Molecular subtypes in canine hemangiosarcoma reveal similarities with human angiosarcoma

Abstract

Angiosarcoma (AS) is a rare neoplasm with limited treatment options and a poor survival rate. Development of effective therapies is hindered by the rarity of this disease. Dogs spontaneously develop hemangiosarcoma (HSA), a common, histologically similar neoplasm. Metastatic disease occurs rapidly and despite chemotherapy, most dogs die several months after diagnosis. These features suggest that HSA might provide a tractable model to test experimental therapies in clinical trials. We previously reported whole exome sequencing of 20 HSA cases. Here we report development of a NGS targeted resequencing panel to detect driver mutations in HSA and other canine tumors. We validated the panel by resequencing the original 20 cases and sequenced 30 additional cases. Overall, we identified potential driver mutations in over 90% of the cases, including well-documented (in human cancers) oncogenic mutations in PIK3CA (46%), PTEN (6%), PLCG1(4%), and TP53 (66%), as well as previously undetected recurrent activating mutations in NRAS (24%). The driver role of these mutations is further demonstrated by augmented downstream signaling crucial to tumor growth. The recurrent, mutually exclusive mutation patterns suggest distinct molecular subtypes of HSA. Driver mutations in some subtypes closely resemble those seen in some AS cases, including NRAS, PLCG1, PIK3CA and TP53. Furthermore, activation of the MAPK and PI3K pathways appear to be key oncogenic mechanisms in both species. Together, these observations suggest that dogs with spontaneous HSA could serve as a useful model for testing the efficacy of targeted therapies, some of which could potentially be of therapeutic value in AS.

Genomic landscapes of canine splenic angiosarcoma (hemangiosarcoma) contain extensive heterogeneity within and between patients

“…Patient 43 (stromal sarcoma) bore a likely pathogenic missense mutation at R789C in GNAS. These driver mutations and their frequencies resemble those identified in HSA in other studies 9,12,20 . The genomic landscape of HSA confirmed here provides a framework to guide study of HSA development while also guiding therapeutic strategies under a precision medicine paradigm in which drug-biomarker relationships may exist in HSA ( Figure S1 ).…”

“…The third and fourth cases bore H1047R and G1049R mutations. Amino acid 1047 is the most frequently mutated PIK3CA hotspot in human cancers, previously shown to be mutated in HSA (30-46% of cases) 9,12,20 . AKT1 was mutated in 3 cases (11%) with two potentially pathogenic missense mutations, G37D and R23W, and one frameshift, L52fs, with unknown significance.…”

“…AS in dogs, also known as hemangiosarcoma (HSA), is a complex disease that shares clinical, histopathologic and molecular characteristics with AS [2][3][4][5][6][7][8][9] . Shared molecular features include transcriptional subtypes (angiogenic, inflammatory, and adipogenic 4,6,8 ), point mutations (TP53, PIK3CA, PTEN, PIK3R1 [8][9][10] ), copy number gains (PDGFRA, VEGFA, KIT, KDR), and copy number deletions (CDKN2A/B, PTEN) 8,11,12 , many of which hold potential as biomarkers to guide clinical management. As a naturally occurring cancer, HSA is a setting in which to perform cross-species comparative studies to improve understanding of AS development and clinical management.…”

“…Tens of thousands of canine diagnoses occur annually, comprising 45-51% of splenic cancers 1 . AS in dogs, also known as hemangiosarcoma (HSA), is a complex disease that shares clinical, histopathologic and molecular characteristics with AS 2–9 . Shared molecular features include transcriptional subtypes (angiogenic, inflammatory, and adipogenic 4,6,8 ), point mutations (TP53, PIK3CA, PTEN, PIK3R1 8–10 ), copy number gains (PDGFRA, VEGFA, KIT, KDR), and copy number deletions (CDKN2A/B, PTEN ) 8,11,12 , many of which hold potential as biomarkers to guide clinical management.…”

Genomically Complex Human Angiosarcoma and Canine Hemangiosarcoma Establish Convergent Angiogenic Transcriptional Programs Driven by Novel Gene Fusions

“…Hemangiosarcoma (HSA) is a malignant vascular tumor that is common in dogs with an estimated tens of thousands of cases diagnosed each year (14)(15)(16). Canine HSA shares clinical and morphological features with human AS, as well as aspects of its mutational landscape (17)(18)(19)(20). We previously documented three molecular subtypes of HSA, characterized by angiogenic, inflammatory, and adipogenic transcriptomic signatures (21).…”