Identification of genomic alterations with clinical impact in canine splenic hemangiosarcoma.

Canine hemangiosarcoma (HSA) is an aggressive cancer of endothelial cells with short survival times. Understanding the genomic landscape of HSA may aid in developing therapeutic strategies for dogs and may also inform therapies for the rare and aggressive human cancer angiosarcoma. The objectives of this study were to build a framework for leveraging real-world genomic and clinical data that could provide the foundation for precision medicine in veterinary oncology, and to determine the relationships between genomic and clinical features in canine splenic HSA. One hundred and nine dogs with primary splenic HSA treated by splenectomy that had tumour sequencing via the FidoCure® Precision Medicine Platform targeted sequencing panel were enrolled. Patient signalment, weight, metastasis at diagnosis and overall survival time were retrospectively evaluated. The incidence of genomic alterations in individual genes and their relationship to patient variables including outcome were assessed. Somatic mutations in TP53 (n = 44), NRAS (n = 20) and PIK3CA (n = 19) were most common. Survival was associated with presence of metastases at diagnosis and germline variants in SETD2 and NOTCH1. Age at diagnosis was associated with somatic NRAS mutations and breed. TP53 and PIK3CA somatic mutations were found in larger dogs, while germline SETD2 variants were found in smaller dogs. We identified both somatic mutations and germline variants associated with clinical variables including age, breed and overall survival. These genetic changes may be useful prognostic factors and provide insight into the genomic landscape of hemangiosarcoma.

Shared hotspot mutations in oncogenes position dogs as an unparalleled comparative model for precision therapeutics.

Naturally occurring canine cancers have remarkable similarities to their human counterparts. To better understand these similarities, we investigated 671 client-owned dogs from 96 breeds with 23 common tumor types, including those whose mutation profile are unknown (anal sac carcinoma and neuroendocrine carcinoma) or understudied (thyroid carcinoma, soft tissue sarcoma and hepatocellular carcinoma). We discovered mutations in 50 well-established oncogenes and tumor suppressors, and compared them to those reported in human cancers. As in human cancer, TP53 is the most commonly mutated gene, detected in 22.5% of canine tumors overall. Canine tumors share mutational hotspots with human tumors in oncogenes including PIK3CA, KRAS, NRAS, BRAF, KIT and EGFR. Hotspot mutations with significant association to tumor type include NRAS G61R and PIK3CA H1047R in hemangiosarcoma, ERBB2 V659E in pulmonary carcinoma, and BRAF V588E (equivalent of V600E in humans) in urothelial carcinoma. Our findings better position canines as a translational model of human cancer to investigate a wide spectrum of targeted therapies.

Analyses of canine cancer mutations and treatment outcomes using real-world clinico-genomics data of 2119 dogs.

Spontaneous tumors in canines share significant genetic and histological similarities with human tumors, positioning them as valuable models to guide drug development. However, current translational studies have limited real world evidence as cancer outcomes are dispersed across veterinary clinics and genomic tests are rarely performed on dogs. In this study, we aim to expand the value of canine models by systematically characterizing genetic mutations in tumors and their response to targeted treatments. In total, we collect and analyze survival outcomes for 2119 tumor-bearing dogs and the prognostic effect of genomic alterations in a subset of 1108 dogs. Our analysis identifies prognostic concordance between canines and humans in several key oncogenes, including TP53 and PIK3CA. We also find that several targeted treatments designed for humans are associated with a positive prognosis when used to treat canine tumors with specific genomic alterations, underscoring the value of canine models in advancing drug discovery for personalized oncology.