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-IDH1(R132H) 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 IDH1(R132H) 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.
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http://dx.doi.org/10.1002/ana.24443 | DOI Listing |
Acta Neuropathol Commun
December 2024
Department of Pathology, University of Michigan Medical School, 2800 Plymouth Road, Ann Arbor, MI, 48109, USA.
The mesenchymal transformations of infiltrating gliomas are uncommon events. This is particularly true of IDH-mutant astrocytomas and oligodendrogliomas, in which mesenchymal transformation is exceedingly rare. oligosarcoma is a newly recognized methylation class (MC) that represents transformed 1p/19q co-deleted oligodendrogliomas, but recent studies indicate it may be non-specific.
View Article and Find Full Text PDFInt J Surg Pathol
December 2024
Department of Neurosurgery, Fortis Memorial Research Institute, Gurugram, India.
Isocitrate dehydrogenase (IDH) mutant gliomas are classified as astrocytoma or oligodendroglioma based on the recent application of mutation, mutation, and 1p/19q co-deletion. Astrocytomas classically show and mutations, whereas oligodendrogliomas are defined by 1p/19q co-deletion. However, there are reports of gliomas that harbor both astrocytoma and oligodendroglioma morphologically and molecularly.
View Article and Find Full Text PDFInt J Mol Sci
December 2024
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.
Gliomas are a heterogeneous group of brain tumors, among which the most aggressive subtype is glioblastoma, accounting for 60% of cases in adults. Available systemic treatment options are few and ineffective, so new approaches to therapies for glioblastoma are in high demand. In total, 131 patients with diffuse glioma were studied.
View Article and Find Full Text PDFDiscov Oncol
November 2024
Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, 420 Fuma Rd, Jin'an District, Fuzhou, 350011, Fujian, China.
Background: Ferroptosis is a novel type of programmed cell death in various tumors; however, underlying mechanisms remain unclear. We aimed to develop ferroptosis-related long non-coding RNA (FRlncRNA) risk scores to predict lower-grade glioma (LGG) prognosis and to conduct functional analyses to explore potential mechanisms.
Methods: LGG-related RNA sequencing data were extracted from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases.
Biomedicines
November 2024
Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, China.
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