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Idh mutant glioma

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https://www.readbyqxmd.com/read/28340142/multigene-signature-for-predicting-prognosis-of-patients-with-1p19q-co-deletion-diffuse-glioma
#1
Xin Hu, Emmanuel Martinez-Ledesma, Siyuan Zheng, Hoon Kim, Floris Barthel, Tao Jiang, Kenneth R Hess, Roel G W Verhaak
Background.: Co-deletion of 1p and 19q marks a diffuse glioma subtype associated with relatively favorable overall survival; however, heterogeneous clinical outcomes are observed within this category. Methods.: We assembled gene expression profiles and sample annotation of 374 glioma patients carrying the 1p/19q co-deletion. We predicted 1p/19q status using gene expression when annotation was missing. A first cohort was randomly split into training (n = 170) and a validation dataset (n = 163)...
March 8, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28319047/isocitrate-dehydrogenase-mutations-suppress-stat1-and-cd8-t-cell-accumulation-in-gliomas
#2
Gary Kohanbash, Diego A Carrera, Shruti Shrivastav, Brian J Ahn, Naznin Jahan, Tali Mazor, Zinal S Chheda, Kira M Downey, Payal B Watchmaker, Casey Beppler, Rolf Warta, Nduka A Amankulor, Christel Herold-Mende, Joseph F Costello, Hideho Okada
Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 are among the first genetic alterations observed during the development of lower-grade glioma (LGG). LGG-associated IDH mutations confer gain-of-function activity by converting α-ketoglutarate to the oncometabolite R-2-hydroxyglutarate (2HG). Clinical samples and gene expression data from The Cancer Genome Atlas (TCGA) demonstrate reduced expression of cytotoxic T lymphocyte-associated genes and IFN-γ-inducible chemokines, including CXCL10, in IDH-mutated (IDH-MUT) tumors compared with IDH-WT tumors...
March 20, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28298040/noninvasive-assessment-of-isocitrate-dehydrogenase-mutation-status-in-cerebral-gliomas-by-magnetic-resonance-spectroscopy-in-a-clinical-setting
#3
Anna Tietze, Changho Choi, Bruce Mickey, Elizabeth A Maher, Benedicte Parm Ulhøi, Ryan Sangill, Yasmin Lassen-Ramshad, Slavka Lukacova, Leif Østergaard, Gorm von Oettingen
OBJECTIVE Mutations in the isocitrate dehydrogenase (IDH) genes are of proven diagnostic and prognostic significance for cerebral gliomas. The objective of this study was to evaluate the clinical feasibility of using a recently described method for determining IDH mutation status by using magnetic resonance spectroscopy (MRS) to detect the presence of 2-hydroxyglutarate (2HG), the metabolic product of the mutant IDH enzyme. METHODS By extending imaging time by 6 minutes, the authors were able to include a point-resolved spectroscopy (PRESS) MRS sequence in their routine glioma imaging protocol...
March 3, 2017: Journal of Neurosurgery
https://www.readbyqxmd.com/read/28259158/detection-of-statistically-significant-network-changes-in-complex-biological-networks
#4
Raghvendra Mall, Luigi Cerulo, Halima Bensmail, Antonio Iavarone, Michele Ceccarelli
BACKGROUND: Biological networks contribute effectively to unveil the complex structure of molecular interactions and to discover driver genes especially in cancer context. It can happen that due to gene mutations, as for example when cancer progresses, the gene expression network undergoes some amount of localized re-wiring. The ability to detect statistical relevant changes in the interaction patterns induced by the progression of the disease can lead to the discovery of novel relevant signatures...
March 4, 2017: BMC Systems Biology
https://www.readbyqxmd.com/read/28255664/adult-infiltrating-gliomas-with-who-2016-integrated-diagnosis-additional-prognostic-roles-of-atrx-and-tert
#5
Melike Pekmezci, Terri Rice, Annette M Molinaro, Kyle M Walsh, Paul A Decker, Helen Hansen, Hugues Sicotte, Thomas M Kollmeyer, Lucie S McCoy, Gobinda Sarkar, Arie Perry, Caterina Giannini, Tarik Tihan, Mitchel S Berger, Joseph L Wiemels, Paige M Bracci, Jeanette E Eckel-Passow, Daniel H Lachance, Jennifer Clarke, Jennie W Taylor, Tracy Luks, John K Wiencke, Robert B Jenkins, Margaret R Wrensch
The "integrated diagnosis" for infiltrating gliomas in the 2016 revised World Health Organization (WHO) classification of tumors of the central nervous system requires assessment of the tumor for IDH mutations and 1p/19q codeletion. Since TERT promoter mutations and ATRX alterations have been shown to be associated with prognosis, we analyzed whether these tumor markers provide additional prognostic information within each of the five WHO 2016 categories. We used data for 1206 patients from the UCSF Adult Glioma Study, the Mayo Clinic and The Cancer Genome Atlas (TCGA) with infiltrative glioma, grades II-IV for whom tumor status for IDH, 1p/19q codeletion, ATRX, and TERT had been determined...
March 2, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28248126/prospective-longitudinal-analysis-of-2-hydroxyglutarate-magnetic-resonance-spectroscopy-identifies-broad-clinical-utility-for-the-management-of-patients-with-idh-mutant-glioma
#6
Changho Choi, Jack M Raisanen, Sandeep K Ganji, Song Zhang, Sarah S McNeil, Zhongxu An, Akshay Madan, Kimmo J Hatanpaa, Vamsidhara Vemireddy, Christie A Sheppard, Dwight Oliver, Keith M Hulsey, Vivek Tiwari, Tomoyuki Mashimo, James Battiste, Samuel Barnett, Christopher J Madden, Toral R Patel, Edward Pan, Craig R Malloy, Bruce E Mickey, Robert M Bachoo, Elizabeth A Maher
Purpose Proton magnetic resonance spectroscopy (MRS) of the brain can detect 2-hydroxyglutarate (2HG), the oncometabolite produced in neoplasms harboring a mutation in the gene coding for isocitrate dehydrogenase ( IDH). We conducted a prospective longitudinal imaging study to determine whether quantitative assessment of 2HG by MRS could serve as a noninvasive clinical imaging biomarker for IDH-mutated gliomas. Patients and Methods 2HG MRS was performed in 136 patients using point-resolved spectroscopy at 3 T in parallel with standard clinical magnetic resonance imaging and assessment...
November 20, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28228392/idh-mutant-tumors-vulnerable-to-parp-inhibition
#7
(no author information available yet)
Several cancers, including glioma and acute myeloid leukemia, carry mutations in IDH1 or IDH2 Researchers have found that these mutations impair homologous recombination, making the tumors sensitive to PARP inhibition. They showed that one such inhibitor, olaparib, killed IDH1/2-mutant cancer cells in culture and slowed tumor growth in mice.
February 22, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28202508/chemosensitivity-of-idh1-mutant-gliomas-due-to-an-impairment-in-parp1-mediated-dna-repair
#8
Yanxin Lu, Jakub Kwintkiewicz, Yang Liu, Katherine Tech, Lauren N Frady, Yu-Ting Su, Wendy Bautista, Seog In Moon, Jeffrey MacDonald, Matthew G Edwend, Mark R Gilbert, Chunzhang Yang, Jing Wu
Mutations in isocitrate dehydrogenase (IDH) are the most prevalent genetic abnormalities in lower grade gliomas. The presence of these mutations in glioma is prognostic for better clinical outcomes with longer patient survival. In the present study, we found that defects in oxidative metabolism and 2-HG production confer chemosensitization in IDH1-mutated glioma cells. In addition, temozolomide (TMZ) treatment induced greater DNA damage and apoptotic changes in mutant glioma cells. The PARP1-associated DNA repair pathway was extensively compromised in mutant cells due to decreased NAD+ availability...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28148839/2-hydroxyglutarate-produced-by-neomorphic-idh-mutations-suppresses-homologous-recombination-and-induces-parp-inhibitor-sensitivity
#9
Parker L Sulkowski, Christopher D Corso, Nathaniel D Robinson, Susan E Scanlon, Karin R Purshouse, Hanwen Bai, Yanfeng Liu, Ranjini K Sundaram, Denise C Hegan, Nathan R Fons, Gregory A Breuer, Yuanbin Song, Ketu Mishra-Gorur, Henk M De Feyter, Robin A de Graaf, Yulia V Surovtseva, Maureen Kachman, Stephanie Halene, Murat Günel, Peter M Glazer, Ranjit S Bindra
2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, whereas the latter is produced under pathologic processes such as hypoxia. We report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors...
February 1, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28124097/pan-mutant-idh1-inhibitor-bay-1436032-for-effective-treatment-of-idh1-mutant-astrocytoma-in-vivo
#10
Stefan Pusch, Sonja Krausert, Viktoria Fischer, Jörg Balss, Martina Ott, Daniel Schrimpf, David Capper, Felix Sahm, Jessica Eisel, Ann-Christin Beck, Manfred Jugold, Viktoria Eichwald, Stefan Kaulfuss, Olaf Panknin, Hartmut Rehwinkel, Katja Zimmermann, Roman C Hillig, Judith Guenther, Luisella Toschi, Roland Neuhaus, Andrea Haegebart, Holger Hess-Stumpp, Markus Bauser, Wolfgang Wick, Andreas Unterberg, Christel Herold-Mende, Michael Platten, Andreas von Deimling
Mutations in codon 132 of isocitrate dehydrogenase (IDH) 1 are frequent in diffuse glioma, acute myeloid leukemia, chondrosarcoma and intrahepatic cholangiocarcinoma. These mutations result in a neomorphic enzyme specificity which leads to a dramatic increase of intracellular D-2-hydroxyglutarate (2-HG) in tumor cells. Therefore, mutant IDH1 protein is a highly attractive target for inhibitory drugs. Here, we describe the development and properties of BAY 1436032, a pan-inhibitor of IDH1 protein with different codon 132 mutations...
April 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28122345/epigenetic-silencing-of-xaf1-in-high-grade-gliomas-is-associated-with-idh1-status-and-improved-clinical-outcome
#11
Thomas R Reich, Olivier J Switzeny, Mirjam Renovanz, Clemens Sommer, Bernd Kaina, Markus Christmann, Maja T Tomicic
XAF1 (X-linked inhibitor of apoptosis (XIAP)-associated factor 1) is a tumor suppressor that counteracts the anti-apoptotic effects of XIAP and can sensitize cells to cell death triggering events. XAF1 knockdown abrogated the temozolomide (TMZ)-induced G2-arrest and prevented TMZ-induced apoptosis in the glioblastoma (GB) cell line LN229. Promoter methylation of XAF1 was found to be inversely correlated with mRNA expression in GB cells. We analyzed XAF1 methylation in a panel of 16 GB cell lines and 80 patients with first-diagnosed WHO grade III/IV high-grade gliomas using methylation-sensitive high-resolution melt (MS-HRM) analysis...
January 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28116838/insular-primary-glioblastomas-with-idh-mutations-clinical-and-biological-specificities
#12
Nobuhiro Hata 秦暢宏, Ryusuke Hatae, Koji Yoshimoto, Hideki Murata, Daisuke Kuga, Yojiro Akagi, Yuhei Sangatsuda, Satoshi O Suzuki, Toru Iwaki, Masahiro Mizoguchi, Koji Iihara
Isocitrate dehydrogenase (IDH) mutation is a good prognostic marker for glioblastoma (GBM). Although it is infrequent in primary tumors, it is found in most lower-grade gliomas. Thus, it is unclear whether IDH mutation is a marker for a specific phenotype of apparently primary de novo GBMs (pGBMs), or a marker for secondary tumors (sGBMs). We addressed this issue by analyzing clinical, radiographic and molecular findings in our institutional case series. Our cases included 92 pGBMs, with five cases of IDH1 mutations at R132 and no IDH2 mutations...
January 24, 2017: Neuropathology: Official Journal of the Japanese Society of Neuropathology
https://www.readbyqxmd.com/read/28110298/idh1-mutation-in-diffuse-gliomas-in-persons-age-55-years-and-over
#13
Chase Robinson, B K Kleinschmidt-DeMasters
Diffuse astrocytoma (DA), anaplastic astrocytoma (AA), and glioblastoma (GBM) are defined by the World Health Organization (WHO) based on IDH-mutational status. The vast majority of IDH-mutated gliomas (90% of which involve a mutation in IDH1 R132H, which can be assessed by IDH1 immunohistochemistry [IHC]) occur in persons younger than 55 years of age. This raises the question as to the prevalence of IDH-mutant tumors in older persons and whether the gliomas in older patients should be routinely tested. Since January 1, 2014, we have employed a standard screening panel for all gliomas regardless of patient age...
January 21, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/28052098/idh1-r132h-mutation-enhances-cell-migration-by-activating-akt-mtor-signaling-pathway-but-sensitizes-cells-to-5-fu-treatment-as-nadph-and-gsh-are-reduced
#14
Huixia Zhu, Ye Zhang, Jianfeng Chen, Jiangdong Qiu, Keting Huang, Mindan Wu, Chunlin Xia
AIM OF STUDY: Mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene were recently discovered in vast majority of World Health Organization (WHO) grade II/III gliomas. This study is to understand the effects of IDH1 R132H mutation in gliomagenesis and to develop new strategies to treat glioma with IDH1 R132H mutation. MATERIALS AND METHODS: Over expression of IDH1 R132H in U87MG cells was done by transfecting cells with IDH1 R132H plasmid. MTT assay, scratch repair assay and western blot were performed to study effects of IDH1 R132H mutation on cell proliferation, migration, regulating AKT-mTOR signaling pathway and cell death respectively...
2017: PloS One
https://www.readbyqxmd.com/read/28040713/the-impact-of-body-mass-index-and-height-on-the-risk-for-glioblastoma-and-other-glioma-subgroups-a-large-prospective-cohort-study
#15
Markus K H Wiedmann, Cathrine Brunborg, Antonio Di Ieva, Kristina Lindemann, Tom B Johannesen, Lars Vatten, Eirik Helseth, John A Zwart
BACKGROUND: Glioma comprises a heterogeneous group of mostly malignant brain tumors, whereof glioblastoma (GBM) represents the largest and most lethal subgroup. Body height and body mass index (BMI) are risk factors for other cancers, but no previous study has examined anthropometric data in relation to different glioma subgroups. METHODS: This prospective cohort study includes 1.8 million Norwegian women and men between ages 14 and 80 years at baseline. Body weight and height were measured, and incident cases of glioma were identified by linkage to the National Cancer Registry...
December 31, 2016: Neuro-oncology
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
#16
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
#17
Lin 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...
January 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/27837434/prediction-of-genetic-subgroups-in-adult-supra-tentorial-gliomas-by-pre-and-intraoperative-parameters
#18
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-therapies-for-glioma
#19
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...
December 2016: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/27788029/establishment-of-anti-human-atrx-monoclonal-antibody-amab-6
#20
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
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