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.
Highlights
Osteosarcoma (OS) is a rare, metastatic, human adolescent cancer that occurs in pet dogs
We evaluated Whole genome sequencing (WGS) and whole exome sequencing (WES) data from constitutional DNA for coding germline variants in 28 genes previously associated with both canine and human OS (Supplementary Data 4) as well as variants in SETD2 and DMD that are described in detail below[14,28]
As canine OS is often used as a spontaneous large animal model of human OS to interrogate novel therapies, developing a comprehensive understanding regarding its genomic landscape is critical
Summary
Osteosarcoma (OS) is a rare, metastatic, human adolescent cancer that occurs in pet dogs. We 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. Whole exome sequencing (WES) of 123 human OS tumors identified somatic mutations in TP53 and RB1 (47% combined) alongside candidate driver mutations in an additional 14 cancer genes including BRCA2, RET, ATM, PTEN, WRN, and ATRX. Whole genome sequencing (WGS) studies have identified additional mutations not detectable by WES such as intronic translocations impacting TP53 and other cancer genes, supporting the notion that virtually all OS tumors bear inactivating TP53 mutations (95%) and that other driver mutations such as DLG2 (53%), ATRX (29%), RB1 (29%), and MDM2 (3%) are more commonly altered[6]. While the biologic consequences of SETD2 mutations in canine OS are unknown, this work highlights the potential contribution of epigenetic modifications to OS pathogenesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
