IDH1 mutant malignant astrocytomas are more amenable to surgical resection and have a survival benefit associated with maximal surgical resection

Beiko, Jason; Suki, Dima; Hess, Kenneth R.; Fox, Benjamin D.; Cheung, Vincent; Cabral, Matthew J.; Shonka, Nicole; Gilbert, Mark R.; Sawaya, Raymond; Prabhu, Sujit S.; Weinberg, Jeffrey S.; Lang, Frederick F.; Aldape, Kenneth; Sulman, Erik P.; Rao, Ganesh; McCutcheon, Ian E.; Cahill, Daniel P.

doi:10.1093/neuonc/not159

Cited by 379 publications

(281 citation statements)

References 47 publications

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“…Indeed, Beiko et al showed that resection of total IDH1 mutant malignant astrocytoma volume-i.e., both T1 enhancing and T2 hyperintense areas-was associated with a median survival longer than 9 years; in comparison, the only survival benefit in IDH1 wild-type malignant astrocytomas was associated with resection of T1 enhancing disease. 5 This study is perhaps the first to demonstrate that an understanding of tumor heterogeneity in glioblastoma is not just a basic science interest but may significantly influence how we surgically manage glioblastomas from patient to patient.…”

Section: Patel Et Al 2014mentioning

confidence: 85%

Molecular and cellular heterogeneity: the hallmark of glioblastoma

Aum

Kim

Beaumont

et al. 2014

FOC

158

105

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There has been increasing awareness that glioblastoma, which may seem histopathologically similar across many tumors, actually represents a group of molecularly distinct tumors. Emerging evidence suggests that cells even within the same tumor exhibit wide-ranging molecular diversity. Parallel to the discoveries of molecular heterogeneity among tumors and their individual cells, intense investigation of the cellular biology of glioblastoma has revealed that not all cancer cells within a given tumor behave the same. The identification of a subpopulation of brain tumor cells termed “glioblastoma cancer stem cells” or “tumor-initiating cells” has implications for the management of glioblastoma. This focused review will therefore summarize emerging concepts on the molecular and cellular heterogeneity of glioblastoma and emphasize that we should begin to consider each individual glioblastoma to be an ensemble of molecularly distinct subclones that reflect a spectrum of dynamic cell states.

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Section: Patel Et Al 2014mentioning

confidence: 85%

Molecular and cellular heterogeneity: the hallmark of glioblastoma

Aum

Kim

Beaumont

et al. 2014

FOC

158

105

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“…Moreover, specimens may be small and not representative, hampering correct diagnosis or even necessitating multiple surgical samplings to clarify final pathologic diagnosis. In addition, the surgical intervention strategy and assessment of the surgical risk-benefit balance depend on the glioma subtype (1, [9][10][11]. This implies that an intraoperative histologic diagnosis may be required, possibly delaying the surgical procedure.…”

Section: Introductionmentioning

confidence: 99%

Molecular Diagnosis of Diffuse Gliomas through Sequencing of Cell-Free Circulating Tumor DNA from Cerebrospinal Fluid

Martínez‐Ricarte

Mayor²,

Martínez‐Sáez

et al. 2018

Clinical Cancer Research

135

133

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Purpose: Diffuse gliomas are the most common primary tumor of the brain and include different subtypes with diverse prognosis. The genomic characterization of diffuse gliomas facilitates their molecular diagnosis. The anatomical localization of diffuse gliomas complicates access to tumor specimens for diagnosis, in some cases incurring high-risk surgical procedures and stereotactic biopsies. Recently, cell-free circulating tumor DNA (ctDNA) has been identified in the cerebrospinal fluid (CSF) of patients with brain malignancies. Experimental Design: We performed an analysis of IDH1, IDH2, TP53, TERT, ATRX, H3F3A, and HIST1H3B gene mutations in two tumor cohorts from The Cancer Genome Atlas (TCGA) including 648 diffuse gliomas. We also performed targeted exome sequencing and droplet digital PCR (ddPCR) analysis of these seven genes in 20 clinical tumor specimens and CSF from glioma patients and performed a histopathologic characterization of the tumors. Results: Analysis of the mutational status of the IDH1, IDH2, TP53, TERT, ATRX, H3F3A, and HIST1H3B genes allowed the classification of 79% of the 648 diffuse gliomas analyzed, into IDH-wild-type glioblastoma, IDH-mutant glioblastoma/diffuse astrocytoma and oligodendroglioma, each subtype exhibiting diverse median overall survival (1.1, 6.7, and 11.2 years, respectively). We developed a sequencing platform to simultaneously and rapidly genotype these seven genes in CSF ctDNA allowing the subclassification of diffuse gliomas. Conclusions: The genomic analysis of IDH1, IDH2, TP53, ATRX, TERT, H3F3A, and HIST1H3B gene mutations in CSF ctDNA facilitates the diagnosis of diffuse gliomas in a timely manner to support the surgical and clinical management of these patients. Clin Cancer Res; 24(12); 2812–9. ©2018 AACR.

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“…Complete resections of enhancing and nonenhancing lesions were associated with better overall outcome, suggesting the benefit of extensive resection for patients with IDH1 mutations. 3 The study also revealed that IDH1-mutant lesions displayed lower volumes of preoperative contrast enhancement but higher complete resection rates than wild-type lesions. Additionally, extensive resection in low-grade glioma predicted improved overall survival, 28 suggesting a possible survival advantage.…”

Section: Clinical Implications For Individualized Surgerymentioning

confidence: 82%

“…12,21 Patients with malignant astrocytoma with IDH1 mutations have nearly twice as long, or even 10 times longer, median overall survival compared with those without mutations. 3,34 A recent study also revealed that refinement of the classification of the 3 most common types of brain tumors could be achieved by telomerase reverse transcriptase promoter and IDH1 mutation status. 16 Mutation in the IDH1 gene mostly affects IDH1 protein, by replacing wild-type arginine in position 132 with histidine (R132H).…”

Section: Feasibility Of Microfluidicsmentioning

confidence: 99%

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Microfluidics for rapid detection of isocitrate dehydrogenase 1 mutation for intraoperative application

Aibaidula

Zhao

et al. 2016

JNS

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S equence analysis of glioblastoma found a mutation in isocitrate dehydrogenase 1 (IDH1), which mostly resulted in the replacement of wild-type arginine in position 132 with histidine (R132H). 25 Studies have reported that the IDH1 mutation is frequently detected in diffuse astrocytoma (59%-88%), anaplastic astrocytoma (52%-78%), oligodendroglioma (68%-82%), anaplastic oligodendroglioma (60%-75%), oligoastrocytoma (50%-94%), anaplastic oligoastrocytoma (66.1%-78%), and secondary glioblastomas (50%-88%), but rarely in primary glioblastomas (3%-7%).1,14 IDH1 mutation was also closely associated with young age and better clinical outcome. 34 Currently, the detection of IDH1 mutation status can be achieved by DNA-based methods, such as DNA pyrosequencing, 10 polymerase chain reaction (PCR), 13,24 and immunohistochemistry (IHC). 5 The majority of laboratories use IHC for initial screening for IDH1 mutation and, if results are negative, use DNA sequencing for less common IDH1 mutant types. DNA sequencing provides direct abbreviatioNs AUC = area under the curve; FFPE = formalin-fixed paraffin-embedded; IDH1 = isocitrate dehydrogenase 1; IHC = immunohistochemistry; PCR = polymerase chain reaction; ROC = receiver operating characteristic. obJective Conventional methods for isocitrate dehydrogenase 1 (IDH1) detection, such as DNA sequencing and immunohistochemistry, are time- and labor-consuming and cannot be applied for intraoperative analysis. To develop a new approach for rapid analysis of IDH1 mutation from tiny tumor samples, this study used microfluidics as a method for IDH1 mutation detection. methods Forty-seven glioma tumor samples were used; IDH1 mutation status was investigated by immunohistochemistry and DNA sequencing. The microfluidic device was fabricated from polydimethylsiloxane following standard soft lithography. The immunoanalysis was conducted in the microfluidic chip. Fluorescence images of the on-chip microcolumn taken by the charge-coupled device camera were collected as the analytical results readout. Fluorescence signals were analyzed by NIS-Elements software to gather detailed information about the IDH1 concentration in the tissue samples. results DNA sequencing identified IDH1 R132H mutation in 33 of 47 tumor samples. The fluorescence signal for IDH1-mutant samples was 5.49 ± 1.87 compared with 3.90 ± 1.33 for wild type (p = 0.005). Thus, microfluidics was capable of distinguishing IDH1-mutant tumor samples from wild-type samples. When the cutoff value was 4.11, the sensitivity of microfluidics was 87.9% and the specificity was 64.3%. coNclusioNs This new approach was capable of analyzing IDH1 mutation status of tiny tissue samples within 30 minutes using intraoperative microsampling. This approach might also be applied for rapid pathological diagnosis of diffuse gliomas, thus guiding personalized resection.

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IDH1 mutant malignant astrocytomas are more amenable to surgical resection and have a survival benefit associated with maximal surgical resection

Cited by 379 publications

References 47 publications

Molecular and cellular heterogeneity: the hallmark of glioblastoma

Molecular and cellular heterogeneity: the hallmark of glioblastoma

Molecular Diagnosis of Diffuse Gliomas through Sequencing of Cell-Free Circulating Tumor DNA from Cerebrospinal Fluid

Microfluidics for rapid detection of isocitrate dehydrogenase 1 mutation for intraoperative application

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