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.
Highlights
To bring this approach to canine oncology, we developed a next generation sequencing (NGS)-based targeted resequencing panel for HSA, which confirmed and extended results from 20 cases we previously studied by whole exome sequencing
The panel performed well, detecting candidate driver mutations in more than 90% of 50 clinical samples examined, with clinical information and driver genetic alterations summarized in S4 Table
NRAS Q61R is a known driver frequently found in human melanoma, angiosarcoma and other cancers [25,26]
Summary
Angiosarcoma (AS) is a rare but deadly form of cancer, arising in several clinical situations: post-irradiation therapy (e.g. for breast cancer), in sun exposed skin, and spontaneous diseases. Comparison of our data with previously published collections of AS sequences along with new data released by the Angiosarcoma Project indicate that some molecular subtypes of HSA strongly resemble mutational patterns in a subset of AS [2] (https://ascproject.org/data-release) These data suggest that therapy of certain forms of human AS might be informed by clinical trials carried out in canine patients with HSA. Deep sequencing of canine HSA reveals molecular subtypes and therapeutic targets in P10 and PIK3CA E726K in P12 (Fig 2 and S2 Table) Together, these data show that the HSA panel can readily detect oncogenic mutations identified by whole exome sequencing, as well as additional mutations with low AF that are missed by exome sequencing. IHC analysis of p-ERK, p-AKT and p-S6 in HSA cases is summarized in S3 Table
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