Molecular Mechanisms That Activate Convergent Oncogenic Pathway In Genomically Complex Angiosarcoma

Angiosarcoma is an aggressive, albeit rare cancer in humans. Angiosarcomas are vascular malignancies that can occur anywhere in the body, and their metastatic propensity is high. The cause of the vast majority of sporadic angiosarcomas is unknown, and no therapeutic targets have been identified to improve outcomes. Angiosarcomas are genomically complex, with chaotic karyotypes and massive chromosomal abnormalities. Despite the genomic complexity, angiosarcomas share a histological morphology that consists of disorganized, malignant vessel-forming cells. Hemangiosarcoma (HSA) is a common cancer of dogs; it shares clinical and morphological features, as well as aspects of its mutational landscape with human angiosarcoma. Our previous work has revealed that canine HSAs and human angiosarcomas share transcriptional signatures that establish angiogenic and inflammatory molecular subtypes. A comparative genomics approach is useful to apply knowledge from appropriately powered canine studies to inform research into human angiosarcomas. In this study, we leveraged next generation RNA-Seq data from a cohort of 76 spontaneous canine HSAs and from thirteen human angiosarcomas to identify fusion genes. Fifteen novel protein-coding fusion genes including MYO16-PTK2, GABRA3-FLT1, and AKT3-XPNPEP1 were identified in 11 of the 76 canine HSAs; these fusion genes were exclusively seen in tumors of the angiogenic molecular subtype. Mutations of TP53 and fusion genes co-occurred in tumors with higher frequency than expected by random chance. Pathway analysis revealed that co-occurring mutations of TP53 and PIK3CA were associated with gene expression signatures of chromatin remodeling and immunosuppression, and co-occurrence of fusion genes and TP53 mutation enriched a gene signature predicting activation of angiogenic pathways. In human angiosarcomas, ten novel protein-coding fusion genes, including TEX2-PECAM1 and ATP8A2-FLT1, were identified in 7 of 13 tumors, with two showing mutations of TP53. Immunohistochemical assays showed that canine HSA and human angiosarcoma activated p53, AKT, and mTOR signaling pathways independent of fusion genes and mutational conditions, suggesting that both tumors activate convergent signaling pathways to retain the ontogenetical properties. In summary, our comparative analysis identified shared molecular signatures between canine HSA and human angiosarcoma. Specifically, the data suggests that genomic instability induced by TP53 mutations might create a predisposition for fusion events that may contribute to tumor progression by promoting selection and/or enhancing fitness through activation of convergent angiogenic pathways. Our ongoing work seeks to define the key molecular programs that establish the mutational landscape, which consequently activates convergent pathways that contribute to angiosarcoma development. Citation Format: Jong Hyuk Kim, Kate Megquier, Aaron L. Sarver, Rachael Thomas, Ashley J. Schulte, Chao Wang, Ingegerd Elvers, Elinor Karlsson, Matthew Breen, Kerstin Lindblad-Toh, Jaime F. Modiano. Molecular mechanisms that activate convergent oncogenic pathway in genomically complex angiosarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 195.