CIC-Rearranged Sarcomas: An Intriguing Entity That May Lead the Way to the Comprehension of More Common Cancers

• Published in: Cancers 2022-11, Vol.14 (21), p.5411
• Main Authors: Mancarella, Caterina, Carrabotta, Marianna, Toracchio, Lisa, Scotlandi, Katia
• Format: Article
• Language: English
• Subjects: Cancer therapies; Cell migration; Chemotherapy; Chimeras; Chromosome translocations; Clinical trials; Development and progression; Disease; Ewings sarcoma; Genes; Genetic aspects; Genetic transcription; Health aspects; Insulin-like growth factors; Kinases; Medical prognosis; Metastases; Metastasis; Morphology; Patients; Review; Sarcoma; Transcription factors; Tumors
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers14215411

Capicua transcriptional repressor (CIC)-rearranged sarcoma, belonging to the undifferentiated round cells sarcoma family, is characterized by high metastatic rate and poor chemo response. CIC sarcoma represents a new entity harboring the recurrent chromosomal translocation between CIC and, in most of the cases, DUX4. CIC-DUX4 imposes a CIC-specific transcriptional signature, which drives cell transformation, proliferation, and migration. While the discovery of the fusion represented the first evidence of a role of CIC in cancer, a complete comprehension of CIC-rearranged activity is still required before providing new potential avenues for therapy. To date, a specific and effective treatment for CIC sarcoma has yet to be defined. In this review, we initially highlight the clinical features and pathogenesis of CIC-rearranged sarcomas along with current therapeutic approaches and then focus on the specific oncogenic mechanisms driven by the CIC-rearrangement. We discuss novel therapeutic options evoked by the aberrant relations of CIC-DUX4 with the IGF system, DUSP6, P300/CBP, and CCNE1. We also discuss how different mutations involving CIC might converge on a common upregulation of CIC-target genes across human cancers. A deeper understanding of the oncogenic mechanisms driven by the chimera CIC-DUX4 might provide novel therapeutic opportunities with a general impact in cancer.