Conservation of driver mutations and oncogenic pathway alterations revealed through a comparative genomic analysis of human angiosarcoma and canine hemangiosarcoma

Angiosarcoma (AS) is a rare and aggressive endothelial malignancy, representing <2% of soft tissue sarcomas in humans. Progress in developing effective therapies has been hindered by its low incidence, genomic heterogeneity, and the scarcity of representative preclinical models.Integrative genomic analyses of two cBioPortal cohorts (n=131) identified recurrent alterations in TP53 (26%), KDR (17.6%), POT1 (17.6%), PIK3CA (14.5%), FLT4 (11.5%), PTPRB (11.5%), and NRAS (5.3%), highlighting pervasive disruptions of DNA damage response, PI3K/AKT/mTOR, and angiogenic receptor signaling. However, the rarity of AS limits functional validation and biomarker-driven therapy development.Canine hemangiosarcoma (HSA) is a biologically analogous vascular tumor that occurs spontaneously with far higher incidence, offering a unique opportunity to model AS in an immunocompetent host. Large-scale profiling of HSA from the FidoCure Precision Medicine Platform (n=1,177) revealed overlapping mutations in TP53 (54.9%), PIK3CA (29.9%), NRAS (15.3%), FLT4 (3.6%), PTEN (3.4%), and KDR (2.6%), mirroring the human landscape.Cross-species analyses showed striking molecular parallels. PIK3CA mutations in both species clustered in the helical and kinase domains, consistent with pathway activation. While mutation at the canonical hotspot (H1047R/L/Y) predominated in HSA, AS was found to harbor heterogeneous variants (P124L, T957P, M1043V/I). TP53 variants localized to conserved DNA-binding regions (human R175, R248, R273; canine R164H, C228R/Y, R263H, R272H), indicating convergent loss of tumor-suppressor function. KDR, NRAS, and PTEN alterations similarly disrupted VEGFR2, RAS/MAPK, and PI3K signaling pathways across species.Collectively, these findings reveal deep evolutionary conservation of molecular drivers in vascular sarcomagenesis. Canine HSA faithfully recapitulates the genetic complexity and therapeutic vulnerabilities of human AS, establishing a robust comparative platform for biomarker discovery, targeted therapy validation, and translational oncology research within an immunocompetent context.