Faculty Opinions recommendation of Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas.

Purpose: We evaluated the relationship between isocitrate dehydrogenase 1 (IDH1) mutation status and metabolic imaging in patients with nonenhancing supratentorial diffuse gliomas using 11C-methionine positron emission tomography (11C-MET PET). Materials and Methods: Between June 2012 and November 2017, we enrolled 86 (38 women and 48 men; mean age, 41.9 ± 13.1 years [range, 8-67 years]) patients with newly diagnosed supratentorial diffuse gliomas. All patients underwent preoperative 11C-MET PET. Tumor samples were obtained and immunohistochemically analyzed for IDH1 mutation status. Results: The mutant and wild-type IDH1 diffuse gliomas had significantly different mean maximum standardized uptake value values (2.73 [95% confidence interval, CI: 2.32-3.16] vs 3.85 [95% CI: 3.22-4.51], respectively; P = .004) and mean tumor-to-background ratio (1.90 [95% CI: 1.65-2.16] vs 2.59 [95% CI: 2.17-3.04], respectively; P = .007). Conclusions: 11C-methionine PET can noninvasively evaluate the IDH1 mutation status of patients with nonenhancing supratentorial diffuse gliomas.

Download Full-text

Study of Histomolecular Classification of Glioma-Integrating Histology and Molecular Analysis in the Diagnosis of Brain Tumors

Indian Journal of Neurosurgery ◽

10.1055/s-0038-1668469 ◽

2018 ◽

Vol 07 (02) ◽

pp. 129-134

Author(s):

Shameen Devi ◽

Michelle De Padua ◽

Iravathy Kalal

Keyword(s):

Anaplastic Astrocytoma ◽

Idh1 Mutation ◽

Tumor Type ◽

Diffuse Astrocytoma ◽

Isocitrate Dehydrogenase 1 ◽

Anaplastic Oligoastrocytoma ◽

Diffuse Gliomas ◽

Grade Ii ◽

Classification Of Gliomas

Abstract Introduction The updated 2016 classification of gliomas incorporates well-established molecular parameters into the classification of diffuse gliomas, taking into account isocitrate dehydrogenase 1 (IDH1) mutation, α-thalassemia/mental retardation syndrome X-linked (ATRX) loss, and 1p/19q co-deletion. Aim and Objectives To study IDH1 and ATRX mutations in gliomas, 1p/19q co-deletion by fluorescent in situ hybridization (FISH) in oligodendroglioma, and to correlate IDH1, ATRX, and 1p/19q with tumor type and grade. Material and Methods Total 73 cases of gliomas were diagnosed on histology and graded as astrocytoma (grades 2–4), oligodendroglioma (grades 2–3), and oligoastrocytoma (grades 2–3) by two pathologists independently. IDH mutation and ATRX expression were analyzed using immunohistochemistry in all cases whereas 1p/19q co-deletion was studied using FISH in cases with oligodendroglioma and oligoastrocytoma morphology. Results Total 48 cases of astrocytoma, 9 cases of oligoastrocytoma, and 16 cases of oligodendroglioma were included. The maximum number of IDH1 mutation cases were seen in diffuse astrocytoma (7/10; 70%) as compared with anaplastic astrocytoma (5/15; 33.33%), glioblastoma multiforme (GBM) (3/23; 13.04%) grade II oligoastrocytoma (3/6; 50%), anaplastic oligoastrocytoma (2/3; 66.67%), and oligodendroglioma grade II (7/10; 70%). ATRX loss was seen in diffuse astrocytoma grade II (6/10; 60%), anaplastic astrocytoma (6/15; 40%), oligoastrocytoma grade II (2/6; 33.33%), and anaplastic oligoastrocytoma (1/3; 33.33%). 1p/19q co-deletion was seen in oligoastrocytoma (2/2; 100%), anaplastic oligoastrocytoma (1/2; 50%), oligodendroglioma (3/4; 75%), and anaplastic oligodendroglioma (1/3; 33.33%). Six of the seven cases with 1p/19q co-deletion also showed IDH1 mutation. One of seven 1p/19q co-deleted cases had loss of expression of ATRX. Conclusion Incorporation of IDH1 mutation, ATRX loss, and 1p/19q co-deletion molecular studies help in a more accurate diagnosis and classification of gliomas.

Download Full-text

Prognostic Effect of Long Noncoding RNA NEAT1 Expression Depends on p53 Mutation Status in Cancer

Journal of Oncology ◽

10.1155/2019/4368068 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7 ◽

Cited By ~ 6

Author(s):

Masashi Idogawa ◽

Hiroshi Nakase ◽

Yasushi Sasaki ◽

Takashi Tokino

Keyword(s):

Noncoding Rna ◽

Suppressive Effect ◽

Good Prognosis ◽

P53 Mutation ◽

Wild Type ◽

Mutation Status ◽

Prognostic Effect ◽

Tumor Suppressive Function ◽

Cancer Tissues ◽

Lncrna Neat1

Recently, many studies have revealed that long noncoding RNAs (lncRNAs) play important roles in various biological and pathological processes. Our previous study reported that lncRNA NEAT1 is a direct transcriptional target of p53. NEAT1 is an essential component of paraspeckles, which have recently been identified as a novel type of nuclear compartment. Although our previous findings indicate that NEAT1 induction contributes to the tumor-suppressor function of p53, the role of NEAT1 in cancer is still controversial. In this study, we comprehensively analyzed the relationship between NEAT1 expression and p53 mutation status. Interestingly, survival analysis based on NEAT1 expression in several cancer tissues revealed that the p53 wild-type group with high NEAT1 expression had a good prognosis, while poor prognosis or no correlation between NEAT1 expression and survival was observed in the p53-mutated group. These results demonstrate that the tumor-suppressive effect of NEAT1 depends on p53 function and is consistent with our previous report showing that NEAT1 supports the tumor-suppressive function of p53. Specifically, NEAT1 seems to play a tumor-suppressive role only in the presence of wild-type p53. These results provide important clues to the roles of NEAT1 in cancer.

Download Full-text

Isocitrate dehydrogenase mutations in diffuse gliomas: clinical and aetiological implications

Journal of Clinical Pathology ◽

10.1136/jclinpath-2011-200227 ◽

2011 ◽

Vol 64 (10) ◽

pp. 835-844 ◽

Cited By ~ 33

Author(s):

R Gupta ◽

R Webb-Myers ◽

S Flanagan ◽

M E Buckland

Keyword(s):

Isocitrate Dehydrogenase ◽

Mutation Detection ◽

Diagnostic Value ◽

Mutation Status ◽

Idh Mutations ◽

Diffuse Gliomas ◽

Prognostic Implications ◽

Classification Of Gliomas ◽

Generation Sequencing

The discovery of isocitrate dehydrogenase (IDH) mutations in gliomas is one example of the large impact that next-generation sequencing is having on the understanding of tumour biology and human disease in general. IDH mutations are early and common events in the development of astrocytomas, oligodendrogliomas and oligoastrocytomas. IDH mutations are also found in some myeloid malignancies and soft tissue tumours, but are rare in other malignancies. IDH mutation detection can be incorporated into routine pathology practice via immunohistochemistry and/or standard sequencing techniques and has great diagnostic value. An emerging theme is that IDH mutation status in gliomas is of great prognostic relevance, and there are proposals to include IDH mutation status in the next iteration of the WHO classification of gliomas. The mechanisms of action(s) of mutant IDH are not fully understood, but the understanding is progressing rapidly, and may provide a mechanism to link diverse proneoplastic processes such as oxidative damage and epigenetic dysregulation. There are exciting prospects of novel therapies for glioma patients emerging from the elucidation of these mechanisms. Given the diagnostic and prognostic implications of IDH mutation, and the potential for new therapies, all gliomas should be assessed for IDH mutation status in the future.

Download Full-text

Rapid intraoperative molecular genetic classification of gliomas using Raman spectroscopy

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz008 ◽

2019 ◽

Vol 1 (1) ◽

Cited By ~ 1

Author(s):

Laurent James Livermore ◽

Martin Isabelle ◽

Ian Mac Bell ◽

Connor Scott ◽

John Walsby-Tickle ◽

...

Keyword(s):

Raman Spectroscopy ◽

Molecular Genetic ◽

Classification Model ◽

Wild Type ◽

Genetic Classification ◽

Fresh Tissue ◽

Tissue Samples ◽

Genetic Subtypes ◽

Classification Of Gliomas

Abstract Background The molecular genetic classification of gliomas, particularly the identification of isocitrate dehydrogenase (IDH) mutations, is critical for clinical and surgical decision-making. Raman spectroscopy probes the unique molecular vibrations of a sample to accurately characterize its molecular composition. No sample processing is required allowing for rapid analysis of tissue. The aim of this study was to evaluate the ability of Raman spectroscopy to rapidly identify the common molecular genetic subtypes of diffuse glioma in the neurosurgical setting using fresh biopsy tissue. In addition, classification models were built using cryosections, formalin-fixed paraffin-embedded (FFPE) sections and LN-18 (IDH-mutated and wild-type parental cell) glioma cell lines. Methods Fresh tissue, straight from neurosurgical theatres, underwent Raman analysis and classification into astrocytoma, IDH-wild-type; astrocytoma, IDH-mutant; or oligodendroglioma. The genetic subtype was confirmed on a parallel section using immunohistochemistry and targeted genetic sequencing. Results Fresh tissue samples from 62 patients were collected (36 astrocytoma, IDH-wild-type; 21 astrocytoma, IDH-mutated; 5 oligodendroglioma). A principal component analysis fed linear discriminant analysis classification model demonstrated 79%–94% sensitivity and 90%–100% specificity for predicting the 3 glioma genetic subtypes. For the prediction of IDH mutation alone, the model gave 91% sensitivity and 95% specificity. Seventy-nine cryosections, 120 FFPE samples, and LN18 cells were also successfully classified. Meantime for Raman data collection was 9.5 min in the fresh tissue samples, with the process from intraoperative biopsy to genetic classification taking under 15 min. Conclusion These data demonstrate that Raman spectroscopy can be used for the rapid, intraoperative, classification of gliomas into common genetic subtypes.

Download Full-text

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

Journal of Neurosurgery ◽

10.3171/2015.4.jns141833 ◽

2016 ◽

Vol 124 (6) ◽

pp. 1611-1618 ◽

Cited By ~ 4

Author(s):

Abudumijiti Aibaidula ◽

Wang Zhao ◽

Jin-song Wu ◽

Hong Chen ◽

Zhi-feng Shi ◽

...

Keyword(s):

Dna Sequencing ◽

Isocitrate Dehydrogenase ◽

Soft Lithography ◽

Idh1 Mutation ◽

Fluorescence Signal ◽

Wild Type ◽

Isocitrate Dehydrogenase 1 ◽

Tissue Samples ◽

Mutation Status ◽

New Approach

OBJECT 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.

Download Full-text

368 Extent of Vascular Dysregulation in Diffuse Gliomas is Determined by IDH1 Mutation Status

Neurosurgery ◽

10.1093/neuros/nyx417.368 ◽

2017 ◽

Vol 64 (CN_suppl_1) ◽

pp. 286-286

Author(s):

Zachary K Englander ◽

Craig I Horenstein ◽

Stephen G Bowden ◽

Marc Louis Otten ◽

Angela Lignelli ◽

...

Keyword(s):

Surgical Resection ◽

Residual Disease ◽

Idh1 Mutation ◽

Wild Type ◽

Mutation Status ◽

Bold Fmri ◽

Tumor Margins ◽

Vascular Dysregulation ◽

Treatment Naïve ◽

Diffuse Gliomas

Abstract INTRODUCTION Mutation of the isocitrate dehydrogenase 1 (IDH1) gene is an important prognostic marker in diffuse gliomas. IDH1 wild-type tumors have worse clinical outcomes and more invasive imaging features than their IDH1 mutant counterparts. However, the degree of glioma infiltration outside radiologically-defined tumor borders has not been quantified. Blood oxygenation level dependent (BOLD) fMRI can detect glioma-induced disruption of normal vascular regulatory function that occurs beyond conventional tumor margins. The present study quantifies the spatial extent of vascular dysregulation associated with IDH1 mutation status in patients with treatment-naïve diffuse gliomas. We hypothesized that IDH1 wild-type gliomas will have larger areas of BOLD signal abnormality in the surrounding brain tissue and will ultimately demonstrate greater residual disease following surgical resection of the tumor. METHODS BOLD maps of vascular dysregulation were generated from preoperative fMRI scans of 34 treatment-naïve patients with WHO grades II-IV gliomas. IDH1 mutation status was determined by immunohistochemical staining for the mutant IDH1 R132H protein. We directly compared the spatial overlap of vascular dysregulation measured by BOLD fMRI and the radiologically-defined tumor using the Dice coefficient. We also performed a regression analysis to compare the relationship between percent of tumor resected and fraction of residual BOLD abnormality. RESULTS >The BOLD abnormality extended further beyond the tumor margins in IDH1 wild-type gliomas than in IDH1 mutants (P = 2 × 10−8). Furthermore, after controlling for patient age, histological subtype, WHO grade, and 1p/19q co-deletion status, IDH1 mutation status remained a significant predictor of the extent of vascular dysregulation beyond the tumor margins (P = 0.0001). Finally, surgical resection eliminated a smaller fraction of the BOLD abnormality in IDH1 wild-type tumors (P = 0.0016). CONCLUSION IDH1 mutation status is a critical variable affecting extent of infiltration and the volume of residual disease following surgical resection. BOLD fMRI may be clinically useful for guiding extent of resection in diffuse gliomas.

Download Full-text

RUNX1 and REXO2 are associated with the heterogeneity and prognosis of IDH wild type lower grade glioma

Scientific Reports ◽

10.1038/s41598-021-91382-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Haiwei Wang ◽

Xinrui Wang ◽

Liangpu Xu ◽

Ji Zhang ◽

Hua Cao

Keyword(s):

Transcription Factor ◽

Low Frequency ◽

Tumor Grade ◽

The Cancer Genome Atlas ◽

Lower Grade ◽

Wild Type ◽

Lower Grade Glioma ◽

Cancer Genome Atlas ◽

Worse Prognosis ◽

Genome Atlas

AbstractBased on isocitrate dehydrogenase (IDH) alterations, lower grade glioma (LGG) is divided into IDH mutant and wild type subgroups. However, the further classification of IDH wild type LGG was unclear. Here, IDH wild type LGG patients in The Cancer Genome Atlas and Chinese Glioma Genome Atlas were divided into two sub-clusters using non-negative matrix factorization. IDH wild type LGG patients in sub-cluster2 had prolonged overall survival and low frequency of CDKN2A alterations and low immune infiltrations. Differentially expressed genes in sub-cluster1 were positively correlated with RUNX1 transcription factor. Moreover, IDH wild type LGG patients with higher stromal score or immune score were positively correlated with RUNX1 transcription factor. RUNX1 and its target gene REXO2 were up-regulated in sub-cluster1 and associated with the worse prognosis of IDH wild type LGG. RUNX1 and REXO2 were associated with the higher immune infiltrations. Furthermore, RUNX1 and REXO2 were correlated with the worse prognosis of LGG or glioma. IDH wild type LGG in sub-cluster2 was hyper-methylated. REXO2 hyper-methylation was associated with the favorable prognosis of LGG or glioma. At last, we showed that, age, tumor grade and REXO2 expression were independent prognostic factors in IDH wild type LGG.

Download Full-text

Multiple PET tracers for use in the classification of gliomas according to the 2016 WHO criteria

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa172 ◽

2020 ◽

Author(s):

Keisuke Miyake ◽

Kenta Suzuki ◽

Tomoya B Ogawa ◽

Daisuke Ogawa ◽

Tetsuhiro Hatakeyama ◽

...

Keyword(s):

Who Classification ◽

Standardized Uptake Value ◽

Metabolic Tumor Volume ◽

Who Criteria ◽

Pet Tracers ◽

Pet Tracer ◽

Positron Emission ◽

18F Fdg ◽

Classification Of Gliomas

Abstract Background The molecular diagnosis of gliomas such as isocitrate dehydrogenase (IDH) status (wild-type [wt] or mutation [mut]) is especially important in the 2016 WHO classification. Positron emission tomography (PET) has afforded molecular and metabolic diagnostic imaging. The present study aimed to define the interrelationship between the 2016 WHO classification of gliomas and the integrated data from PET images using multiple tracers, including 18F-fluorodeoxyglucose ( 18F-FDG), 11C-methionine ( 11C-MET), 18F-fluorothymidine ( 18F-FLT), and 18F-fluoromisonidazole ( 18F-FMISO). Methods This retrospective, single-center study comprised 113 patients with newly diagnosed glioma based on the 2016 WHO criteria. Patients were divided into four glioma subtypes (Mut, Codel, Wt, and glioblastoma multiforme [GBM]). Tumor standardized uptake value (SUV) divided by mean normal cortical SUV (tumor-normal tissue ratio [TNR]) was calculated for 18F-FDG, 11C-MET, and 18F-FLT. Tumor-blood SUV ratio (TBR) was calculated for 18F-FMISO. To assess the diagnostic accuracy of PET tracers in distinguishing glioma subtypes, a comparative analysis of TNRs and TBR as well as the metabolic tumor volume (MTV) were calculated by Scheffe’s multiple comparison procedure for each PET tracer following the Kruskal–Wallis test. Results The differences in mean 18F-FLT TNR and 18F-FMISO TBR were significant between GBM and other glioma subtypes (p < 0.001). Regarding the comparison between Gd-T1WI volumes and 18F-FLT MTVs or 18F-FMISO MTVs, we identified significant differences between Wt and Mut or Codel (p < 0.01). Conclusion Combined administration of four PET tracers might aid in the preoperative differential diagnosis of gliomas according to the 2016 WHO criteria.

Download Full-text