Abstract
Osteosarcoma affects about 2.8% of dogs with cancer, with a one-year survival rate of approximately 45%. The purpose of this study was to characterize mutation and expression profiles of osteosarcoma and its association with outcome in dogs. The number of somatic variants identified across 26 samples ranged from 145 to 2,697 with top recurrent mutations observed in TP53 and SETD2. Additionally, 47 cancer genes were identified with copy number variations. Missense TP53 mutation status and low pre-treatment blood monocyte counts were associated with a longer disease-free interval (DFI). Patients with longer DFI also showed increased transcript levels of anti-tumor immune response genes. Although, T-cell and myeloid cell quantifications were not significantly associated with outcome; immune related genes, PDL-1 and CD160, were correlated with T-cell abundance. Overall, the association of gene expression and mutation profiles to outcome provides insights into pathogenesis and therapeutic interventions in osteosarcoma patients.
Highlights
Osteosarcoma affects about 2.8% of dogs with cancer, with a one-year survival rate of approximately 45%
We report a prevalence of copy number variants (CNV) over short variants (SNVs and insertion and deletions (INDELs))
Along with TP53 mutation status, we evaluated six clinical co-variates that included age at diagnosis, tumor location, sex, pre-treatment peripheral blood monocyte count, serum alkaline phosphatase levels, and body weight to identify their association with disease-free interval (DFI) via univariate Cox proportional hazards (COXPH) regression analysis
Summary
Osteosarcoma affects about 2.8% of dogs with cancer, with a one-year survival rate of approximately 45%. OSAs commonly arise in the metaphysis of long bones in both dogs and humans, and produce an extracellular matrix called tumor osteoid This is the most common type of bone cancer in children, adolescents, and to a lesser extent in the aging adult population (>60 years old). In addition to recurrent TP53 point mutations and CNVs, these studies identified two other recurrently mutated genes: SETD2 (histone lysine methyltransferase) and DMD (dystrophin) not previously identified in human OSA. It is not clear if these genes represent cancer drivers in dogs. Like human OSA, the short variant mutational burden was low in comparison to structural (SV) and copy number variants (CNV) in canine bone tumors
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