CIC inactivating mutations identify aggressive subset of 1p19q codeleted gliomas
Vincent Gleize PhD
Sorbonne Université, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris, France
Search for more papers by this authorAgusti Alentorn MD, PhD
Sorbonne Université, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris, France
AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2, Paris, France
Search for more papers by this authorLéa Connen de Kérillis MSc
Sorbonne Université, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris, France
Search for more papers by this authorMarianne Labussière PhD
Sorbonne Université, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris, France
Search for more papers by this authorAravidan A Nadaradjane BSc
Sorbonne Université, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris, France
Search for more papers by this authorEmeline Mundwiller MSC
Institut du Cerveau et de la Moelle Epinière, Plateforme de Génotypage et Séquençage, Paris, France
Search for more papers by this authorChris Ottolenghi MD, PhD
Biochimie Métabolique, Université Paris Descartes et Inserm U1124, Paris, France
Search for more papers by this authorStephanie Mangesius MSc
Sorbonne Université, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris, France
Search for more papers by this authorFrançois Ducray MD, PhD
Hôpital Neurologique, Service de Neurologie B, Lyon, France
Search for more papers by this authoron behalf of the POLA network
Search for more papers by this authorKarima Mokhtari MD
Sorbonne Université, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris, France
AP-HP, Onconeurothèque, Paris, France
AP-HP, Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Neuropathologie R Escourolle, Paris, France
Search for more papers by this authorChiara Villa MD
AP-HP, Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Neuropathologie R Escourolle, Paris, France
Search for more papers by this authorCorresponding Author
Marc Sanson MD, PhD
Sorbonne Université, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris, France
AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2, Paris, France
AP-HP, Onconeurothèque, Paris, France
Address correspondance to Dr Marc Sanson, Service de Neurologie 2, Groupe Hospitalier Pitié-Salpêtrière, 75651, Paris cedex 13, France. E-mail: [email protected]Search for more papers by this authorVincent Gleize PhD
Sorbonne Université, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris, France
Search for more papers by this authorAgusti Alentorn MD, PhD
Sorbonne Université, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris, France
AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2, Paris, France
Search for more papers by this authorLéa Connen de Kérillis MSc
Sorbonne Université, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris, France
Search for more papers by this authorMarianne Labussière PhD
Sorbonne Université, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris, France
Search for more papers by this authorAravidan A Nadaradjane BSc
Sorbonne Université, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris, France
Search for more papers by this authorEmeline Mundwiller MSC
Institut du Cerveau et de la Moelle Epinière, Plateforme de Génotypage et Séquençage, Paris, France
Search for more papers by this authorChris Ottolenghi MD, PhD
Biochimie Métabolique, Université Paris Descartes et Inserm U1124, Paris, France
Search for more papers by this authorStephanie Mangesius MSc
Sorbonne Université, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris, France
Search for more papers by this authorFrançois Ducray MD, PhD
Hôpital Neurologique, Service de Neurologie B, Lyon, France
Search for more papers by this authoron behalf of the POLA network
Search for more papers by this authorKarima Mokhtari MD
Sorbonne Université, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris, France
AP-HP, Onconeurothèque, Paris, France
AP-HP, Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Neuropathologie R Escourolle, Paris, France
Search for more papers by this authorChiara Villa MD
AP-HP, Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Neuropathologie R Escourolle, Paris, France
Search for more papers by this authorCorresponding Author
Marc Sanson MD, PhD
Sorbonne Université, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris, France
AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2, Paris, France
AP-HP, Onconeurothèque, Paris, France
Address correspondance to Dr Marc Sanson, Service de Neurologie 2, Groupe Hospitalier Pitié-Salpêtrière, 75651, Paris cedex 13, France. E-mail: [email protected]Search for more papers by this authorAbstract
Objective
CIC gene is frequently mutated in oligodendroglial tumors with 1p19q codeletion. However, clinical and biological impact remain poorly understood.
Methods
We sequenced the CIC gene on 127 oligodendroglial tumors (109 with the 1p19q codeletion) and analyzed patients' outcome. We compared magnetic resonance imaging, transcriptomic profile, and CIC protein expression of CIC wild-type (WT) and mutant gliomas. We compared the level of expression of CIC target genes on Hs683-IDH1R132H cells transfected with lentivirus encoding mutant and WT CIC.
Results
We found 63 mutations affecting 60 of 127 patients, virtually all 1p19q codeleted and IDH mutated (59 of 60). In the 1p19q codeleted gliomas, CIC mutations were associated with a poorer outcome by uni- (p = 0.001) and multivariate analysis (p < 0.016). CIC mutation prognostic impact was validated on the TCGA cohort. CIC mutant grade II codeleted gliomas spontaneously grew faster than WTs. Transcriptomic analysis revealed an enrichment of proliferative pathways and oligodendrocyte precursor cell gene expression profile in CIC mutant gliomas, with upregulation 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 IDH1R132H and overexpression of CCND1 and other new target genes of CIC, such as DUSP4 and SPRED1.
Interpretation
CIC mutations result in protein inactivation with upregulation of CIC target genes, activation of proliferative pathways, inhibition of differentiation, and poorer outcome in patients with a 1p19q codeleted glioma. Ann Neurol 2015;78:355–374
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