Whole exome sequencing and gene expression analysis of canine osteosarcomas identify mutant TP53 and enriched immune pathways associated with longer survival

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 the mutation and expression profiles of canine osteosarcoma associated with outcome in samples from dogs treated by amputation and chemotherapy. The number of somatic variants identified across 26 samples ranged from 145 to 2,697 with top recurrent mutations observed in TP53 (82% of the samples) and SETD2 (22%). Additionally, 47 cancer genes were identified with copy number variations in at least 58% of the samples. We observed transcriptional down-regulation of myogenesis genes and up-regulation of extracellular matrix genes in tumors compared to normal bone. Patients with longer disease-free intervals (DFI) showed increased transcript levels of anti-tumor immune response genes. Wild-type/NULL TP53 mutation status and high pre-treatment blood monocyte counts were associated with a shorter DFI. Immune cell infiltration was quantified via immunohistochemistry and gene expression profiling. CD3+ and MAC387+ myeloid cell quantifications were not significantly associated with outcome. Expression of immune related genes PDL-1, CD160 and ICOS 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.