CIC gene is frequently mutated in oligodendroglial tumors with 1p19q codeletion. However, the clinical and biological impact remains poorly understood.

We sequenced the CIC gene on 127 oligodendroglial tumors (109 with the 1p19q codeletion) and analyzed patients' outcome. We compared MRI, transcriptomic profile, CIC protein expression of CIC wild type and mutant gliomas. We compared the level of expression of CIC target genes on Hs683-IDH1(R132H) cells transfected with lentivirus encoding mutant and wild type CIC.

We found 63 mutations affecting 60/127 patients, virtually all 1p19q codeleted and IDH mutated (59/60). In the 1p19q codeleted gliomas, CIC mutations were associated with a poorer outcome by univariate (p=0.001) and multivariate analysis (p<0.016). CIC mutations prognostic impact was validated on the TCGA cohort. CIC mutants grade II codeleted gliomas spontaneously grew faster than wild types. Transcriptomic analysis revealed an enrichment of proliferative pathways and oligodendrocyte precursor cell (OPC) genes expression profile in CIC mutant gliomas, with up-regulation of normally CIC repressed genes: ETV1, ETV4, ETV5 and CCND1. Various missense mutations resulted in CIC protein expression loss. Moreover, a truncating CIC mutation resulted in a defect of nuclear targeting of CIC protein to the nucleus in a human glioma cell line expressing IDH1(R132H) and overexpression of CCND1 and others new target genes of CIC, such as DUSP4 and SPRED1.

CIC mutations result in protein inactivation with up-regulation of CIC target genes, activation of proliferative pathways, inhibition of differentiation, and poorer outcome in patients with a 1p19q codeleted gliomas. This article is protected by copyright. All rights reserved.