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diffuse astrocytoma IDH mutant

Yashna Paul, Baisakhi Mondal, Vikas Patil, Kumaravel Somasundaram
BACKGROUND: Glioma is the most common of all primary brain tumors with poor prognosis and high mortality. The 2016 World Health Organization classification of the tumors of central nervous system uses molecular parameters in addition to histology to redefine many tumor entities. The new classification scheme divides diffuse gliomas into low-grade glioma (LGG) and glioblastoma (GBM) as per histology. LGGs are further divided into isocitrate dehydrogenase (IDH) wild type or mutant, which is further classified into either oligodendroglioma that harbors 1p/19q codeletion or diffuse astrocytoma that has an intact 1p/19q loci but enriched for ATRX loss and TP53 mutation...
2017: Clinical Epigenetics
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
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...
February 1, 2017: Journal of Neuropathology and Experimental Neurology
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
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...
January 2017: Amino Acids
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
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...
July 16, 2015: Nature Reviews. Disease Primers
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
Michele Ceccarelli, Floris P Barthel, Tathiane M Malta, Thais S Sabedot, Sofie R Salama, Bradley A Murray, Olena Morozova, Yulia Newton, Amie Radenbaugh, Stefano M Pagnotta, Samreen Anjum, Jiguang Wang, Ganiraju Manyam, Pietro Zoppoli, Shiyun Ling, Arjun A Rao, Mia Grifford, Andrew D Cherniack, Hailei Zhang, Laila Poisson, Carlos Gilberto Carlotti, Daniela Pretti da Cunha Tirapelli, Arvind Rao, Tom Mikkelsen, Ching C Lau, W K Alfred Yung, Raul Rabadan, Jason Huse, Daniel J Brat, Norman L Lehman, Jill S Barnholtz-Sloan, Siyuan Zheng, Kenneth Hess, Ganesh Rao, Matthew Meyerson, Rameen Beroukhim, Lee Cooper, Rehan Akbani, Margaret Wrensch, David Haussler, Kenneth D Aldape, Peter W Laird, David H Gutmann, Houtan Noushmehr, Antonio Iavarone, Roel G W Verhaak
Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length...
January 28, 2016: Cell
Ulrich Herrlinger, David T W Jones, Martin Glas, Elke Hattingen, Dorothee Gramatzki, Moritz Stuplich, Jörg Felsberg, Oliver Bähr, Gerrit H Gielen, Matthias Simon, Dorothee Wiewrodt, Martin Schabet, Volker Hovestadt, David Capper, Joachim P Steinbach, Andreas von Deimling, Peter Lichter, Stefan M Pfister, Michael Weller, Guido Reifenberger
Gliomatosis cerebri (GC) is presently considered a distinct astrocytic glioma entity according to the WHO classification for CNS tumors. It is characterized by widespread, typically bilateral infiltration of the brain involving three or more lobes. Genetic studies of GC have to date been restricted to the analysis of individual glioma-associated genes, which revealed mutations in the isocitrate dehydrogenase 1 (IDH1) and tumor protein p53 (TP53) genes in subsets of patients. Here, we report on a genome-wide analysis of DNA methylation and copy number aberrations in 25 GC patients...
February 2016: Acta Neuropathologica
Robert J Macaulay
BACKGROUND: Progress in molecular oncology during the last decade has enabled investigators to more precisely define and group gliomas. The impacts of isocitrate dehydrogenase (IDH) mutation (mut) status and other molecular markers on the classification, prognostication, and management of diffuse gliomas are likely to be far-reaching. METHODS: Clinical experience and the medical literature were used to assess the current status of glioma categorization and the likely impact of the pending revision of the classification scheme of the World Health Organization (WHO)...
April 2015: Cancer Control: Journal of the Moffitt Cancer Center
Christina L Appin, Daniel J Brat
The diffuse gliomas are primary central nervous system tumors that arise most frequently in the cerebral hemispheres of adults. They are currently classified as astrocytomas, oligodendrogliomas or oligoastrocytomas and range in grade from II to IV. Glioblastoma (GBM), grade IV, is the highest grade and most common form. The diagnosis of diffuse gliomas has historically been based primarily on histopathologic features, yet these tumors have a wide range of biological behaviors that are only partially explained by morphology...
November 2015: Molecular Aspects of Medicine
David E Reuss, Yasin Mamatjan, Daniel Schrimpf, David Capper, Volker Hovestadt, Annekathrin Kratz, Felix Sahm, Christian Koelsche, Andrey Korshunov, Adriana Olar, Christian Hartmann, Jaap C Reijneveld, Pieter Wesseling, Andreas Unterberg, Michael Platten, Wolfgang Wick, Christel Herold-Mende, Kenneth Aldape, Andreas von Deimling
The WHO 2007 classification of tumors of the CNS distinguishes between diffuse astrocytoma WHO grade II (A II(WHO2007)) and anaplastic astrocytoma WHO grade III (AA III(WHO2007)). Patients with A II(WHO2007) are significantly younger and survive significantly longer than those with AA III(WHO2007). So far, classification and grading relies on morphological grounds only and does not yet take into account IDH status, a molecular marker of prognostic relevance. We here demonstrate that WHO 2007 grading performs poorly in predicting prognosis when applied to astrocytoma carrying IDH mutations...
June 2015: Acta Neuropathologica
Jennie W Taylor, Andrew S Chi, Daniel P Cahill
Diffuse gliomas are the most common primary malignant brain tumors in adults and continue to be almost universally fatal. Nevertheless, a striking variability in outcome has long been observed, with a subset of patients having prolonged survival. Recent molecular discoveries have provided new insights into gliomagenesis and have enhanced clinical subclassification of gliomas. Mutations in the isocitrate dehydrogenase (IDH) genes occur frequently in low-grade astrocytomas and oligodendrogliomas (World Health Organization [WHO] grade II), and in higher-grade gliomas (WHO grades III and IV) that arise after malignant progression of low-grade tumors...
June 2013: Oncology (Williston Park, NY)
Keisuke Ishizawa, Takanori Hirose, Kazuhiko Sugiyama, Teruyoshi Kageji, Sumihito Nobusawa, Taku Homma, Takashi Komori, Atsushi Sasaki
Glioneuronal tumor with neuropil-like islands (GTNI) is featured by "neuropil-like islands (NIs)" within dominating astroglial components. Isocitrate dehydrogenase (IDH) mutations, particularly IDH1 R132H (G395A), are found in WHO Grade II and III diffuse gliomas as well as secondary, but not primary, glioblastomas. We reviewed 5 cases of GTNI, and assessed histology and immunohistochemistry with various antibodies, including those for IDH1 R132H, as well as direct DNA sequencing for IDH1 G395A. NIs were variable in morphology, and constantly synaptophysin-positive and glial fibrillary acidic protein-negative...
March 2012: Clinical Neuropathology
R Gupta, R Webb-Myers, S Flanagan, M E Buckland
The discovery of isocitrate dehydrogenase (IDH) mutations in gliomas is one example of the large impact that next-generation sequencing is having on the understanding of tumour biology and human disease in general. IDH mutations are early and common events in the development of astrocytomas, oligodendrogliomas and oligoastrocytomas. IDH mutations are also found in some myeloid malignancies and soft tissue tumours, but are rare in other malignancies. IDH mutation detection can be incorporated into routine pathology practice via immunohistochemistry and/or standard sequencing techniques and has great diagnostic value...
October 2011: Journal of Clinical Pathology
Felix Sahm, David Capper, Stefan Pusch, Jörg Balss, Arend Koch, Claus-Dieter Langhans, Jürgen G Okun, Andreas von Deimling
Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes occur frequently in diffuse astrocytoma and oligodendroglioma. The consecutive amino acid substitutions in the mutant proteins result in a gain of the function to catalyze the reduction of alpha-ketoglutarate to 2-hydroxyglutarate (2HG). So far, all investigated IDH mutations share this gain of function. We here describe a method to detect 2HG levels in archival formalin-fixed paraffin-embedded tumor specimens by stable isotope dilution using gas chromatography followed by mass spectrometry (GC/MS)...
January 2012: Brain Pathology
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