Isocitrate dehydrogenase 1 mutant glioblastomas demonstrate a decreased rate of pseudoprogression: a multi-institutional experience
Homan MohammadiKevin ShiueG. Daniel GrassVivek VermaKay EngellandtDirk DaubnerGabriele SchackertMercia GondimDibson D. GondimAlexander O. VortmeyerAaron KamerWilliam JinTimothy J. RobinsonGordon A. WatsonYa-Yu TsaiTim Lautenschlaeger
5
Citation
41
Reference
10
Related Paper
Citation Trend
Abstract:
Abstract Background Pseudoprogression (psPD) represents false radiologic evidence of tumor progression and is observed in some glioblastoma (GBM) patients after postoperative chemoradiation (CRT) with temozolomide (TMZ). The ambiguity of the psPD diagnosis confounds identification of true progression and may lead to unnecessary interventions. The association between psPD and isocitrate dehydrogenase 1 (IDH1) mutational (mut) status is understudied, and its incidence may alter clinical decision making. Methods We retrospectively evaluated 120 patients with IDH1-mut (n = 60) and IDH1–wild-type (IDH-WT; [n = 60]) GBMs who received postoperative CRT with TMZ at 4 academic institutions. Response Assessment in Neuro-Oncology criteria were used to identify psPD rates in routine brain MRIs performed up to 90 days after CRT completion. Results Within 90 days of completing CRT, 9 GBM patients (1 [1.7%] IDH1-mut and 8 [13.3%] IDH1-WTs) demonstrated true progression, whereas 17 patients (3 [5%] IDH1-muts and 14 [23.3%] IDH1-WTs) demonstrated psPD (P = .004). IDH1-mut GBMs had a lower probability of psPD (hazard ratio: 0.173, 95% CI, 0.047-0.638, P = .008). Among the patients with radiologic signs suggestive of progression (n = 26), psPD was found to be the cause in 3 of 4 (75.0%) of the IDH1-mut GBMs and 14 of 22 (63.6%) of the IDH1-WT GBMs (P = .496). Median overall survival for IDH1-mut and IDH1-WT GBM patients was 40.3 and 23.0 months, respectively (P < .001). Conclusions IDH1-mut GBM patients demonstrate lower absolute rates of psPD expression. Irrespective of GBM subtype, psPD expression was more likely than true progression within 90 days of completing CRT. Continuing adjuvant treatment for IDH1-mut GBMs is suggested if radiologic progression is suspected during this time interval.Keywords:
Isocitrate dehydrogenase
Temozolomide
IDH2
Isocitrate dehydrogenase
Cite
Citations (213)
Introduction . Glioblastoma multiforme (GBM) is the most malignant primary brain tumor in adults. Recent whole-genome studies revealed novel GBM prognostic biomarkers such as mutations in metabolic enzyme IDH—isocitrate dehydrogenases (IDH1 and IDH2). The distinctive mutation IDH1 R132H was uncovered to be a strong prognostic biomarker for glioma patients. We investigated the prognostic role of IDH1 R132H mutation in GBM patients in West Bohemia. Methods . The IDH1 R132H mutation was assessed by the RT-PCR in the tumor samples from 45 GBM patients treated in the Faculty Hospital in Pilsen and was correlated with the progression free and overall survival. Results . The IDH1 R132H mutation was identified in 20 from 44 GBM tumor samples (45.4%). The majority of mutated tumors were secondary GBMs (16 in 18, 89.9%). Low frequency of IDH1 mutations was observed in primary GBMs (4 in 26, 15.3%). Patients with IDH R132H mutation had longer PFS, 136 versus 51 days (P < 0.021 P < 0.024
Isocitrate dehydrogenase
Cite
Citations (28)
Isocitrate dehydrogenase
Cite
Citations (7)
A recent cancer genome-sequencing project revealed that that novel point mutations in isocitrate dehydrogenase 1(IDH1) in the majority of gliomas at WHO Grade Ⅱ and Ⅲ and secondary glioblastomas at grade IV.IDH1 mutations are early events in the development of gliomas,and are related with prolonged survival in gliomas at various grades.Mutated IDH1 shows an altered catalytic activity that results in the elevated levels of α-ketoglutarate and 2-hydroxyglutarate.The correlations among the gliomas pathological diagnosis,tumor genesis,the therapeutic potential for targeting mutant IDH enzymes are discussed in this review.
Isocitrate dehydrogenase
IDH2
Cite
Citations (0)
Isocitrate dehydrogenase
IDH2
Myeloid leukaemia
Cite
Citations (9)
Background: The gene mutation of isocitrate dehydrogenase-1 (IDH1) is commonly found in LGG and some GBM patients and usually carries tumor protein 53 (TP53) mutations. However, the underlying mechanisms on both mutations of glioma patients in IDH1 and TP53 are still unclear. Aim: To find the potential target markers in GBM and LGG patients with IDH1 and TP53 mutation.Method: A total of 1122 glioma patients from The Cancer Genome Atlas were enrolled and divided as wild-type (without IDH1 and TP53 mutations) or both mutant (both IDH1 and TP53 mutations). The data of clinicopathological characteristics, mRNA, mutations, and copy number alteration were analyzed. Results: IDH1 and TP53 mutations, not gene expression, affect the survival probability of GBM and LGG patients, which might be related to neuron function, immune function, tumor invasion, and metastasis. The effects of the selected gene (EMILIN3, SAA1, VSTM2A, HAMP, IFT80, and CHIC2) on glioma patients could be regulated by IDH1 and TP53 mutations and had a higher survival possibility in these patients. Conclusions: The selected genes in GBM and LGG patients with IDH1 and TP53 mutations could be a potential prognosis marker in the future.
Isocitrate dehydrogenase
Tumor progression
Cite
Citations (1)
Isocitrate dehydrogenase 1 (IDH1) mutations have been discovered to be frequent and highly conserved in secondary glioblastoma multiforme and lower-grade gliomas. Although IDH1 mutations confer a unique genotype that has been associated with a favorable prognosis, the role of the mutated IDH1 enzyme and its metabolites in tumor initiation and maintenance remains unresolved. However, given that IDH1 mutations are homogeneously expressed and are limited solely to tumor tissue, targeting this mutation could potentially yield novel treatment strategies for patients with glioblastoma multiforme.
Isocitrate dehydrogenase
Cite
Citations (19)
We explored whether spontaneous imaging tumor growth (estimated by the velocity of diametric expansion) and isocitrate dehydrogenase 1 (IDH1) mutation (estimated by IDH1 immunoexpression) were independent predictors of long-term outcomes of diffuse low-grade gliomas in adults.
Isocitrate dehydrogenase
Cite
Citations (53)
Purpose of review Isocitrate dehydrogenases, IDH1 and IDH2, decarboxylate isocitrate to α-ketoglutarate (α-KG) and reduce NADP to NADPH. Point mutations of IDH1 and IDH2 have been discovered in gliomas. IDH mutations cause loss of native enzymatic activities and confer novel activity of converting α-KG to 2-hydroxyglutarate (2-HG). The mechanisms of IDH mutations in gliomagenesis, and their value as diagnostic, prognostic marker and therapeutic target have been extensively studied. This review is to summarize the findings of these studies. Recent findings Crystal structural studies revealed conformation changes in mutant IDHs, which may explain the gain of function by mutant IDHs. The product of mutant IDHs, 2-HG, is an inhibitor of α-KG-dependent dioxygenases, which may cause genome-wide epigenetic changes in human gliomas. IDH mutations are a favorable prognostic factor for human glioma and can be used as biomarker for differential diagnosis and subclassification rather than predictor of response to treatment. Preliminary data suggested that inhibiting production of the substrate of mutant IDH enzymes caused slow-down of glioma cell growth. Summary As valuable diagnostic and prognostic markers of human gliomas, there is still a lack of knowledge on biological functions of mutant IDHs, making targeting IDHs in glioma both difficult and unsecured.
Isocitrate dehydrogenase
IDH2
Cite
Citations (84)
A mutation in IDH1, which encodes an isocitrate dehydrogenase, is associated with susceptibility to glioma. This mutation results in an acquired enzyme activity that points to a potential biomarker of the mutant tumor.
Isocitrate dehydrogenase
IDH2
Cite
Citations (16)