IDH1/IDH2 Mutations Define the Prognosis and Molecular Profiles of Patients with Gliomas: A Meta-Analysis

et al. (2013) IDH1/IDH2 Mutations Define the Prognosis and Molecular Profiles of Patients with Gliomas: A Meta- Analysis. PLoS ONE 8(7): e68782. doi:10.1371/journal.pone.0068782 IDH1/IDH2 Mutations Define the Prognosis and Molecular Profiles of Patients with Gliomas: A Meta- Analysis Peng Zou 0 Haitao Xu 0 Pin Chen 0 Qing Yan 0 Lin Zhao 0 Peng Zhao 0 Aihua Gu 0 Isaac Yang, UCLA, United States of America 0 1 Department of Neurosurgery, The First Affiliated Hospital, Nanjing Medical University , Nanjing , China , 2 School of Public Health, Nanjing Medical University , Nanjing , China Background: Isocitrate dehydrogenase isoforms 1 and 2 (IDH1 and IDH2) mutations have received considerable attention since the discovery of their relation with human gliomas. The predictive value of IDH1 and IDH2 mutations in gliomas remains controversial. Here, we present the results of a meta-analysis of the associations between IDH mutations and both progression-free survival (PFS) and overall survival (OS) in gliomas. The interrelationship between the IDH mutations and MGMT promoter hypermethylation, EGFR amplification, codeletion of chromosomes 1p/19q and TP53 gene mutation were also revealed. Methodology and Principal Findings: An electronic literature search of public databases (PubMed, Embase databases) was performed. In total, 10 articles, including 12 studies in English, with 2,190 total cases were included in the meta-analysis. The IDH mutations were frequent in WHO grade II and III glioma (59.5%) and secondary glioblastomas (63.4%) and were less frequent in primary glioblastomas (7.13%). Our study provides evidence that IDH mutations are tightly associated with MGMT promoter hypermethylation (P,0.001), 1p/19q codeletion (P,0.001) and TP53 gene mutation (P,0.001) but are mutually exclusive with EGFR amplification (P,0.001). This meta-analysis showed that the combined hazard ratio (HR) estimate for overall survival and progression-free survival in patients with IDH mutations was 0.33 (95% CI: 0.25-0.42) and 0.38 (95% CI: 0.21-0.68), compared with glioma patients whose tumours harboured the wild-type IDH. Subgroup analyses based on tumour grade also revealed that the presence of IDH mutations was associated with a better outcome. Conclusion: Our study suggests that IDH mutations, which are closely linked to the genomic profile of gliomas, are potential prognostic biomarkers for gliomas. - Funding: This work was supported by the National Natural Science Foundation of China (grant No. 81172694); the Grant for the 135 Key Medical Project of Jiangsu Province (No. XK201117); the practice innovation training program projects for the Jiangsu College students; and the Priority Academic Program Development of Jiangsu Higher Education Institutions. The funders had no role in study design, data collection and analysis. Competing Interests: The authors have declared that no competing interests exist. Gliomas, which are the most common primary intracranial tumours, are classified as grade I to grade IV, according to the 2007 WHO Classification of Tumours of the Central Nervous System [1]. Despite advances in diagnostic and therapeutic techniques, the prognosis for most glioma patients remains dismal. Histomorphological criteria alone are not sufficient to predict the clinical outcome of gliomas. Thus, new avenues must be taken to integrate the molecular advances with the histological assessment of gliomas. Recently, the sequencing of human gliomas has identified mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes [24]. IDH mutations are relatively glioma-specific. However, IDH1 and IDH2 mutations are also found in acute myeloid leukaemia (AML) [5]. The IDH gene mutations are found frequently in malignant gliomas and are likely to be involved in the early stage of gliomagenesis, even before TP53 mutations or loss of 1p and 19q [6]. The IDH1 mutations occur in the highly conserved residue R132, which is in the catalytic domain, where it binds to its substrate. The mutations in IDH2 consistently occur at the analogous amino acid R172 [7], which is functionally equivalent to amino acid 132 of IDH1. IDH1 mutations have been found in approximately 80% of grades II-III gliomas and secondary glioblastomas but have been found in less than 10% of primary glioblastomas [2,4,6]. The IDH2 mutations have also been described in gliomas, although at a lower frequency [4,8]. The IDH1 and IDH2 enzymes catalyse oxidative decarboxylation of isocitrate into a-ketoglutarate (aKG), thereby reducing NADP to NADPH [9,10]. The tumourigenic potential of a mutant IDH protein is under intense investigation. First, a heterozygous point mutation in codon 132 impairs the interaction of the enzyme with isocitrate both sterically and electrostatically, and the mutant IDH1 molecules dominantly inhibit the activity of wild-type IDH1 by forming a catalytically inactive heterodimer [11]. Second, the mutations cause reduced formation of aKG and decreased cytoplasmic levels of aKG increase levels of hypoxia-inducible factor subunit HIF-1alpha [1113], a component of the hypoxiaresponsive transcription factor complex that facilitates tumour angiogenesis and growth. Third, heterozygous IDH mutations confer neomorphic enzyme activity rather than inactivating the enzyme; the mutant enzyme converts aKG to 2-hydroxyglutarate (2-HG) in the process of consuming NADPH [14]. The excess accumulation of 2-HG has been shown to be associated with tumour progression and leads to an elevated risk of malignant gliomas [14,15]. Recently, an increasing number of studies have evaluated the relative prognostic impact of IDH mutations and the clinical outcome of gliomas [1625], with conflicting results due to the relatively small sample sizes in the studies. Here, we performed a meta-analysis to further clarify the prevalence of IDH mutations, their relationship to other genetic alterations and their impact on prognosis for glioma patients. Identification of relevant studies A comprehensive literature search of the PubMed and Embase databases (last search updated in October 2012) was conducted to identify all studies that analysed the prognostic role of IDH mutations in patients with gliomas. The following keywords were used in various combinations: prognosis, prognostic, survival, IDH1 and IDH2. The reference lists from the relevant original articles and review articles were also examined for additional relevant publications. Study eligibility The studies eligible for inclusion in this meta-analysis had to meet the following criteria: (1) proven diagnosis of gliomas in humans; (2) evaluate the association between IDH mutations and the prognosis of glioma patients, e.g., progression-free survival (PFS) and overall survival (OS); (3) have a hazard ratio (HR) for OS or PFS, according to IDH mutations, either reported directly in the study or calculated from the data presented; (4) be the most recent or complete report if th (...truncated)