TY - JOUR
T1 - Canine osteosarcoma genome sequencing identifies recurrent mutations in DMD and the histone methyltransferase gene SETD2
AU - Gardner, Heather L.
AU - Sivaprakasam, Karthigayini
AU - Briones, Natalia
AU - Zismann, Victoria
AU - Perdigones, Nieves
AU - Drenner, Kevin
AU - Facista, Salvatore
AU - Richholt, Ryan
AU - Liang, Winnie
AU - Aldrich, Jessica
AU - Trent, Jeffrey M.
AU - Shields, Peter G.
AU - Robinson, Nicholas
AU - Johnson, Jeremy
AU - Lana, Susan
AU - Houghton, Peter
AU - Fenger, Joelle
AU - Lorch, Gwendolen
AU - Janeway, Katherine A.
AU - London, Cheryl A.
AU - Hendricks, William P.D.
N1 - Funding Information:
Financial support for this research provided administrative supplements to the Dana-Farber/Harvard Cancer Center Support Grant (P30 CA006516) and the OSU Comprehensive Cancer Center Support Grant (P30 CA016058) from the National Cancer Institute. Additional support was provided by the UL1TR002733 from the National Center for Advancing Translational Sciences and by the Office of The Director and National Institutes of Health under Award Numbers P01CA165995-01A1 and K01OD019923. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We also thank Drs. William Kisseberth, Holly Borghese, Amy LeBlanc, and Christina Mazcko for assistance with sample collection, and Shukmei Wong and Alex Follette with assistance in data analysis.
Funding Information:
Competing interests: K.A.J. has received research funding from Amgen and Pfizer, and travel support from Loxo. C.A.L. has performed consulting work for The One Health Company, Anivive, Karyopharm therapeutics, Zoetis, and Blue Buffalo. W.P.D.H. has performed consulting work for The One Health Company, received research funding from Ethos Veterinary Health, and received travel support from Pathway Vet Alliance. The other authors declare no competing interests.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s42003-019-0487-2
DO - 10.1038/s42003-019-0487-2
M3 - Article
C2 - 31925090
AN - SCOPUS:85071163145
VL - 2
JO - Communications Biology
JF - Communications Biology
SN - 2399-3642
IS - 1
M1 - 266
ER -