumors from 59 dogs, including whole genome sequencing (n = 24) and whole exome sequencing (WES; n = 13) of primary tumors and matched normal tissue, WES (n = 10) of matched primary/metastatic/normal samples and RNA sequencing (n = 54) of primary tumors. We found that canine OS recapitulates features of human OS including low point mutation burden (median 1.98 per Mb) with a trend towards higher burden in metastases, high structural complexity, frequent TP53 (71%), PI3K pathway (37%), and MAPK pathway mutations (17%), and low expression of immune-associated genes. We also identified novel features of canine OS including putatively inactivating somatic SETD2 (42%) and DMD (50%) aberrations. These findings set the stage for understanding OS development in dogs and humans, and establish genomic contexts for future comparative analyses.

Original language	English (US)
Article number	266
Journal	Communications Biology
Volume	2
Issue number	1
DOIs	https://doi.org/10.1038/s42003-019-0487-2
State	Published - Dec 1 2019

ASJC Scopus subject areas

Medicine (miscellaneous)
General Biochemistry, Genetics and Molecular Biology
General Agricultural and Biological Sciences

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Gardner, H. L., Sivaprakasam, K., Briones, N., Zismann, V., Perdigones, N., Drenner, K., Facista, S., Richholt, R., Liang, W., Aldrich, J., Trent, J. M., Shields, P. G., Robinson, N., Johnson, J., Lana, S., Houghton, P., Fenger, J., Lorch, G., Janeway, K. A., ... Hendricks, W. P. D. (2019). Canine osteosarcoma genome sequencing identifies recurrent mutations in DMD and the histone methyltransferase gene SETD2. Communications Biology, 2(1), Article 266. https://doi.org/10.1038/s42003-019-0487-2

Gardner, HL, Sivaprakasam, K, Briones, N, Zismann, V, Perdigones, N, Drenner, K, Facista, S, Richholt, R, Liang, W, Aldrich, J, Trent, JM, Shields, PG, Robinson, N, Johnson, J, Lana, S, Houghton, P, Fenger, J, Lorch, G, Janeway, KA, London, CA & Hendricks, WPD 2019, 'Canine osteosarcoma genome sequencing identifies recurrent mutations in DMD and the histone methyltransferase gene SETD2', Communications Biology, vol. 2, no. 1, 266. https://doi.org/10.1038/s42003-019-0487-2

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abstract = "Osteosarcoma (OS) is a rare, metastatic, human adolescent cancer that also occurs in pet dogs. To define the genomic underpinnings of canine OS, we performed multi-platform analysis of OS tumors from 59 dogs, including whole genome sequencing (n = 24) and whole exome sequencing (WES; n = 13) of primary tumors and matched normal tissue, WES (n = 10) of matched primary/metastatic/normal samples and RNA sequencing (n = 54) of primary tumors. We found that canine OS recapitulates features of human OS including low point mutation burden (median 1.98 per Mb) with a trend towards higher burden in metastases, high structural complexity, frequent TP53 (71%), PI3K pathway (37%), and MAPK pathway mutations (17%), and low expression of immune-associated genes. We also identified novel features of canine OS including putatively inactivating somatic SETD2 (42%) and DMD (50%) aberrations. These findings set the stage for understanding OS development in dogs and humans, and establish genomic contexts for future comparative analyses.",

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AU - Zismann, Victoria

AU - Perdigones, Nieves

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AU - Facista, Salvatore

AU - Richholt, Ryan

AU - Liang, Winnie

AU - Aldrich, Jessica

AU - Trent, Jeffrey M.

AU - Shields, Peter G.

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AU - Johnson, Jeremy

AU - Lana, Susan

AU - Houghton, Peter

AU - Fenger, Joelle

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AU - Janeway, Katherine A.

AU - London, Cheryl A.

AU - Hendricks, William P.D.

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Canine osteosarcoma genome sequencing identifies recurrent mutations in DMD and the histone methyltransferase gene SETD2

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