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Idh mutant glioma

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https://www.readbyqxmd.com/read/27888628/impact-of-epidemiological-characteristics-of-supratentorial-gliomas-in-adults-brought-about-by-the-2016-world-health-organization-classification-of-tumors-of-the-central-nervous-system
#1
Haihui Jiang, Yong Cui, Junmei Wang, Song Lin
The latest World Health Organization (WHO) classification of tumors of the central nervous system (CNS) integrates both histological and molecular features in the definition of diagnostic entities. This new approach enrolls novel entities of gliomas. In this study, we aimed to reveal the epidemiological characteristics, including age at diagnosis, gender ratio, tumor distribution and survival, of these new entities. We retrospectively reclassified 1210 glioma samples according to the 2016 CNS WHO diagnostic criteria...
November 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/27852048/igfbp2-expression-predicts-idh-mutant-glioma-patient-survival
#2
L Eric Huang, Adam L Cohen, Howard Colman, Randy L Jensen, Daniel W Fults, William T Couldwell
Mutations of the isocitrate dehydrogenase (IDH) 1 and 2 genes occur in ~80% of lower-grade (WHO grade II and grade III) gliomas. Mutant IDH produces (R)-2-hydroxyglutarate, which induces DNA hypermethylation and presumably drives tumorigenesis. Interestingly, IDH mutations are associated with improved survival in glioma patients, but the underlying mechanism for the difference in survival remains unclear. Through comparative analyses of 286 cases of IDH-wildtype and IDH-mutant lower-grade glioma from a TCGA data set, we report that IDH-mutant gliomas have increased expression of tumor-suppressor genes (NF1, PTEN, and PIK3R1) and decreased expression of oncogenes(AKT2, ARAF, ERBB2, FGFR3, and PDGFRB) and glioma progression genes (FOXM1, IGFBP2, and WWTR1) compared with IDH-wildtype gliomas...
November 12, 2016: Oncotarget
https://www.readbyqxmd.com/read/27837434/prediction-of-genetic-subgroups-in-adult-supra-tentorial-gliomas-by-pre-and-intraoperative-parameters
#3
Shunsuke Nakae, Kazuhiro Murayama, Hikaru Sasaki, Masanobu Kumon, Yuya Nishiyama, Shigeo Ohba, Kazuhide Adachi, Shinya Nagahisa, Takuro Hayashi, Joji Inamasu, Masato Abe, Mitsuhiro Hasegawa, Yuichi Hirose
Recent progress in neuro-oncology has validated the significance of genetic diagnosis in gliomas. We previously investigated IDH1/2 and TP53 mutations via Sanger sequencing for adult supratentorial gliomas and reported that PCR-based sequence analysis classified gliomas into three genetic subgroups that have a strong association with patient prognosis: IDH mutant gliomas without TP53 mutations, IDH and TP53 mutant gliomas, and IDH wild-type gliomas. Furthermore, this analysis had a strong association with patient prognosis...
November 11, 2016: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/27809598/emerging-targeted-therapy-for-glioma
#4
Julie J Miller, Patrick Y Wen
Gliomas are the most common malignant primary brain tumors in adults. Despite aggressive treatment with surgery, radiation and chemotherapy, these tumors are incurable and invariably recur. Molecular characterization of these tumors in recent years has advanced our understanding of gliomagenesis and offered an array of pathways that can be specifically targeted. Areas Covered: The most commonly dysregulated signaling pathways found in gliomas will be discussed, as well as the biologic importance of these disrupted pathways and how each may contribute to tumor development...
November 4, 2016: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/27788029/establishment-of-anti-human-atrx-monoclonal-antibody-amab-6
#5
Satoshi Ogasawara, Yuki Fujii, Mika K Kaneko, Hiroharu Oki, Hemragul Sabit, Mitsutoshi Nakada, Hiroyoshi Suzuki, Koichi Ichimura, Takashi Komori, Yukinari Kato
Gliomas are the most frequently occurring brain tumors with a heterogeneous molecular background. The molecular subgrouping of gliomas more prognostically stratifies patients into distinct groups compared with conventional histological classification. The most important molecules for the subtype diagnosis of diffuse gliomas are mutations of isocitrate dehydrogenase (IDH), TERT promoter, and α-thalassemia/mental-retardation-syndrome-X-linked (ATRX) and the codeletion of 1p/19q. Among them, IDH and ATRX mutations can be diagnosed using specific monoclonal antibodies (mAbs)...
October 2016: Monoclonal Antibodies in Immunodiagnosis and Immunotherapy
https://www.readbyqxmd.com/read/27758882/mutant-idh1-expression-drives-tert-promoter-reactivation-as-part-of-the-cellular-transformation-process
#6
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 low-grade glioma, where they result in the production of 2-hydroxyglutarate (2HG), disrupted patterns of histone methylation, and gliomagenesis. IDH1 mutations also cosegregate 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 whether and how this may occur, we investigated the phenotype of pRb-/p53-deficient human astrocytes engineered with IDH1 wild-type (WT) or R132H-mutant (IDH1(mut)) genes as they progressed through their lifespan...
October 6, 2016: Cancer Research
https://www.readbyqxmd.com/read/27752843/glutamate-and-%C3%AE-ketoglutarate-key-players-in-glioma-metabolism
#7
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
https://www.readbyqxmd.com/read/27696222/gene-expression-profiling-stratifies-idh1-mutant-glioma-with-distinct-prognoses
#8
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
https://www.readbyqxmd.com/read/27659543/non-invasive-detection-of-2-hydroxyglutarate-in-idh-mutated-gliomas-using-two-dimensional-localized-correlation-spectroscopy-2d-l-cosy-at-7-tesla
#9
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...
September 22, 2016: Journal of Translational Medicine
https://www.readbyqxmd.com/read/27573687/prognostic-impact-of-the-2016-who-classification-of-diffuse-gliomas-in-the-french-pola-cohort
#10
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
https://www.readbyqxmd.com/read/27568302/idh1-associated-with-neuronal-apoptosis-in-adult-rats-brain-following-intracerebral-hemorrhage
#11
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
https://www.readbyqxmd.com/read/27543943/tumor-cells-with-neuronal-intermediate-progenitor-features-define-a-subgroup-of-1p-19q-co-deleted-anaplastic-gliomas
#12
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
https://www.readbyqxmd.com/read/27460417/identification-of-a-novel-inactivating-mutation-in-isocitrate-dehydrogenase-1-idh1-r314c-in-a-high-grade-astrocytoma
#13
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
https://www.readbyqxmd.com/read/27382115/volumetric-relationship-between-2-hydroxyglutarate-and-flair-hyperintensity-has-potential-implications-for-radiotherapy-planning-of-mutant-idh-glioma-patients
#14
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...
November 2016: Neuro-oncology
https://www.readbyqxmd.com/read/27355333/targeting-isocitrate-dehydrogenase-idh-in-cancer
#15
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
https://www.readbyqxmd.com/read/27340277/selective-detection-of-the-d-enantiomer-of-2-hydroxyglutarate-in-the-csf-of-glioma-patients-with-mutated-isocitrate-dehydrogenase
#16
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
https://www.readbyqxmd.com/read/27292784/the-evolving-landscape-in-the-development-of-isocitrate-dehydrogenase-mutant-inhibitors
#17
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 confer a neomorphic activity that allow 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%)...
2016: Mini Reviews in Medicinal Chemistry
https://www.readbyqxmd.com/read/27282637/idh-mutant-glioma-specific-association-of-rs55705857-located-at-8q24-21-involves-myc-deregulation
#18
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
https://www.readbyqxmd.com/read/27258564/identification-of-new-biomarkers-associated-with-idh-mutation-and-prognosis-in-astrocytic-tumors-using-nanostring-ncounter-analysis-system
#19
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
https://www.readbyqxmd.com/read/27196377/world-health-organization-grade-ii-iii-astrocytomas-consist-of-genetically-distinct-tumor-lineages
#20
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
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