Abstract PR06: Functional genomics of CIC-DUX4 fusions in zebrafish recapitulates the spectrum of human CIC-rearranged cancers

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Abstract CIC-DUX4 sarcomas are aggressive soft-tissue malignancies characterized by frequent metastases and poor survival. Histologically, CIC-DUX4 sarcomas resemble Ewing sarcomas but do not express EWS-FLI1 or other FET-ETS fusion genes typical of Ewing sarcoma. The tumors arise from chromosomal translocations that fuse the transcriptional repressor CIC with the homeodomain-containing protein DUX4, creating an aberrant transcription factor. However, the critical targets of CIC-DUX4 have been only partly described, the cell of origin and mechanism of transformation are unknown, and animal models of the disease are lacking. Owing to this poor biologic understanding, patients with CIC-DUX4 sarcomas are treated with the same regimens used for classical Ewing sarcoma, despite generally poor outcomes. To comprehensively address these problems, we are taking a cross-species comparative oncology approach via analysis of human CIC-DUX4 sarcomas and genetically engineered in vivo zebrafish models. Human CIC-DUX4 transgenes exerted strong effects on zebrafish embryonic development. Beginning at 5 weeks of age, almost 40% of injected animals developed invasive, rapidly growing tumors. Strikingly, two classes of tumors emerged: small round blue cell sarcomas developed in soft tissues including the trunk musculature and the ventral abdomen, and CNS-PNETs arose in the head. This recapitulates the spectrum of human tumors with CIC gene rearrangements. To further understand the molecular mechanisms of tumorigenesis, we performed RNASeq on zebrafish CIC-DUX4 sarcoma and zebrafish EWS-FLI1 sarcomas alongside human tumors and nonmalignant tissues. This analysis revealed pathways conserved between fish and human, including RAS-MAPK signaling, and highlighted the central importance of ETV4 in this disease. Further studies established ETV4 as a valuable new marker of the human disease. Taken together these findings demonstrate that CIC-DUX4 expression is sufficient to promote the development of tumors, give insight into the cellular origins of CIC-DUX4 tumors, and provide a valuable new animal model for translational research. Citation Format: Sarah Watson, Genevieve C. Kendall, Whitney A. Murchison, Olivier Delattre, Franck Tirode, James F. Amatruda. Functional genomics of CIC-DUX4 fusions in zebrafish recapitulates the spectrum of human CIC-rearranged cancers [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr PR06.