O8.08 * CIC MUTATION IS A POOR PROGNOSIS FACTOR IN 1P19Q CODELETED GLIOMAS, ASSOCIATED TO AN UP-REGULATION OF PROLIFERATION PATHWAYS

Abstract

BACKGROUND: Mutations affecting the Capicua transcriptional repressor gene (CIC) on 19q13.2 are frequently associated with a chromosomes 1p and 19q codeletion in oligodendroglial tumors. However, their impact remains poorly understood. EXPERIMENTAL DESIGN: We sequenced the CIC gene on 132 oligodendroglial tumors (109 with 1p19q codeletion), analyzed the patients' outcomes, compared the transcriptomic profile of mutated vs. non mutated tumors, analyzed CIC expression on glioma sections, and transfected the Hs683 cell line with plasmids encoding mutant and wild type CIC. RESULTS: We found 62 (37 truncating and 25 missense) mutations affecting 58/109 codeleted gliomas vs. 1/23 non-codeleted. CIC mutations were associated with a poorer outcome, and a shorter time to anaplastic transformation in grade II codeleted gliomas. Transcriptomic analysis revealed an enrichment of proliferative pathways and oligodendrocyte precursor cell genes' expression profile. Of particular interest are the up-regulation of normally CIC repressed genes such as ETV1, ETV4, ETV5, which promote cell proliferation and invasion, and CCND1 (encoding cyclinD1), suggesting that CIC mutation results in an inactive protein. This hypothesis was further supported by the results of transfecting cells with a truncated form of the protein, resulting in a defect of nuclear addressing, and by the loss of protein expression observed in oligodendrogliomas affected by various mutations. Finally, survival analysis suggested a synergistic effect of CIC mutation and CDKN2A alteration in tumor progression. CONCLUSION: CIC mutations are associated with the activation of proliferative pathways, inhibition of differentiation, and poorer outcome in patients with a 1p19q codeleted gliomas.