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  • 1
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    mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy (2013)
    National Academy of Sciences
    Details
    Publication Date: 2013-12-23
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 2
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    Inositol-requiring enzyme 1  is a key regulator of angiogenesis and invasion in malignant glioma (2010)
    National Academy of Sciences
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    Publication Date: 2010-08-11
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 3
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    Protein kinase Cβ as a therapeutic target stabilizing blood–brain barrier disruption in experimental autoimmune encephalomyelitis (2013)
    National Academy of Sciences
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    Publication Date: 2013-08-19
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 4
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    cGAS produces a 2'-5'-linked cyclic dinucleotide second messenger that activates STING (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-06-01
    Description: Detection of cytoplasmic DNA represents one of the most fundamental mechanisms of the innate immune system to sense the presence of microbial pathogens. Moreover, erroneous detection of endogenous DNA by the same sensing mechanisms has an important pathophysiological role in certain sterile inflammatory conditions. The endoplasmic-reticulum-resident protein STING is critically required for the initiation of type I interferon signalling upon detection of cytosolic DNA of both exogenous and endogenous origin. Next to its pivotal role in DNA sensing, STING also serves as a direct receptor for the detection of cyclic dinucleotides, which function as second messenger molecules in bacteria. DNA recognition, however, is triggered in an indirect fashion that depends on a recently characterized cytoplasmic nucleotidyl transferase, termed cGAMP synthase (cGAS), which upon interaction with DNA synthesizes a dinucleotide molecule that in turn binds to and activates STING. We here show in vivo and in vitro that the cGAS-catalysed reaction product is distinct from previously characterized cyclic dinucleotides. Using a combinatorial approach based on mass spectrometry, enzymatic digestion, NMR analysis and chemical synthesis we demonstrate that cGAS produces a cyclic GMP-AMP dinucleotide, which comprises a 2'-5' and a 3'-5' phosphodiester linkage 〉Gp(2'-5')Ap(3'-5')〉. We found that the presence of this 2'-5' linkage was required to exert potent activation of human STING. Moreover, we show that cGAS first catalyses the synthesis of a linear 2'-5'-linked dinucleotide, which is then subject to cGAS-dependent cyclization in a second step through a 3'-5' phosphodiester linkage. This 13-membered ring structure defines a novel class of second messenger molecules, extending the family of 2'-5'-linked antiviral biomolecules.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143541/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143541/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ablasser, Andrea -- Goldeck, Marion -- Cavlar, Taner -- Deimling, Tobias -- Witte, Gregor -- Rohl, Ingo -- Hopfner, Karl-Peter -- Ludwig, Janos -- Hornung, Veit -- 243046/European Research Council/International -- U19AI083025/AI/NIAID NIH HHS/ -- England -- Nature. 2013 Jun 20;498(7454):380-4. doi: 10.1038/nature12306. Epub 2013 May 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, 53127 Bonn, Germany. andrea.ablasser@uni-bonn.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23722158" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Monophosphate/chemistry ; Animals ; Biocatalysis ; Cell Line ; Cyclic GMP/chemistry ; Cyclization ; HEK293 Cells ; Humans ; Magnetic Resonance Spectroscopy ; Membrane Proteins/*metabolism ; Mice ; Models, Molecular ; Molecular Structure ; Nucleotidyltransferases/genetics/*metabolism ; Oligoribonucleotides/biosynthesis/chemistry/*metabolism ; Second Messenger Systems/*physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 5
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    Structural mechanism of cytosolic DNA sensing by cGAS (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-06-01
    Description: Cytosolic DNA arising from intracellular bacterial or viral infections is a powerful pathogen-associated molecular pattern (PAMP) that leads to innate immune host defence by the production of type I interferon and inflammatory cytokines. Recognition of cytosolic DNA by the recently discovered cyclic-GMP-AMP (cGAMP) synthase (cGAS) induces the production of cGAMP to activate the stimulator of interferon genes (STING). Here we report the crystal structure of cGAS alone and in complex with DNA, ATP and GTP along with functional studies. Our results explain the broad DNA sensing specificity of cGAS, show how cGAS catalyses dinucleotide formation and indicate activation by a DNA-induced structural switch. cGAS possesses a remarkable structural similarity to the antiviral cytosolic double-stranded RNA sensor 2'-5'oligoadenylate synthase (OAS1), but contains a unique zinc thumb that recognizes B-form double-stranded DNA. Our results mechanistically unify dsRNA and dsDNA innate immune sensing by OAS1 and cGAS nucleotidyl transferases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3768140/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3768140/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Civril, Filiz -- Deimling, Tobias -- de Oliveira Mann, Carina C -- Ablasser, Andrea -- Moldt, Manuela -- Witte, Gregor -- Hornung, Veit -- Hopfner, Karl-Peter -- 243046/European Research Council/International -- U19 AI083025/AI/NIAID NIH HHS/ -- U19AI083025/AI/NIAID NIH HHS/ -- England -- Nature. 2013 Jun 20;498(7454):332-7. doi: 10.1038/nature12305. Epub 2013 May 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Gene Center, Ludwig-Maximilians-University, 81377 Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23722159" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/chemistry/metabolism ; Animals ; Base Sequence ; Catalytic Domain ; Crystallography, X-Ray ; *Cytosol ; DNA/chemistry/*metabolism/pharmacology ; Guanosine Triphosphate/chemistry/metabolism ; HEK293 Cells ; Humans ; Membrane Proteins/genetics/metabolism ; Mice ; Models, Biological ; Models, Molecular ; Mutation ; Nucleotidyltransferases/*chemistry/genetics/metabolism ; Protein Conformation/drug effects ; Structure-Activity Relationship ; Substrate Specificity ; Swine ; Uridine Triphosphate/chemistry/metabolism ; Zinc/chemistry/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 6
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    Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-07-22
    Description: Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201514/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201514/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Northcott, Paul A -- Lee, Catherine -- Zichner, Thomas -- Stutz, Adrian M -- Erkek, Serap -- Kawauchi, Daisuke -- Shih, David J H -- Hovestadt, Volker -- Zapatka, Marc -- Sturm, Dominik -- Jones, David T W -- Kool, Marcel -- Remke, Marc -- Cavalli, Florence M G -- Zuyderduyn, Scott -- Bader, Gary D -- VandenBerg, Scott -- Esparza, Lourdes Adriana -- Ryzhova, Marina -- Wang, Wei -- Wittmann, Andrea -- Stark, Sebastian -- Sieber, Laura -- Seker-Cin, Huriye -- Linke, Linda -- Kratochwil, Fabian -- Jager, Natalie -- Buchhalter, Ivo -- Imbusch, Charles D -- Zipprich, Gideon -- Raeder, Benjamin -- Schmidt, Sabine -- Diessl, Nicolle -- Wolf, Stephan -- Wiemann, Stefan -- Brors, Benedikt -- Lawerenz, Chris -- Eils, Jurgen -- Warnatz, Hans-Jorg -- Risch, Thomas -- Yaspo, Marie-Laure -- Weber, Ursula D -- Bartholomae, Cynthia C -- von Kalle, Christof -- Turanyi, Eszter -- Hauser, Peter -- Sanden, Emma -- Darabi, Anna -- Siesjo, Peter -- Sterba, Jaroslav -- Zitterbart, Karel -- Sumerauer, David -- van Sluis, Peter -- Versteeg, Rogier -- Volckmann, Richard -- Koster, Jan -- Schuhmann, Martin U -- Ebinger, Martin -- Grimes, H Leighton -- Robinson, Giles W -- Gajjar, Amar -- Mynarek, Martin -- von Hoff, Katja -- Rutkowski, Stefan -- Pietsch, Torsten -- Scheurlen, Wolfram -- Felsberg, Jorg -- Reifenberger, Guido -- Kulozik, Andreas E -- von Deimling, Andreas -- Witt, Olaf -- Eils, Roland -- Gilbertson, Richard J -- Korshunov, Andrey -- Taylor, Michael D -- Lichter, Peter -- Korbel, Jan O -- Wechsler-Reya, Robert J -- Pfister, Stefan M -- 5P30CA030199/CA/NCI NIH HHS/ -- P01 CA096832/CA/NCI NIH HHS/ -- P30 CA030199/CA/NCI NIH HHS/ -- P41GM103504/GM/NIGMS NIH HHS/ -- R01 CA159859/CA/NCI NIH HHS/ -- England -- Nature. 2014 Jul 24;511(7510):428-34. doi: 10.1038/nature13379. Epub 2014 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2]. ; 1] Biomedical Sciences Graduate Program, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093-0685, USA [2] Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA [3]. ; 1] European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany [2]. ; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany. ; 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany. ; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. ; Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; The Donnelly Centre, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada. ; Department of Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. ; Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA. ; Department of Neuropathology, NN Burdenko Neurosurgical Institute, 4th Tverskaya-Yamskaya 16, Moscow 125047, Russia. ; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Data Management Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, Berlin 14195, Germany. ; Division of Translational Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg 69120, Germany. ; 1] Division of Translational Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg 69120, Germany [2] Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; 1st Department of Pathology and Experimental Cancer Research, Semmelweis University SE, II.sz. Gyermekklinika, Budapest 1094, Hungary. ; 2nd Department of Pediatrics, Semmelweis University, SE, II.sz. Gyermekklinika, Budapest 1094, Hungary. ; 1] Glioma Immunotherapy Group, Division of Neurosurgery, Lund University, Paradisgatan 2, Lund 221 00, Sweden [2] Department of Clinical Sciences, Lund University, Paradisgatan 2, Lund 221 00, Sweden. ; Department of Pediatric Oncology, Masaryk University and University Hospital, Brno, Cernopolni 9 Brno 613 00, Czech Republic. ; Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, V Uvalu 84, Prague 150 06, Czech Republic. ; Department of Oncogenomics, AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, AZ Netherlands. ; Department of Neurosurgery, Tubingen University Hospital, Hoppe-Seyler Strasse 3, Tubingen 72076, Germany. ; Division of Immunobiology, Program in Cancer Pathology of the Divisions of Experimental Hematology and Pathology, Program in Hematologic Malignancies of the Cancer and Blood Disease Insitute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 452229, USA. ; 1] Department of Developmental Neurobiology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA [2] Department of Oncology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA. ; Department of Oncology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA. ; Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany. ; Department of Neuropathology, University of Bonn, Sigmund-Freud-Str. 25, Bonn 53105, Germany. ; Cnopf'sche Kinderklinik, Nurnberg Children's Hospital, St-Johannis-Muhlgasse 19, Nurnberg 90419, Germany. ; Department of Neuropathology, Heinrich-Heine-University Dusseldorf, Moorenstrasse 5, Dusseldorf 40225, Germany. ; Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany. ; Department of Neuropathology, University of Heidelberg, Im Neuenheimer Feld 220, Heidelberg 69120, Germany. ; 1] Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; 1] The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada [2] Division of Neurosurgery, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. ; 1] Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Heidelberg Center for Personalised Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, Heidelberg 69120, Germany. ; 1] European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany [2] EMBL, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Saffron Walden CB10 1SD, UK. ; 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany [2] Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 430, Heidelberg 69120, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043047" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Child ; Chromosomes, Human, Pair 9/genetics ; DNA-Binding Proteins/*genetics/metabolism ; Enhancer Elements, Genetic/*genetics ; Genomic Structural Variation/*genetics ; Humans ; Medulloblastoma/classification/*genetics/pathology ; Mice ; Oncogenes/*genetics ; Proto-Oncogene Proteins/*genetics/metabolism ; Repressor Proteins/*genetics/metabolism ; Transcription Factors/*genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
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    An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-10-07
    Description: Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO-AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Opitz, Christiane A -- Litzenburger, Ulrike M -- Sahm, Felix -- Ott, Martina -- Tritschler, Isabel -- Trump, Saskia -- Schumacher, Theresa -- Jestaedt, Leonie -- Schrenk, Dieter -- Weller, Michael -- Jugold, Manfred -- Guillemin, Gilles J -- Miller, Christine L -- Lutz, Christian -- Radlwimmer, Bernhard -- Lehmann, Irina -- von Deimling, Andreas -- Wick, Wolfgang -- Platten, Michael -- England -- Nature. 2011 Oct 5;478(7368):197-203. doi: 10.1038/nature10491.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases, University Hospital of Heidelberg, 69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21976023" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autocrine Communication ; Brain Neoplasms/genetics/immunology/*metabolism/*pathology ; Cell Line, Tumor ; Cell Survival ; Disease Progression ; Gene Expression Regulation, Neoplastic ; Glioma/genetics/immunology/*metabolism/*pathology ; Humans ; Kynurenine/immunology/*metabolism/pharmacology/secretion ; Ligands ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Neoplasm Transplantation ; Paracrine Communication ; Receptors, Aryl Hydrocarbon/immunology/*metabolism ; Tryptophan/metabolism ; Tryptophan Oxygenase/deficiency/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
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    Dissecting the genomic complexity underlying medulloblastoma (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-07-27
    Description: Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662966/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662966/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jones, David T W -- Jager, Natalie -- Kool, Marcel -- Zichner, Thomas -- Hutter, Barbara -- Sultan, Marc -- Cho, Yoon-Jae -- Pugh, Trevor J -- Hovestadt, Volker -- Stutz, Adrian M -- Rausch, Tobias -- Warnatz, Hans-Jorg -- Ryzhova, Marina -- Bender, Sebastian -- Sturm, Dominik -- Pleier, Sabrina -- Cin, Huriye -- Pfaff, Elke -- Sieber, Laura -- Wittmann, Andrea -- Remke, Marc -- Witt, Hendrik -- Hutter, Sonja -- Tzaridis, Theophilos -- Weischenfeldt, Joachim -- Raeder, Benjamin -- Avci, Meryem -- Amstislavskiy, Vyacheslav -- Zapatka, Marc -- Weber, Ursula D -- Wang, Qi -- Lasitschka, Barbel -- Bartholomae, Cynthia C -- Schmidt, Manfred -- von Kalle, Christof -- Ast, Volker -- Lawerenz, Chris -- Eils, Jurgen -- Kabbe, Rolf -- Benes, Vladimir -- van Sluis, Peter -- Koster, Jan -- Volckmann, Richard -- Shih, David -- Betts, Matthew J -- Russell, Robert B -- Coco, Simona -- Tonini, Gian Paolo -- Schuller, Ulrich -- Hans, Volkmar -- Graf, Norbert -- Kim, Yoo-Jin -- Monoranu, Camelia -- Roggendorf, Wolfgang -- Unterberg, Andreas -- Herold-Mende, Christel -- Milde, Till -- Kulozik, Andreas E -- von Deimling, Andreas -- Witt, Olaf -- Maass, Eberhard -- Rossler, Jochen -- Ebinger, Martin -- Schuhmann, Martin U -- Fruhwald, Michael C -- Hasselblatt, Martin -- Jabado, Nada -- Rutkowski, Stefan -- von Bueren, Andre O -- Williamson, Dan -- Clifford, Steven C -- McCabe, Martin G -- Collins, V Peter -- Wolf, Stephan -- Wiemann, Stefan -- Lehrach, Hans -- Brors, Benedikt -- Scheurlen, Wolfram -- Felsberg, Jorg -- Reifenberger, Guido -- Northcott, Paul A -- Taylor, Michael D -- Meyerson, Matthew -- Pomeroy, Scott L -- Yaspo, Marie-Laure -- Korbel, Jan O -- Korshunov, Andrey -- Eils, Roland -- Pfister, Stefan M -- Lichter, Peter -- P30 HD018655/HD/NICHD NIH HHS/ -- R01 CA109467/CA/NCI NIH HHS/ -- England -- Nature. 2012 Aug 2;488(7409):100-5. doi: 10.1038/nature11284.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22832583" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/genetics ; Amino Acid Sequence ; Cell Transformation, Neoplastic ; Cerebellar Neoplasms/classification/diagnosis/*genetics/pathology ; Child ; Chromatin/metabolism ; Chromosomes, Human/genetics ; DEAD-box RNA Helicases/genetics ; DNA Helicases/genetics ; DNA-Binding Proteins/genetics ; Genome, Human/*genetics ; Genomics ; Hedgehog Proteins/metabolism ; High-Throughput Nucleotide Sequencing ; Histone Demethylases/genetics ; Humans ; Medulloblastoma/classification/diagnosis/*genetics/pathology ; Methylation ; Mutation/genetics ; Mutation Rate ; Neoplasm Proteins/genetics ; Nuclear Proteins/genetics ; Oncogene Proteins, Fusion/genetics ; Phosphoprotein Phosphatases/genetics ; Polyploidy ; Receptors, Cell Surface/genetics ; Sequence Analysis, RNA ; Signal Transduction ; T-Box Domain Proteins/genetics ; Transcription Factors/genetics ; Wnt Proteins/metabolism ; beta Catenin/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
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    Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-01-31
    Description: Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (alpha-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schwartzentruber, Jeremy -- Korshunov, Andrey -- Liu, Xiao-Yang -- Jones, David T W -- Pfaff, Elke -- Jacob, Karine -- Sturm, Dominik -- Fontebasso, Adam M -- Quang, Dong-Anh Khuong -- Tonjes, Martje -- Hovestadt, Volker -- Albrecht, Steffen -- Kool, Marcel -- Nantel, Andre -- Konermann, Carolin -- Lindroth, Anders -- Jager, Natalie -- Rausch, Tobias -- Ryzhova, Marina -- Korbel, Jan O -- Hielscher, Thomas -- Hauser, Peter -- Garami, Miklos -- Klekner, Almos -- Bognar, Laszlo -- Ebinger, Martin -- Schuhmann, Martin U -- Scheurlen, Wolfram -- Pekrun, Arnulf -- Fruhwald, Michael C -- Roggendorf, Wolfgang -- Kramm, Christoph -- Durken, Matthias -- Atkinson, Jeffrey -- Lepage, Pierre -- Montpetit, Alexandre -- Zakrzewska, Magdalena -- Zakrzewski, Krzystof -- Liberski, Pawel P -- Dong, Zhifeng -- Siegel, Peter -- Kulozik, Andreas E -- Zapatka, Marc -- Guha, Abhijit -- Malkin, David -- Felsberg, Jorg -- Reifenberger, Guido -- von Deimling, Andreas -- Ichimura, Koichi -- Collins, V Peter -- Witt, Hendrik -- Milde, Till -- Witt, Olaf -- Zhang, Cindy -- Castelo-Branco, Pedro -- Lichter, Peter -- Faury, Damien -- Tabori, Uri -- Plass, Christoph -- Majewski, Jacek -- Pfister, Stefan M -- Jabado, Nada -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2012 Jan 29;482(7384):226-31. doi: 10.1038/nature10833.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉McGill University and Genome Quebec Innovation Centre, Montreal, Quebec H3A 1A4, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22286061" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/genetics ; Base Sequence ; Child ; Chromatin/*genetics/metabolism ; Chromatin Assembly and Disassembly/*genetics ; DNA Helicases/genetics ; DNA Mutational Analysis ; Exome/genetics ; Gene Expression Profiling ; Glioblastoma/*genetics ; Histones/*genetics/metabolism ; Humans ; Molecular Sequence Data ; Mutation/*genetics ; Nuclear Proteins/genetics ; Telomere/genetics ; Tumor Suppressor Protein p53/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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    A vaccine targeting mutant IDH1 induces antitumour immunity (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-07-22
    Description: Monoallelic point mutations of isocitrate dehydrogenase type 1 (IDH1) are an early and defining event in the development of a subgroup of gliomas and other types of tumour. They almost uniformly occur in the critical arginine residue (Arg 132) in the catalytic pocket, resulting in a neomorphic enzymatic function, production of the oncometabolite 2-hydroxyglutarate (2-HG), genomic hypermethylation, genetic instability and malignant transformation. More than 70% of diffuse grade II and grade III gliomas carry the most frequent mutation, IDH1(R132H) (ref. 3). From an immunological perspective, IDH1(R132H) represents a potential target for immunotherapy as it is a tumour-specific potential neoantigen with high uniformity and penetrance expressed in all tumour cells. Here we demonstrate that IDH1(R132H) contains an immunogenic epitope suitable for mutation-specific vaccination. Peptides encompassing the mutated region are presented on major histocompatibility complexes (MHC) class II and induce mutation-specific CD4(+) T-helper-1 (TH1) responses. CD4(+) TH1 cells and antibodies spontaneously occurring in patients with IDH1(R132H)-mutated gliomas specifically recognize IDH1(R132H). Peptide vaccination of mice devoid of mouse MHC and transgenic for human MHC class I and II with IDH1(R132H) p123-142 results in an effective MHC class II-restricted mutation-specific antitumour immune response and control of pre-established syngeneic IDH1(R132H)-expressing tumours in a CD4(+) T-cell-dependent manner. As IDH1(R132H) is present in all tumour cells of these slow-growing gliomas, a mutation-specific anti-IDH1(R132H) vaccine may represent a viable novel therapeutic strategy for IDH1(R132H)-mutated tumours.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schumacher, Theresa -- Bunse, Lukas -- Pusch, Stefan -- Sahm, Felix -- Wiestler, Benedikt -- Quandt, Jasmin -- Menn, Oliver -- Osswald, Matthias -- Oezen, Iris -- Ott, Martina -- Keil, Melanie -- Balss, Jorg -- Rauschenbach, Katharina -- Grabowska, Agnieszka K -- Vogler, Isabel -- Diekmann, Jan -- Trautwein, Nico -- Eichmuller, Stefan B -- Okun, Jurgen -- Stevanovic, Stefan -- Riemer, Angelika B -- Sahin, Ugur -- Friese, Manuel A -- Beckhove, Philipp -- von Deimling, Andreas -- Wick, Wolfgang -- Platten, Michael -- England -- Nature. 2014 Aug 21;512(7514):324-7. doi: 10.1038/nature13387. Epub 2014 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [3]. ; 1] Department of Neuropathology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; 1] Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Translational Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany. ; 1] Department of Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; 1] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK) Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Immunotherapy and -prevention Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Ribological GmbH, 55131 Mainz, Germany. ; Translational Oncology, 55131 Mainz, Germany. ; Department of Immunology, University of Tubingen, 72076 Tubingen, Germany. ; Metabolic Centre Heidelberg, University Children's Hospital, 69120 Heidelberg, Germany. ; Center for Molecular Neurobiology, University Medical Center, Hamburg-Eppendorf, 20251 Hamburg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043048" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibody Specificity ; Antigens, Neoplasm/genetics/immunology ; Cancer Vaccines/*immunology/*therapeutic use ; Female ; Glioma/enzymology/genetics/*immunology/*therapy ; Histocompatibility Antigens Class II/immunology ; Humans ; Immunity, Humoral ; Immunotherapy/methods ; Isocitrate Dehydrogenase/*genetics/*immunology ; Male ; Mice ; Mutant Proteins/genetics/*immunology ; Mutation ; T-Lymphocytes, Helper-Inducer/immunology ; Xenograft Model Antitumor Assays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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