SO01 - Tumor Mutational Burden in Canine Uv-induced Actinic Cutaneous Hemangiosarcoma

Abstract: Background – Actinic cutaneous hemangiosarcoma (HSA) arises from chronic ultraviolet radiation exposure in sun-exposed canine skin. Tumor mutational burden (TMB) ≥ 10 mut/Mb is a predictive biomarker for immune checkpoint inhibitor (ICI) efficacy, with higher TMB correlating with increased neoantigen presentation and enhanced T-cell recognition. UV-induced human malignancies exhibit exceptionally high TMB (melanoma median 20–31 mut/Mb; cutaneous angiosarcoma median ~ 20 mut/Mb) and demonstrate robust ICI responses.

Hypothesis/Objectives – To determine whether canine actinic cutaneous HSA exhibits high TMB. Secondary objectives included identifying and characterizing genomic alterations.

Animals – Five client-owned dogs with actinic cutaneous HSA (six histologic samples). A single board-certified veterinary pathologist reviewed all histologic samples to confirm diagnosis and UV-induced actinic changes.

Methods – This retrospective case series utilized whole-exome sequencing (Canine GCP, VetOmics) targeting 20,257 genes (~ 40 Mb). TMB was calculated as non-synonymous mutations per megabase and compared to VetOmics' reference database of 592 diverse canine cancers and 70 non-cutaneous HSA cases.

Results – Actinic cutaneous HSA demonstrated markedly elevated TMB (range 24.2–345 mut/Mb; mean 132; median 94), significantly exceeding all other cancers (range 2.6–186 mut/Mb; median 12.4) and non-cutaneous HSA (range 3.5–24.8 mut/Mb; median 11). Putative driver mutations included inactivating TP53 and alterations in NRAS, PIK3CA, ATRX, KDR, and MRE11. These mutations overlapped with human angiosarcoma and visceral canine HSA.

Conclusions and Clinical Importance – These findings establish actinic cutaneous HSA as having exceptionally high TMB, suggesting potential therapeutic utility of ICI. We also identified putative driver mutations with potential therapeutic and prognostic implications.