Loss of CIC and FUBP1 expressions are potential markers of shorter time to recurrence in oligodendroglial tumors

Chan, Aden Ka Yin; Pang, Jesse Chung Sean; Chung, Nellie Yuk Fei; Li, Kay Ka Wai; Poon, Wai Sang; Chan, Danny Tat Ming; Shi, Zhifeng; Chen, Liang; Zhou, Lei; Ng, Ho Keung

doi:10.1038/modpathol.2013.165

Cited by 49 publications

(65 citation statements)

References 32 publications

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“…This is consistent with recent studies indicating that CIC mutations are associated with a more aggressive subtype in ODs (51,52). Among these Cic-regulated genes, the ones that are essential in mediating the pathogenic role of Cic deletion are still unclear.…”

Section: Discussionsupporting

confidence: 93%

Cic Loss Promotes Gliomagenesis via Aberrant Neural Stem Cell Proliferation and Differentiation

et al. 2017

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Inactivating mutations in the transcriptional repression factor Capicua (CIC) occur in ~50% of human oligodendrogliomas (OD), but mechanistic links to pathogenesis are unclear. To address this question, we generated Cic-deficient mice and human OD cell models. Genetic deficiency in mice resulted in a partially penetrant embryonic or perinatal lethal phenotype, with the production of an aberrant proliferative neural population in surviving animals. In vitro cultured neural stem cells derived from Cic conditional knockout mice bypassed an EGF requirement for proliferation and displayed a defect in their potential for oligodendrocyte differentiation. Cic is known to participate in gene suppression that can be relieved by EGFR signal, but we found that cic also activated expression of a broad range of EGFR-independent genes. In an orthotopic mouse model of glioma, we found that Cic loss potentiated the formation and reduced the latency in tumor development. Collectively, our results define an important role for Cic in regulating neural cell proliferation and lineage specification, and suggest mechanistic explanations for how CIC mutations may impact the pathogenesis and therapeutic targeting of oligodendroglioma.

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Section: Discussionsupporting

confidence: 93%

Cic Loss Promotes Gliomagenesis via Aberrant Neural Stem Cell Proliferation and Differentiation

et al. 2017

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“…In this regard, the co-existence of IDH1 with CIC or FUBP1 mutations may partially explain the slower tumor growth and longer survival of oligodendrogliomas with mutations in IDH1 and a codeletion of 1p/19q when compared to other diffuse gliomas [90]. The overall survival rate of patients with oligodendrogliomas with CIC mutations was lower than that of patients without CIC mutations, and the FUBP1 mutation was significantly associated with unfavorable progression-free survival [15]. However, oligodendrogliomas cannot be diagnosed with CIC or FUBP1 mutations only [15].…”

Section: Important Molecular Genetics Found In Brain Tumorsmentioning

confidence: 99%

“…The overall survival rate of patients with oligodendrogliomas with CIC mutations was lower than that of patients without CIC mutations, and the FUBP1 mutation was significantly associated with unfavorable progression-free survival [15]. However, oligodendrogliomas cannot be diagnosed with CIC or FUBP1 mutations only [15]. …”

Section: Important Molecular Genetics Found In Brain Tumorsmentioning

confidence: 99%

Molecular Testing of Brain Tumor

Park

Won

Kim

et al. 2017

J Pathol Transl Med

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The World Health Organization (WHO) classification of central nervous system (CNS) tumors was revised in 2016 with a basis on the integrated diagnosis of molecular genetics. We herein provide the guidelines for using molecular genetic tests in routine pathological practice for an accurate diagnosis and appropriate management. While astrocytomas and IDH-mutant (secondary) glioblastomas are characterized by the mutational status of IDH, TP53, and ATRX, oligodendrogliomas have a 1p/19q codeletion and mutations in IDH, CIC, FUBP1, and the promoter region of telomerase reverse transcriptase (TERTp). IDH-wildtype (primary) glioblastomas typically lack mutations in IDH, but are characterized by copy number variations of EGFR, PTEN, CDKN2A/B, PDGFRA, and NF1 as well as mutations of TERTp. High-grade pediatric gliomas differ from those of adult gliomas, consisting of mutations in H3F3A, ATRX, and DAXX, but not in IDH genes. In contrast, well-circumscribed low-grade neuroepithelial tumors in children, such as pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and ganglioglioma, often have mutations or activating rearrangements in the BRAF, FGFR1, and MYB genes. Other CNS tumors, such as ependymomas, neuronal and glioneuronal tumors, embryonal tumors, meningothelial, and other mesenchymal tumors have important genetic alterations, many of which are diagnostic, prognostic, and predictive markers and therapeutic targets. Therefore, the neuropathological evaluation of brain tumors is increasingly dependent on molecular genetic tests for proper classification, prediction of biological behavior and patient management. Identifying these gene abnormalities requires cost-effective and high-throughput testing, such as next-generation sequencing. Overall, this paper reviews the global guidelines and diagnostic algorithms for molecular genetic testing of brain tumors.

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“…Mutational hotspots of IDH1 at R132 and IDH2 at R172 were evaluated by direct sequencing as previously described. 19 …”

Section: Mutation Analysis Of Tert Promoter and Idh1/idh2mentioning

confidence: 99%

TERT promoter mutations contribute to subset prognostication of lower-grade gliomas

Chan

Zhang

et al. 2015

Modern Pathology

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Recurrent mutations in the promoter region of telomerase reverse transcriptase (TERT) have been found in various cancers including diffuse gliomas. Mutations lead to TERT upregulation and are associated with aggressive clinical behavior in glioblastomas. However, the clinical significance of TERT promoter mutations in lower-grade gliomas remains undetermined. The aim of this study is to evaluate the status of TERT promoter and the respective prognostic significance in a cohort of 237 lower-grade gliomas comprising grades II and III astrocytomas, oligodendrogliomas, and oligoastrocytomas. Mutually exclusive mutations in TERT promoter, C228T and C250T, were identified in 16/105 (15%) diffuse astrocytomas, 16/63 (25%) anaplastic astrocytomas, 13/18 (72%) oligodendrogliomas, 3/3 (100%) anaplastic oligodendrogliomas, 17/45 (38%) oligoastrocytomas, and 2/3 (67%) anaplastic oligoastrocytomas. Mutations co-occurred with 1p/19q codeletion (Po0.001) and are associated with oligodendroglial histology (Po0.001). Kaplan-Meier's survival analysis showed that TERT promoter mutation (P ¼ 0.037), Isocitrate dehydrogenase (IDH) mutation (Po0.001), and 1p/19q codeletion (Po0.001) were associated with favorable overall survival (OS). In the subset of 116 IDH-mutated lower-grade gliomas lacking 1p/19q codeletion, 19 TERT promoter-mutated tumors exhibited longer progression-free survival (PFS) (P ¼ 0.027) and OS (P ¼ 0.004). Consistent with this observation, in the subset of 97 IDH-mutated astrocytomas, 14 TERT promoter-mutated tumors showed longer PFS (P ¼ 0.001) and OS (P ¼ 0.001). In contrast, among the subset of 74 IDH wild-type lower-grade gliomas with intact 1p/19q, TERT promoter mutation was associated with shorter PFS (P ¼ 0.001) and OS (P ¼ 0.001). Similarly, in the subset of 65 IDH wild-type astrocytomas, 16 TERT promoter-mutated tumors exhibited unfavorable PFS (P ¼ 0.007) and OS (P ¼ 0.008). Our results indicate that when combined with IDH status, TERT promoter mutation contributes to prognostic subgroups of lower-grade astrocytic tumors or 1p/19q intact lower-grade gliomas and this may further refine future molecular classification of lower-grade gliomas.

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Loss of CIC and FUBP1 expressions are potential markers of shorter time to recurrence in oligodendroglial tumors

Cited by 49 publications

References 32 publications

Cic Loss Promotes Gliomagenesis via Aberrant Neural Stem Cell Proliferation and Differentiation

Cic Loss Promotes Gliomagenesis via Aberrant Neural Stem Cell Proliferation and Differentiation

Molecular Testing of Brain Tumor

TERT promoter mutations contribute to subset prognostication of lower-grade gliomas

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