Characterization of canine osteosarcoma by array comparative genomic hybridization and RT‐qPCR: Signatures of genomic imbalance in canine osteosarcoma parallel the human counterpart

Abstract

Osteosarcoma (OS) is the most commonly diagnosed malignant bone tumor in humans and dogs, characterized in both species by extremely complex karyotypes exhibiting high frequencies of genomic imbalance. Evaluation of genomic signatures in human OS using array comparative genomic hybridization (aCGH) has assisted in uncovering genetic mechanisms that result in disease phenotype. Previous low-resolution (10-20 Mb) aCGH analysis of canine OS identified a wide range of recurrent DNA copy number aberrations, indicating extensive genomic instability. In this study, we profiled 123 canine OS tumors by 1 Mb-resolution aCGH to generate a dataset for direct comparison with current data for human OS, concluding that several high frequency aberrations in canine and human OS are orthologous. To ensure complete coverage of gene annotation, we identified the human refseq genes that map to these orthologous aberrant dog regions and found several candidate genes warranting evaluation for OS involvement. Specifically, subsequenct FISH and qRT-PCR analysis of RUNX2, TUSC3, and PTEN indicated that expression levels correlated with genomic copy number status, showcasing RUNX2 as an OS associated gene and TUSC3 as a possible tumor suppressor candidate. Together these data demonstrate the ability of genomic comparative oncology to identify genetic abberations which may be important for OS progression. Large scale screening of genomic imbalance in canine OS further validates the use of the dog as a suitable model for human cancers, supporting the idea that dysregulation discovered in canine cancers will provide an avenue for complementary study in human counterparts.

Anchoring the dog to its relatives reveals new evolutionary breakpoints across 11 species of the Canidae and provides new clues for the role of B chromosomes

“…Recurrent genomic imbalances within the CFA19 breakpoint region (21.8-25.1 Mb) were again evident in lymphoma and leukemia and also among cases of appendicular osteosarcoma (Angstadt et al 2011) and hemangiosarcoma (unpublished). Osteosarcoma cases also exhibited aberrations consistent with the CFA1 (27.6-28.7 Mb) breakpoint and with the CFA18 (27.4-29.0 Mb) region (Angstadt et al 2011), in common with lymphoma ). These findings provide intriguing new data supportive of an association between cancer-associated genomic instability and karyotypic rearrangement during speciation.…”

Targeting osteosarcoma

“…With the increased incidence of OS in canines, these trials would be easier to enroll, and ultimately identify promising treatments for pediatric patients faster. Most importantly, the key hallmark of OS identified in the Perry et al (1) study was the extreme genetic heterogeneity of this rare cancer, a feature known to be shared with the canine version of OS (17).…”

Pamidronate functionalized nanoconjugates for targeted therapy of focal skeletal malignant osteolysis

“…The clinical presentation, biologic behavior, and genetics of OS are strongly conserved between humans and pet dogs (26,28,29,44), and canine OS has emerged as a powerful comparative tumor model for guiding and expediting the drug development pathway for pediatric OS patients (45,46). One of the critical factors that contribute to the future clinical translation of nanomedicine is the experimental models used for evaluating the safety and efficiency of targeted NP treatment strategies.…”

“…Dogs spontaneously develop OS with the highest frequency of all mammal species; OS commonly affects older dogs of large or giant skeletal size (24). Biological, histological, and genomic features of OS in humans and dogs are highly similar and have provided a basis to evaluate novel therapeutics in dogs with OS (25)(26)(27)(28)(29). In addition, given the comparable anatomic size of humans and dogs (50 kg or greater) afflicted with OS, dogs might serve as more predictive models for comparable human pathologies based upon allometric scale similarities.…”