CIC inactivating mutations identify aggressive subset of 1p19q codeleted gliomas. Issue 3 (27th July 2015)

• Record Type: Journal Article
• Authors: Gleize, Vincent; Alentorn, Agusti; Connen de Kérillis, Léa; Labussière, Marianne; Nadaradjane, Aravidan A; Mundwiller, Emeline; Ottolenghi, Chris; Mangesius, Stephanie; Rahimian, Amithys; Ducray, François; on behalf of the POLA network; Mokhtari, Karima; Villa, Chiara; Sanson, Marc
• Is Part Of: Annals of neurology. Volume 78:Issue 3(2015:Sep.)
• Page Start: 355
• Page End: 374
• Publication Date: 2015-07-27
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.24443
• Languages: English
• ISSNs: 0364-5134

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ana24443-sec-0001" sec-type="section"> <title>Objective</title> <p> <italic>CIC</italic> gene is frequently mutated in oligodendroglial tumors with 1p19q codeletion. However, clinical and biological impact remain poorly understood.</p> </sec> <sec id="ana24443-sec-0002" sec-type="section"> <title>Methods</title> <p>We sequenced the <italic>CIC</italic> 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 <italic>CIC</italic> wild‐type (WT) and mutant gliomas. We compared the level of expression of CIC target genes on Hs683‐<italic>IDH1<sup>R132H</sup></italic> cells transfected with lentivirus encoding mutant and WT <italic>CIC</italic>.</p> </sec> <sec id="ana24443-sec-0003" sec-type="section"> <title>Results</title> <p>We found 63 mutations affecting 60 of 127 patients, virtually all 1p19q codeleted and <italic>IDH</italic> mutated (59 of 60). In the 1p19q codeleted gliomas, <italic>CIC</italic> mutations were associated with a poorer outcome by uni‐ (<italic>p</italic> = 0.001) and multivariate analysis (<italic>p</italic> < 0.016). <italic>CIC</italic> mutation prognostic impact was validated on the TCGA cohort. <italic>CIC</italic> 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 <italic>CIC</italic> mutant gliomas, with upregulation of normally CIC repressed genes <italic>ETV1</italic>, <italic>ETV4</italic>, <italic>ETV5</italic>, and <italic>CCND1</italic>. 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<sup>R132H</sup> and overexpression of <italic>CCND1</italic> and other new target genes of CIC, such as <italic>DUSP4</italic> and <italic>SPRED1</italic>.</p> </sec> <sec id="ana24443-sec-0004" sec-type="section"> <title>Interpretation</title> <p> <italic>CIC</italic> 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</p> </sec> </abstract>