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Idh mutant glioma

Shigeo Ohba, Joydeep Mukherjee, Tor-Christian Johannessen, Andrew Mancini, Tracy T Chow, Matthew Wood, Lindsey Jones, Tali Mazor, Roxanne E Marshall, Pavithra Viswanath, Kyle M Walsh, Arie Perry, Robert J A Bell, Joanna J Phillips, Joseph F Costello, Sabrina M Ronen, Russell O Pieper
Mutations in the isocitrate dehydrogenase gene IDH1 are common in lower-grade glioma where they result in the production of 2-hydroxyglutarate (2HG), disrupted patterns of histone methylation and gliomagenesis. IDH1 mutations also co-segregate with mutations in the ATRX gene and the TERT promoter, suggesting that IDH mutation may drive the creation or selection of telomere-stabilizing events as part of immortalization/transformation process. To determine if and how this may occur, we investigated the phenotype of pRb/p53-deficient human astrocytes engineered with IDH1 wild-type (WT) or R132H mutant (IDH1mut) genes as they progressed through their lifespan...
October 6, 2016: Cancer Research
Andreas Maus, Godefridus J Peters
Glioblastoma multiforme (GBM), or grade IV astrocytoma, is the most common type of primary brain tumor. It has a devastating prognosis with a 2-year-overall survival rate of only 26 % after standard treatment, which includes surgery, radiation, and adjuvant chemotherapy with temozolomide. Also lower grade gliomas are difficult to treat, because they diffusely spread into the brain, where extensive removal of tissue is critical. Better understanding of the cancer's biology is a key for the development of more effective therapy approaches...
October 17, 2016: Amino Acids
Wen Cheng, Xiufang Ren, Chuanbao Zhang, Jinquan Cai, Sheng Han, Anhua Wu
Isocitrate dehydrogenase (IDH)1 mutation is one of the most important genetic aberrations in glioma. Even several genetic events have refined its prognostic value, the genome-wide expression alteration has not been systematically profiled. In this work, RNA-seq expression data from 310 patients in the Chinese Glioma Genome Atlas database were included as training set, while another 297 patients with microarray data were used as internal validation set. An independent cohort of GSE16011 (n = 205) constituted an external validation set...
September 30, 2016: Molecular Neurobiology
Gaurav Verma, Suyash Mohan, MacLean P Nasrallah, Steven Brem, John Y K Lee, Sanjeev Chawla, Sumei Wang, Rajakumar Nagarajan, M Albert Thomas, Harish Poptani
BACKGROUND: Mutations in the isocitrate dehydrogenase enzyme are present in a majority of lower-grade gliomas and secondary glioblastomas. This mis-sense mutation results in the neomorphic reduction of isocitrate dehydrogenase resulting in an accumulation of the "oncometabolite" 2-hydroxyglutarate (2HG). Detection of 2HG can thus serve as a surrogate biomarker for these mutations, with significant translational implications including improved prognostication. Two dimensional localized correlated spectroscopy (2D L-COSY) at 7T is a highly-sensitive non-invasive technique for assessing brain metabolism...
2016: Journal of Translational Medicine
Emeline Tabouret, Anh Tuan Nguyen, Caroline Dehais, Catherine Carpentier, François Ducray, Ahmed Idbaih, Karima Mokhtari, Anne Jouvet, Emmanuelle Uro-Coste, Carole Colin, Olivier Chinot, Hugues Loiseau, Elisabeth Moyal, Claude-Alain Maurage, Marc Polivka, Emmanuèle Lechapt-Zalcman, Christine Desenclos, David Meyronet, Jean-Yves Delattre, Dominique Figarella-Branger
The new WHO classification of diffuse gliomas has been refined and now includes the 1p/19q codeletion, IDH1/2 mutation, and histone H3-K27M mutation. Our objective was to assess the prognostic value of the updated 2016 WHO classification in the French POLA cohort. All cases of high-grade oligodendroglial tumors sent for central pathological review and included into the French nationwide POLA cohort were reclassified according to the updated 4th WHO classification. In total, 1041 patients were included, with a median age at diagnosis of 50...
October 2016: Acta Neuropathologica
Xing Chen, Hongmei Wang, Weibing Yu, Fen Chen, Guiyun Wang, Jiajia Shi, Chunying Zhou
Isocitrate dehydrogenase 1 (IDH1), one member of the IDH family can convert isocitrate to α-ketoglutarate (α-KG) via oxidative decarboxylation. IDH1 and IDH2 mutations have been identified in multiple tumor types and the mutations confer neomorphic activity in the mutant protein, resulting in the conversion of α-KG to the oncometabolite, D-2-hydroxyglutarate (2-HG). The subsequent accumulation of 2-HG results in epigenetic dysregulation via inhibition of α-KG-dependent histone and DNA demethylase. And the glutamate levels are reduced in IDH mutant cells compared to wild-type...
August 27, 2016: Cellular and Molecular Neurobiology
Franck Bielle, François Ducray, Karima Mokhtari, Caroline Dehais, Homa Adle-Biassette, Catherine Carpentier, Anaïs Chanut, Marc Polivka, Sylvie Poggioli, Shaï Rosenberg, Marine Giry, Yannick Marie, Charles Duyckaerts, Marc Sanson, Pola Network, Dominique Figarella-Branger, Ahmed Idbaih
The integrated diagnosis of anaplastic oligodendroglioma, IDH mutant and 1p/19q co-deleted, grade III (O3(id) ) is a histomolecular entity that WHO 2016 classification distinguished from other diffuse gliomas by specific molecular alterations. In contrast, its cell portrait is less well-known. The present study is focused on intertumor and intratumor, cell lineage-oriented, heterogeneity in O3(id) . Based on pathological, transcriptomic and immunophenotypic studies, a novel subgroup of newly diagnosed O3(id) overexpressing neuronal intermediate progenitor (NIP) genes was identified...
August 20, 2016: Brain Pathology
Sanne A M van Lith, Anna C Navis, Krissie Lenting, Kiek Verrijp, Jan T G Schepens, Wiljan J A J Hendriks, Nil A Schubert, Hanka Venselaar, Ron A Wevers, Arno van Rooij, Pieter Wesseling, Remco J Molenaar, Cornelis J F van Noorden, Stefan Pusch, Bastiaan Tops, William P J Leenders
The majority of low-grade and secondary high-grade gliomas carry heterozygous hotspot mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) or the mitochondrial variant IDH2. These mutations mostly involve Arg132 in IDH1, and Arg172 or Arg140 in IDH2. Whereas IDHs convert isocitrate to alpha-ketoglutarate (α-KG) with simultaneous reduction of NADP(+) to NADPH, these IDH mutants reduce α-KG to D-2-hydroxyglutarate (D-2-HG) while oxidizing NADPH. D-2-HG is a proposed oncometabolite, acting via competitive inhibition of α-KG-dependent enzymes that are involved in metabolism and epigenetic regulation...
2016: Scientific Reports
Kourosh Jafari-Khouzani, Franziska Loebel, Wolfgang Bogner, Otto Rapalino, Gilberto R Gonzalez, Elizabeth Gerstner, Andrew S Chi, Tracy T Batchelor, Bruce R Rosen, Jan Unkelbach, Helen A Shih, Daniel P Cahill, Ovidiu C Andronesi
BACKGROUND: Gliomas with mutant isocitrate dehydrogenase (IDH) produce high levels of 2-hydroxyglutarate (2HG) that can be quantitatively measured by 3D magnetic resonance spectroscopic imaging (MRSI). Current glioma MRI primarily relies upon fluid-attenuated inversion recovery (FLAIR) hyperintensity for treatment planning, although this lacks specificity for tumor cells. Here, we investigated the relationship between 2HG and FLAIR in mutant IDH glioma patients to determine whether 2HG mapping is valuable for radiotherapy planning...
July 5, 2016: Neuro-oncology
Takeo Fujii, Muhammad Rizwan Khawaja, Courtney D DiNardo, Johnique T Atkins, Filip Janku
Isocitrate dehydrogenase (IDH) is an essential enzyme for cellular respiration in the tricarboxylic acid (TCA) cycle. Recurrent mutations in IDH1 or IDH2 are prevalent in several cancers including glioma, acute myeloid leukemia (AML), cholangiocarcinoma and chondrosarcoma. The mutated IDH1 and IDH2 proteins have a gain-of-function, neomorphic activity, catalyzing the reduction of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG) by NADPH. Cancer-associated IDH mutations block normal cellular differentiation and promote tumorigenesis via the abnormal production of the oncometabolite 2-HG...
May 2016: Discovery Medicine
Juliya Kalinina, Jun Ahn, Narra S Devi, Liya Wang, Yuancheng Li, Jeffrey J Olson, Michael Glantz, Thomas Smith, Ella Kim, Alf Giese, Randy L Jensen, Clark Chen, Bob Carter, Hui Mao, Miao He, Erwin G Van Meir
PURPOSE: Elevation in D-2-Hydroxyglutarate (D-2HG) has recently emerged as a mandatory byproduct of mutated Isocitrate Dehydrogenase (IDH) genes 1 and 2 in glioma patients. The goal of the present study was to demonstrate the feasibility of detection of elevated levels of D-2HG in the cerebrospinal fluid (CSF) of glioma patients that carry point substitutions in the IDH gene. EXPERIMENTAL DESIGN: We developed a Mass Spectroscopy (MS)-based platform to detect and quantify the D- and L-forms of 2HG in the CSF of glioma patients...
June 23, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Jiao Chen, Jie Yang, Peng Cao
Isocitrate dehydrogenase (IDH) is a metabolic enzyme that converts isocitrate to α-ketoglutarate (α-KG). Genetic gain-of-function mutations in IDH1 and IDH2 confers a neomorphic activity that allows reduction of α-KG to (R)-2-hydroxyglutarate, the accumulation of which results in the development of cancers like low grade gliomas and leukemia. After treatment with AG-221 in clinical trials, a first-in-class inhibitor of mutated IDH2, 29 patients with acute myeloid leukemia or myelodysplastic syndrome experience complete remissions and the overall response rate is 59/159 (37%)...
June 8, 2016: Mini Reviews in Medicinal Chemistry
Yavuz Oktay, Ege Ülgen, Özge Can, Cemaliye B Akyerli, Şirin Yüksel, Yiğit Erdemgil, I Melis Durası, Octavian Ioan Henegariu, E Paolo Nanni, Nathalie Selevsek, Jonas Grossmann, E Zeynep Erson-Omay, Hanwen Bai, Manu Gupta, William Lee, Şevin Turcan, Aysel Özpınar, Jason T Huse, M Aydın Sav, Adrienne Flanagan, Murat Günel, O Uğur Sezerman, M Cengiz Yakıcıer, M Necmettin Pamir, Koray Özduman
The single nucleotide polymorphism rs55705857, located in a non-coding but evolutionarily conserved region at 8q24.21, is strongly associated with IDH-mutant glioma development and was suggested to be a causal variant. However, the molecular mechanism underlying this association has remained unknown. With a case control study in 285 gliomas, 316 healthy controls, 380 systemic cancers, 31 other CNS-tumors, and 120 IDH-mutant cartilaginous tumors, we identified that the association was specific to IDH-mutant gliomas...
2016: Scientific Reports
Ming Zhang, Yi Pan, Xueling Qi, Yan Liu, Rongfang Dong, Danfeng Zheng, Qing Chang, Jing Zhang, Weigang Fang, Yanfeng Zhong
BACKGROUND: Isocitrate dehydrogenase (IDH) mutations have been reported as biomarkers associated with tumorigenesis and prognosis in gliomas. However, genes affected by these mutations are still under investigation. The purpose of this study is to identify new molecular biomarkers associated with IDH mutation and prognosis in astrocytic tumors, which account for the largest proportion of gliomas. MATERIALS AND METHODS: NanoString analysis was conducted on 40 astrocytic tumors...
June 2, 2016: Applied Immunohistochemistry & Molecular Morphology: AIMM
Natsuki Hattori, Yuichi Hirose, Hikaru Sasaki, Shunsuke Nakae, Saeko Hayashi, Shigeo Ohba, Kazuhide Adachi, Takuro Hayashi, Yuya Nishiyama, Mitsuhiro Hasegawa, Masato Abe
Recent investigations revealed genetic analysis provides important information in management of gliomas, and we previously reported grade II-III gliomas could be classified into clinically relevant subgroups based on the DNA copy number aberrations (CNAs). To develop more precise genetic subgrouping, we investigated the correlation between CNAs and mutational status of the gene encoding isocitrate dehydrogenase (IDH) of those tumors. We analyzed the IDH status and CNAs of 174 adult supratentorial gliomas of astrocytic or oligodendroglial origin by PCR-based direct sequencing and comparative genomic hybridization, respectively...
August 2016: Cancer Science
Michael Weller, Wolfgang Wick, Ken Aldape, Michael Brada, Mitchell Berger, Stefan M Pfister, Ryo Nishikawa, Mark Rosenthal, Patrick Y Wen, Roger Stupp, Guido Reifenberger
Gliomas are primary brain tumours that are thought to derive from neuroglial stem or progenitor cells. On the basis of their histological appearance, they have been traditionally classified as astrocytic, oligodendroglial or ependymal tumours and assigned WHO grades I-IV, which indicate different degrees of malignancy. Tremendous progress in genomic, transcriptomic and epigenetic profiling has resulted in new concepts of classifying and treating gliomas. Diffusely infiltrating gliomas in adults are now separated into three overarching tumour groups with distinct natural histories, responses to treatment and outcomes: isocitrate dehydrogenase (IDH)-mutant, 1p/19q co-deleted tumours with mostly oligodendroglial morphology that are associated with the best prognosis; IDH-mutant, 1p/19q non-co-deleted tumours with mostly astrocytic histology that are associated with intermediate outcome; and IDH wild-type, mostly higher WHO grade (III or IV) tumours that are associated with poor prognosis...
2015: Nature Reviews. Disease Primers
Satish K Chitneni, Zachary J Reitman, David M Gooden, Hai Yan, Michael R Zalutsky
INTRODUCTION: Malignant gliomas frequently harbor mutations in the isocitrate dehydrogenase 1 (IDH1) gene. Studies suggest that IDH mutation contributes to tumor pathogenesis through mechanisms that are mediated by the neomorphic metabolite of the mutant IDH1 enzyme, 2-hydroxyglutarate (2-HG). The aim of this work was to synthesize and evaluate radiolabeled compounds that bind to the mutant IDH1 enzyme with the goal of enabling noninvasive imaging of mutant IDH1 expression in gliomas by positron emission tomography (PET)...
August 25, 2016: European Journal of Medicinal Chemistry
David N Louis, Arie Perry, Guido Reifenberger, Andreas von Deimling, Dominique Figarella-Branger, Webster K Cavenee, Hiroko Ohgaki, Otmar D Wiestler, Paul Kleihues, David W Ellison
The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor. For the first time, the WHO classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities, thus formulating a concept for how CNS tumor diagnoses should be structured in the molecular era. As such, the 2016 CNS WHO presents major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors, and incorporates new entities that are defined by both histology and molecular features, including glioblastoma, IDH-wildtype and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M-mutant; RELA fusion-positive ependymoma; medulloblastoma, WNT-activated and medulloblastoma, SHH-activated; and embryonal tumour with multilayered rosettes, C19MC-altered...
June 2016: Acta Neuropathologica
Peng-Fei Wang, Ning Liu, Hong-Wang Song, Kun Yao, Tao Jiang, Shou-Wei Li, Chang-Xiang Yan
WHO2007 grading of diffuse gliomas in adults is well-established. However, IDH mutations make classification of gliomas according to the WHO2007 edition controversial. Here, we characterized IDH-1R132H mut status in a cohort of 670 adult patients with different WHO2007 grades of diffuse glioma. Patient characteristics, clinical data and prognoses were obtained from medical records. Patients with IDH-1R132H mut were younger and had better clinical outcomes than those without mutations. Differences in age among patients with astrocytomas of different WHO2007 grades were eliminated after patients were grouped based on IDH-1R132H status...
May 24, 2016: Oncotarget
Xiaoran Zhang, Aparana Rao, Paola Sette, Christopher Deibert, Alexander Pomerantz, Wi Jin Kim, Gary Kohanbash, Yigang Chang, Yongseok Park, Johnathan Engh, Jaehyuk Choi, Timothy Chan, Hideho Okada, Michael Lotze, Paola Grandi, Nduka Amankulor
BACKGROUND: Diffuse gliomas are poorly immunogenic, fatal brain tumors. The basis for insufficient antitumor immunity in diffuse gliomas is unknown. Gain-of-function mutations in isocitrate dehydrogenases (IDH1 and IDH2) promote diffuse glioma formation through epigenetic reprogramming of a number of genes, including immune-related genes. Here, we identify epigenetic dysregulation of natural killer (NK) cell ligand genes as significant contributors to immune escape in glioma. METHODS: We analyzed the database of The Cancer Genome Atlas for immune gene expression patterns in IDH mutant or wild-type gliomas and identified differentially expressed immune genes...
October 2016: Neuro-oncology
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