IDH1 and IDH2 Mutations Are Prognostic but not Predictive for Outcome in Anaplastic Oligodendroglial Tumors: A Report of the European Organization for Research and Treatment of Cancer Brain Tumor Group

Abstract

Purpose: Recent studies have shown the prognostic significance of IDH1 mutations in glioma. It is yet unclear if IDH1 mutations are predictive for outcome to chemotherapy. We determined the effect of IDH1 mutations on progression-free survival and overall survival (OS), and its correlation with other clinical and molecular features in the prospective randomized European Organization for Research and Treatment of Cancer study 26951 on adjuvant procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-L-nitrosourea, and vincristine (PCV) in anaplastic oligodendroglioma.Experimental Design: IDH1 and IDH2 alterations of the mutational hotspot codons R132 and R172 were assessed by the bidirectional cycle sequencing of PCR-amplified fragments. MGMT promoter methylation was assessed using methylation-specific multiplex ligation-dependant probe amplification based on methylation-sensitive restriction analysis. Loss of chromosomes 1p, 19q, 10, and 10q and the gain of 7 and the EGFR gene were assessed with fluorescence in situ hybridization.Results: From 159 patients, sufficient material was available for IDH1 analysis. In 151 and 118 of these patients, respectively, the 1p/19q status and the MGMT promoter methylation status were known. In 73 cases (46%), an IDH1 mutation was found and only one IDH2 mutation was identified. The presence of IDH1 mutations correlated with 1p/19q codeletion and MGMT promoter methylation, and inversely correlated with loss of chromosome 10, EGFR amplification, polysomy of chromosome 7, and the presence of necrosis. IDH1 mutations were found to be prognostic in the radiotherapy-and the radiotherapy/PCVtreated patients, for both progression-free survival and OS. With Cox proportional hazard modeling for OS with stepwise selection, IDH1 mutations and 1p/19q codeletion but not MGMT promoter methylation were independent prognostic factors.Conclusion: In this homogeneously treated group of anaplastic oligodendroglioma patients, the presence of IDH1 mutations was found to carry a very strong prognostic significance for OS but without evidence of a predictive significance for outcome to PCV chemotherapy. IDH1 mutations were strongly associated with 1p/ 19q codeletion and MGMT promoter methylation. Clin Cancer Res; 16(5); 1597-604. ©2010 AACR.

Prognostic value of preoperative von Willebrand factor plasma levels in patients with Glioblastoma

“…Several clinical predictors of survival have been identified, such as age, preoperative functional status, and tumor extent 22. In addition, some genetic and epigenetic features may be used as prognostic factors 2, 3. Nevertheless, despite many efforts to treat this disease, the mortality rate remains high, recurrence seems to be the rule, and still the outcome is invariably fatal.…”

“…Putative genetic and epigenetic prognostic factors have been investigated in order to optimize treatment strategies. These include 1p/19q codeletion, isocitrate dehydrogenase (IDH) 1 and 2 gene ( IDH1/2 ) mutations, and methylation of the O(6)‐methylguanine‐DNA methyltransferase (MGMT) promoter 2, 3, which confer a better responsiveness to radio‐ and chemotherapy 4, 5, 6, even the disease is still incurable. A prominent feature of GBM is the aberrant angiogenesis.…”

Significance of complete 1p/19q co-deletion, IDH1 mutation and MGMT promoter methylation in gliomas: use with caution

“…All three markers are considered as indicators of favorable prognosis. [6][7][8][9] MGMT hypermethylation status is already included in the nomogram for predicting survival of patients with newly diagnosed glioblastoma, and IDH1/2 mutation was shown to be a reliable genetic marker of secondary glioblastomas and their precursor lesions. [10][11][12] In contrast, the presence of other markers such as loss of PTEN and CDKN2A and amplification of EGFR are reported to be indicative for more aggressive tumor behavior.…”

Molecular Investigation of Isocitrate Dehydrogenase Gene (IDH) Mutations in Gliomas: First Report of IDH2 Mutations in Indian Patients

“…In this context, identification of mutations in the isocitrate dehydrogenase (IDH1/ IDH2) either in the R132 or R172 residues were recently highlighted, and has already become a molecular marker of significant diagnostic and prognostic relevance in the assessment of human gliomas (Parsons et al, 2008;Yan et al, 2009). Mutations of the IDH1 R132 are reported in 55-80% of grade II/III oligodendroglioma/astrocytomas, over 90% of secondary glioblastomas (GBMs), rarely in primary glioblastoma (Van den Bent et al, 2010), and are associated with favorable prognosis (Uno et al, 2011). In contrast IDH2 mutations are rare, but more common in oligodendroglial tumors, as compared to astrocy¬tomas (Raynaud et al, 2010 protective mechanism in glioma patients which could be the reason for better outcome in patients with mutant IDH than those with the wild-type IDH genes (Zhu et al, 2011).…”

“…In contrast IDH2 mutations are rare, but more common in oligodendroglial tumors, as compared to astrocy¬tomas (Raynaud et al, 2010 protective mechanism in glioma patients which could be the reason for better outcome in patients with mutant IDH than those with the wild-type IDH genes (Zhu et al, 2011). Most of the available studies on IDH1 and 2 mutations are reported from western countries (Bleeker et al, 2009;Metellus et al, 2010;Van den Bent et al, 2010;Cykowski et al, 2012), few reports from Asia (Mukasa et al, 2012;Song Tao et al, 2012), while there is only one report of IDH1 mutations in Indian glioma patients (Jha et al, 2011). In the current study we evaluated IDH1 and IDH2 mutations in glioma patients of different histological types and grades with the aim of assessing their frequency, distribution pattern and their correlation with clinicopathological findings.…”