Isocitrate Dehydrogenase 1 Mutation In Gliomas Research Articles

A qBOLD-based clinical radiomics-integrated model for predicting isocitrate dehydrogenase-1 mutation in gliomas.

Quantitative blood oxygenation level-dependent (qBOLD) technique can be applied to detect tissue damage and changes in hemodynamic in gliomas. It is not known whether qBOLD-based radiomics approaches can improve the prediction of isocitrate dehydrogenase-1 (IDH-1) mutation. To establish a qBOLD-based clinical radiomics-integrated model for predicting IDH-1 mutation in gliomas. A total of 125 patients of grade II-IV glioma (IDH1 mutation: IDH1 wild-type=50:75) were divided into a training group (n=87) and a validation group (n=38). Contrast enhanced T1-weighted (CE-T1W), T2-weighted (T2W), and 3D multi-gradient-recalled-echo (MGRE) images were acquired. Radiomics features were extracted from the region of interests of each image. The feature selection and support vector machine radiomics models were established for each sequence. A clinical radiomics-integrated model was finally constructed combining the best radiomics model with age. The predictive effectiveness of the models was evaluated by area under the receiver operating characteristic curve (AUC). Brier score was used to assess overall predictive performance. Decision curve analysis and calibration curve were also conducted. The best radiomics model was CE-T1W + T2W + qBOLD with AUCs of 0.823 (95% confidence interval [CI]: 0.743-0.831) in the training group and 0.751 (95% CI: 0.655-0.794) in the validation group, respectively. The clinical radiomics-integrated model, incorporating the best radiomics model with age, showed the best predictive effectiveness with AUCs of 0.851 (95% CI 0.759-0.918) in the training group and 0.786 (95% CI 0.622-0.902) in the validation group. A clinical radiomics-integrated model that combined qBOLD parametric maps, CE-T1W, and T2W images with age achieved promising performance for predicting IDH1 mutation in glioma patients.

Association Between Oral Microbiota and Human Brain Glioma Grade: A Case-Control Study.

Gliomas are the most prevalent form of primary malignant brain tumor, which currently have no effective treatments. Evidence from human studies has indicated that oral microbiota is closely related to cancers; however, whether oral microbiota plays a role in glioma malignancy remains unclear. The present study aimed to investigate the association between oral microbiota and grade of glioma and examine the relationship between malignancy-related oral microbial features and the isocitrate dehydrogenase 1 (IDH1) mutation in glioma. High-grade glioma (HGG; n=23) patients, low-grade glioma (LGG; n=12) patients, and healthy control (HCs; n=24) participants were recruited for this case-control study. Saliva samples were collected and analyzed for 16S ribosomal RNA (rRNA) sequencing. We found that the shift in oral microbiota β-diversity was associated with high-grade glioma (p=0.01). The phylum Patescibacteria was inversely associated with glioma grade (LGG and HC: p=0.035; HGG and HC: p<0.01). The genera Capnocytophaga (LGG and HC: p=0.043; HGG and HC: p<0.01) and Leptotrichia (LGG and HC: p=0.044; HGG and HC: p<0.01) were inversely associated with glioma grades. The genera Bergeyella and Capnocytophaga were significantly more positively correlated with the IDH1 mutation in gliomas when compared with the IDH1-wild-type group. We further identified five oral microbial features (Capnocytophaga Porphyromonas, Haemophilus, Leptotrichia, and TM7x) that accurately discriminated HGG from LGG (area under the curve [AUC]: 0.63, 95% confidence interval [CI]: 0.44–0.83) and HCs (AUC: 0.79, 95% CI: 0.68–0.92). The functional prediction analysis of oral bacterial communities showed that genes involved in cell adhesion molecules (p<0.001), extracellular matrix molecule-receptor interaction (p<0.001), focal adhesion (p<0.001), and regulation of actin cytoskeleton (p<0.001) were associated with glioma grades, and some microbial gene functions involving lipid metabolism and the adenosine 5'-monophosphate-activated protein kinase signaling pathway were significantly more enriched in IDH1 mutant gliomas than compared with the IDH1-wild-type gliomas. In conclusion, our work revealed oral microbiota features and gene functions that were associated with glioma malignancy and the IDH1 mutation in glioma.

Intravoxel incoherent motion magnetic resonance imaging in predicting IDH1 gene mutations in high-grade gliomas.

Intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) has been applied to gliomas; however, the relationships between its parameters and isocitrate dehydrogenase 1 (IDH1) mutations in gliomas remain to be investigated. To investigate the value of IVIM in predicting IDH1 mutations in high-grade gliomas before surgery. A total of 72 patients with pathologically confirmed high-grade gliomas underwent conventional brain MRI and IVIM from September 2016 to May 2020. Among them, 22 cases were IDH1 mutant and 50 cases were IDH1 wild type. The independent samples t test (normal distribution and homogeneity of variance) or Mann-Whitney rank-sum test (non-normal distribution or heterogeneity of variance) was conducted, and receiver operating characteristic curves were generated to determine parameters for distinguishing IDH1-mutated from IDH1 wild-type high-grade gliomas. These parameters included apparent diffusion coefficient (ADC), true diffusivity (D), pseudo-diffusivity (D*), and perfusion fraction (f). ADC, D, and f were significantly higher in IDH1-mutated gliomas than in IDH1 wild-type gliomas (P < 0.05 for all). There was no significant difference in the D* value between the two groups (P = 0.053). The areas under the curve of ADC, D, and f in predicting IDH1 mutations in gliomas were 0.798, 0.810, and 0.823, respectively. The specificity of ADC was highest (80.0%), and the sensitivity of the f value was the highest (100.0%). IVIM can be used for the quantitative prediction of IDH1 mutations in high-grade gliomas before surgery, and the f value is the most effective.

A vaccine targeting mutant IDH1 in newly diagnosed glioma

Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma1–3. The most common IDH1 mutation in gliomas affects codon 132 and encodes IDH1(R132H), which harbours a shared clonal neoepitope that is presented on major histocompatibility complex (MHC) class II4,5. An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H)+ tumours in syngeneic MHC-humanized mice4,6–8. Here we describe a multicentre, single-arm, open-label, first-in-humans phase I trial that we carried out in 33 patients with newly diagnosed World Health Organization grade 3 and 4 IDH1(R132H)+ astrocytomas (Neurooncology Working Group of the German Cancer Society trial 16 (NOA16), ClinicalTrials.gov identifier NCT02454634). The trial met its primary safety endpoint, with vaccine-related adverse events restricted to grade 1. Vaccine-induced immune responses were observed in 93.3% of patients across multiple MHC alleles. Three-year progression-free and death-free rates were 0.63 and 0.84, respectively. Patients with immune responses showed a two-year progression-free rate of 0.82. Two patients without an immune response showed tumour progression within two years of first diagnosis. A mutation-specificity score that incorporates the duration and level of vaccine-induced IDH1(R132H)-specific T cell responses was associated with intratumoral presentation of the IDH1(R132H) neoantigen in pre-treatment tumour tissue. There was a high frequency of pseudoprogression, which indicates intratumoral inflammatory reactions. Pseudoprogression was associated with increased vaccine-induced peripheral T cell responses. Combined single-cell RNA and T cell receptor sequencing showed that tumour-infiltrating CD40LG+ and CXCL13+ T helper cell clusters in a patient with pseudoprogression were dominated by a single IDH1(R132H)-reactive T cell receptor.

Identification of MGMT promoter methylation sites correlating with gene expression and IDH1 mutation in gliomas.

O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation was reported to be an independent prognostic and predictive factor in glioma patients who received temozolomide treatment. However, the predictive value of MGMT methylation was recently questioned by several large clinical studies. The purpose of this study is to identify MGMT gene promoter CpG sites or region whose methylation were closely correlated with its gene expression to elucidate this contradictory clinical observations. The methylation status for all CpG dinucleotides in MGMT promoter and first exon region were determined in 42 Chinese glioma patients, which were then correlated with MGMT gene expression, IDH1 mutation, and tumor grade. In whole 87 CpG dinucleotides analyzed, three distinct CpG regions covering 28 CpG dinucleotides were significantly correlated with MGMT gene expression; 10 CpG dinucleotides were significantly correlated with glioma classification (p<0.05). Isocitrate dehydrogenase 1 (IDH1) mutation and MGMT gene hypermethylation significantly co-existed, but not for MGMT gene expression. The validation cohort of gliomas treated with standard of care and comparison of the CpGs we identified with the current CpGs used in clinical setting will be very important for gliomas individual medicine in the future.

A high-sensitive HMab-2 specifically detects IDH1-R132H, the most common IDH mutation in gliomas

Isocitrate dehydrogenase 1 (IDH1) mutations have been detected in gliomas and other tumors. Although IDH1 catalyzes the oxidative carboxylation of isocitrate to α-ketoglutarate (α-KG) in cytosol, mutated IDH1 proteins possess the ability to change α-KG into the oncometabolite D-2-hydroxyglutarate (D-2HG). Several monoclonal antibodies (mAbs) specific for IDH1 mutations have been established, such as H09, IMab-1, and HMab-1 against IDH1-R132H, which is the most frequent IDH1 mutation in gliomas. In this study, we established a novel high-sensitive mAb HMab-2, which reacts with IDH1-R132H but not with wild type IDH1 in ELISA. HMab-2 reacted only with IDH1-R132H, not with wild type IDH1/2 and other IDH1/2 mutants in Western-blot analysis. Furthermore, HMab-2 recognized IDH1-R132H more sensitively compared with our previously established HMab-1. HMab-2 detected endogenous IDH1-R132H protein expressed in glioblastoma in immunohistochemical analysis. HMab-2 is expected to be useful for the diagnosis of IDH1-R132H-bearing tumors.

Imaging Markers of Isocitrate Dehydrogenase-1 Mutations in Gliomas.

Stephen Price is supported with a Clinician Scientist Fellowship from the National Institute of Health Research.

IDH1 Mutation in Gliomas in Mosul City - Iraq.

BACKGROUND:IDH1 (isocitrate dehydrogenase 1) mutation might be encounter in the low grade glioma and directs the progression of the tumor to a higher grade.OBJECTIVE:To assess the frequency of IDH1 mutations in gliomas and to correlate the IDH1 positivity with the type and grade of tumors, the age and sex of the patients.MATERIAL AND METHODS:A retro– and prospective case series study. One hundred and nine cases of intracranial gliomas were collected between 2008 and 2014 from Mosul Private Laboratories and Al-Jamboree Teaching Hospitals in Mosul. IDH1 mutations were assessed immunohistochemically using anti-IDH1 R132H mouse monoclonal antibody.RESULTS:IDH1 mutation was perceived in 34.86% of gliomas. In adult gliomas, the secondary glioblastoma and the low-grade astrocytoma had the greatest values of IDH1 positivity (88.88% and 62.5% respectively), followed by oligoastrocytoma/oligodendroglioma (50.0%), and anaplastic astrocytoma (47.36%). The primary glioblastomsa showed 17.64% IDH1 positivity. Males and females expressed the IDH1 equally. While, there was no role of IDH1 in pediatric gliomas.CONCLUSION:IDH1 mutation is commonly present in adult gliomas particularly in low-grade gliomas, and secondary glioblastoma, with equal sex distribution, but it has no role in pediatric gliomas.

Comparison of immunohistochemistry, DNA sequencing and allele-specific PCR for the detection of IDH1 mutations in gliomas

Previous studies have identified mutations of the isocitrate dehydrogenase 1 (IDH1) gene in more than 70% of World Health Organization (WHO) grade II and III gliomas. The most frequent mutation leads to a specific amino acid change from arginine to histidine at codon 132 (c.395G>A, p.R132H). IDH1 mutated tumors have a better prognosis than IDH1 non-mutated tumors. The aim of our study was to evaluate and compare the methods of mIDH1 R132H immunohistochemistry, allele-specific PCR and DNA sequencing for determination of IDH1 status. We performed a retrospective study of 91 patients with WHO grade II (n=43) and III (n=48) oligodendrogliomas. A fragment of exon 4 spanning the sequence encoding the catalytic domain of IDH1, including codon 132, was amplified and sequenced using standard conditions. Allele-specific amplification was performed using two forward primers with variations in their 3' nucleotides such that each was specific for the wild-type or the mutated variant, and one reverse primer. Immunohistochemistry was performed with mouse monoclonal mIDH1 R132H. DNA was extracted from FFPE sections following macrodissection. IDH1 mutations were found in 55/90 patients (61.1%) by direct sequencing. R132H mutations were found in 47/55 patients (85.4%). The results of the allele-specific PCR positively correlated with those from DNA sequencing. Other mutations (p.R132C, p.R132S and pR132G) were found by DNA sequencing in 3, 3 and 2 tumors, respectively (8/55 patients, 14.6%). mIDH1 R132H immunostaining was found in the 47 patients presenting the R132H mutation (sensitivity 47/47, 100% for this mutation). None of the tumors presenting a wild-type IDH1 gene were stained (specificity 35/35, 100%). Our results demonstrate that immunohistochemistry using the mIDH1 R132H antibody and allele-specific amplification are highly sensitive techniques to detect the most frequent mutation of the IDH1 gene.

Establishment of a novel monoclonal antibody SMab-1 specific for IDH1-R132S mutation

Isocitrate dehydrogenase 1 (IDH1) mutations, which are early and frequent genetic alterations in gliomas, are specific to a single codon in the conserved and functionally important Arginine 132 (R132) in IDH1. We earlier established a monoclonal antibody (mAb), IMab-1, which is specific for R132H-containing IDH1 (IDH1-R132H), the most frequent IDH1 mutation in gliomas. To establish IDH1-R132S-specific mAb, we immunized mice with R132S-containing IDH1 (IDH1-R132S) peptide. After cell fusion using Sendai virus envelope, IDH1-R132S-specific mAbs were screened in ELISA. One mAb, SMab-1, reacted with the IDH1-R132S peptide, but not with other IDH1 mutants. Western-blot analysis showed that SMab-1 reacted only with the IDH1-R132S protein, not with IDH1-WT protein or IDH1 mutants, indicating that SMab-1 is IDH1-R132S-specific. Furthermore, SMab-1 specifically stained the IDH1-R132S-expressing glioblastoma cells in immunocytochemistry and immunohistochemistry, but did not react with IDH1-WT or IDH1-R132H-containing glioblastoma cells. We newly established an anti-IDH1-R132S-specific mAb SMab-1 for use in diagnosis of mutation-bearing gliomas.