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  • 1
    Keywords: POOR-PROGNOSIS ; BRAIN-TUMORS ; CHILDHOOD MEDULLOBLASTOMA ; RISK STRATIFICATION ; outcome prediction ; TP53 MUTATIONS ; PATHWAY ACTIVATION ; MOLECULAR SUBGROUPS ; NEUROTROPHIN RECEPTOR TRKC ; MYCN AMPLIFICATION
    Abstract: Purpose Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Patients and Methods Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Results Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Conclusion Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.
    Type of Publication: Journal article published
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  • 2
    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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  • 3
    Publication Date: 2012-07-24
    Description: Medulloblastomas are the most common malignant brain tumours in children. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis of transcriptional and copy number profiles. Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR and LDB1. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant, but not wild-type, beta-catenin. Together, our study reveals the alteration of WNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic beta-catenin signalling in medulloblastoma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413789/" 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/PMC3413789/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pugh, Trevor J -- Weeraratne, Shyamal Dilhan -- Archer, Tenley C -- Pomeranz Krummel, Daniel A -- Auclair, Daniel -- Bochicchio, James -- Carneiro, Mauricio O -- Carter, Scott L -- Cibulskis, Kristian -- Erlich, Rachel L -- Greulich, Heidi -- Lawrence, Michael S -- Lennon, Niall J -- McKenna, Aaron -- Meldrim, James -- Ramos, Alex H -- Ross, Michael G -- Russ, Carsten -- Shefler, Erica -- Sivachenko, Andrey -- Sogoloff, Brian -- Stojanov, Petar -- Tamayo, Pablo -- Mesirov, Jill P -- Amani, Vladimir -- Teider, Natalia -- Sengupta, Soma -- Francois, Jessica Pierre -- Northcott, Paul A -- Taylor, Michael D -- Yu, Furong -- Crabtree, Gerald R -- Kautzman, Amanda G -- Gabriel, Stacey B -- Getz, Gad -- Jager, Natalie -- Jones, David T W -- Lichter, Peter -- Pfister, Stefan M -- Roberts, Thomas M -- Meyerson, Matthew -- Pomeroy, Scott L -- Cho, Yoon-Jae -- CA050661/CA/NCI NIH HHS/ -- L40 NS063706/NS/NINDS NIH HHS/ -- P30 HD018655/HD/NICHD NIH HHS/ -- P30 HD18655/HD/NICHD NIH HHS/ -- R01 CA030002/CA/NCI NIH HHS/ -- R01 CA105607/CA/NCI NIH HHS/ -- R01 CA109467/CA/NCI NIH HHS/ -- R01 CA148699/CA/NCI NIH HHS/ -- R01 CA154480/CA/NCI NIH HHS/ -- R01 NS046789/NS/NINDS NIH HHS/ -- R01CA105607/CA/NCI NIH HHS/ -- R01CA109467/CA/NCI NIH HHS/ -- R01CA148699/CA/NCI NIH HHS/ -- R25 NS070682/NS/NINDS NIH HHS/ -- R25NS070682/NS/NINDS NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- U54HG003067/HG/NHGRI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Aug 2;488(7409):106-10. doi: 10.1038/nature11329.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22820256" target="_blank"〉PubMed〈/a〉
    Keywords: Cerebellar Neoplasms/classification/*genetics ; Child ; DEAD-box RNA Helicases/chemistry/genetics/metabolism ; DNA Helicases/chemistry/genetics ; DNA-Binding Proteins/genetics ; Exome/*genetics ; Genome, Human/*genetics ; Hedgehog Proteins/metabolism ; Histone-Lysine N-Methyltransferase/genetics/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; LIM Domain Proteins/genetics ; Medulloblastoma/classification/*genetics ; Models, Molecular ; Mutation/*genetics ; Neoplasm Proteins/genetics ; Nuclear Proteins/chemistry/genetics ; Promoter Regions, Genetic/genetics ; Protein Structure, Tertiary/genetics ; Proto-Oncogene Proteins/genetics ; Receptors, Cell Surface/genetics ; Repressor Proteins/genetics ; Signal Transduction ; TCF Transcription Factors/metabolism ; Transcription Factors/chemistry/genetics ; Tumor Suppressor Protein p53/genetics ; Wnt Proteins/metabolism ; beta Catenin/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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  • 4
    Publication Date: 2012-02-22
    Description: Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord. Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour. Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288636/" 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/PMC3288636/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Xiaochong -- Northcott, Paul A -- Dubuc, Adrian -- Dupuy, Adam J -- Shih, David J H -- Witt, Hendrik -- Croul, Sidney -- Bouffet, Eric -- Fults, Daniel W -- Eberhart, Charles G -- Garzia, Livia -- Van Meter, Timothy -- Zagzag, David -- Jabado, Nada -- Schwartzentruber, Jeremy -- Majewski, Jacek -- Scheetz, Todd E -- Pfister, Stefan M -- Korshunov, Andrey -- Li, Xiao-Nan -- Scherer, Stephen W -- Cho, Yoon-Jae -- Akagi, Keiko -- MacDonald, Tobey J -- Koster, Jan -- McCabe, Martin G -- Sarver, Aaron L -- Collins, V Peter -- Weiss, William A -- Largaespada, David A -- Collier, Lara S -- Taylor, Michael D -- K01CA122183/CA/NCI NIH HHS/ -- NS055089/NS/NINDS NIH HHS/ -- R01 CA108622/CA/NCI NIH HHS/ -- R01 CA113636/CA/NCI NIH HHS/ -- R01 CA148699/CA/NCI NIH HHS/ -- R01 CA148699-03/CA/NCI NIH HHS/ -- R01 NS055089/NS/NINDS NIH HHS/ -- R01CA148699/CA/NCI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2012 Feb 15;482(7386):529-33. doi: 10.1038/nature10825.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Arthur and Sonia Labatt Brain Tumour Research Center, Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22343890" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Clonal Evolution/*genetics ; CpG Islands/genetics ; DNA Methylation ; DNA Transposable Elements/genetics ; Disease Models, Animal ; Genes, p53/genetics ; Germ-Line Mutation/genetics ; Humans ; Li-Fraumeni Syndrome/complications/genetics ; Medulloblastoma/complications/*genetics/*pathology ; Mice ; Mutagenesis, Insertional ; Neoplasm Metastasis/*genetics/*pathology ; Survival Rate
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2013-05-24
    Description: Recent exon-sequencing studies of human tumours have revealed that subunits of BAF (mammalian SWI/SNF) complexes are mutated in more than 20% of all human malignancies, but the mechanisms involved in tumour suppression are unclear. BAF chromatin-remodelling complexes are polymorphic assemblies that use energy provided by ATP hydrolysis to regulate transcription through the control of chromatin structure and the placement of Polycomb repressive complex 2 (PRC2) across the genome. Several proteins dedicated to this multisubunit complex, including BRG1 (also known as SMARCA4) and BAF250a (also known as ARID1A), are mutated at frequencies similar to those of recognized tumour suppressors. In particular, the core ATPase BRG1 is mutated in 5-10% of childhood medulloblastomas and more than 15% of Burkitt's lymphomas. Here we show a previously unknown function of BAF complexes in decatenating newly replicated sister chromatids, a requirement for proper chromosome segregation during mitosis. We find that deletion of Brg1 in mouse cells, as well as the expression of BRG1 point mutants identified in human tumours, leads to anaphase bridge formation (in which sister chromatids are linked by catenated strands of DNA) and a G2/M-phase block characteristic of the decatenation checkpoint. Endogenous BAF complexes interact directly with endogenous topoisomerase IIalpha (TOP2A) through BAF250a and are required for the binding of TOP2A to approximately 12,000 sites across the genome. Our results demonstrate that TOP2A chromatin binding is dependent on the ATPase activity of BRG1, which is compromised in oncogenic BRG1 mutants. These studies indicate that the ability of TOP2A to prevent DNA entanglement at mitosis requires BAF complexes and suggest that this activity contributes to the role of BAF subunits as tumour suppressors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3668793/" 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/PMC3668793/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dykhuizen, Emily C -- Hargreaves, Diana C -- Miller, Erik L -- Cui, Kairong -- Korshunov, Andrey -- Kool, Marcel -- Pfister, Stefan -- Cho, Yoon-Jae -- Zhao, Keji -- Crabtree, Gerald R -- R01 CA163915/CA/NCI NIH HHS/ -- R01 NS046789/NS/NINDS NIH HHS/ -- R03 DA032469/DA/NIDA NIH HHS/ -- R37 NS046789/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2013 May 30;497(7451):624-7. doi: 10.1038/nature12146. Epub 2013 May 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23698369" target="_blank"〉PubMed〈/a〉
    Keywords: Anaphase ; Animals ; Antigens, Neoplasm/genetics/*metabolism ; Cell Cycle Checkpoints ; Chromatids/metabolism ; Chromatin Assembly and Disassembly ; Chromosome Segregation ; DNA Helicases/deficiency/genetics/*metabolism ; DNA Replication ; DNA Topoisomerases, Type II/genetics/*metabolism ; DNA, Catenated/*chemistry/*metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Fibroblasts ; G2 Phase ; HEK293 Cells ; Humans ; Medulloblastoma/genetics ; Mice ; Mitosis ; Nuclear Proteins/deficiency/genetics/*metabolism ; Transcription Factors/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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  • 6
    Publication Date: 2014-02-21
    Description: Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174313/" 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/PMC4174313/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mack, S C -- Witt, H -- Piro, R M -- Gu, L -- Zuyderduyn, S -- Stutz, A M -- Wang, X -- Gallo, M -- Garzia, L -- Zayne, K -- Zhang, X -- Ramaswamy, V -- Jager, N -- Jones, D T W -- Sill, M -- Pugh, T J -- Ryzhova, M -- Wani, K M -- Shih, D J H -- Head, R -- Remke, M -- Bailey, S D -- Zichner, T -- Faria, C C -- Barszczyk, M -- Stark, S -- Seker-Cin, H -- Hutter, S -- Johann, P -- Bender, S -- Hovestadt, V -- Tzaridis, T -- Dubuc, A M -- Northcott, P A -- Peacock, J -- Bertrand, K C -- Agnihotri, S -- Cavalli, F M G -- Clarke, I -- Nethery-Brokx, K -- Creasy, C L -- Verma, S K -- Koster, J -- Wu, X -- Yao, Y -- Milde, T -- Sin-Chan, P -- Zuccaro, J -- Lau, L -- Pereira, S -- Castelo-Branco, P -- Hirst, M -- Marra, M A -- Roberts, S S -- Fults, D -- Massimi, L -- Cho, Y J -- Van Meter, T -- Grajkowska, W -- Lach, B -- Kulozik, A E -- von Deimling, A -- Witt, O -- Scherer, S W -- Fan, X -- Muraszko, K M -- Kool, M -- Pomeroy, S L -- Gupta, N -- Phillips, J -- Huang, A -- Tabori, U -- Hawkins, C -- Malkin, D -- Kongkham, P N -- Weiss, W A -- Jabado, N -- Rutka, J T -- Bouffet, E -- Korbel, J O -- Lupien, M -- Aldape, K D -- Bader, G D -- Eils, R -- Lichter, P -- Dirks, P B -- Pfister, S M -- Korshunov, A -- Taylor, M D -- P30 CA016672/CA/NCI NIH HHS/ -- P50 CA097257/CA/NCI NIH HHS/ -- R01 CA121941/CA/NCI NIH HHS/ -- R01 CA148621/CA/NCI NIH HHS/ -- R01 CA163737/CA/NCI NIH HHS/ -- R01CA148699/CA/NCI NIH HHS/ -- R01CA159859/CA/NCI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2014 Feb 27;506(7489):445-50. doi: 10.1038/nature13108. Epub 2014 Feb 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada [3] Division of Neurosurgery, University of Toronto, Toronto, Ontario M5S 1A8, Canada [4]. ; 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany [3] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [4]. ; 1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. ; 1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. ; Department of Molecular Genetics, Banting and Best Department of Medical Research, The Donnelly Centre, University of Toronto, Toronto, Ontario M4N 1X8, Canada. ; 1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Genome Biology, European Molecular Biology, Laboratory Meyerhofstr. 1, Heidelberg 69117, Germany. ; 1] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada. ; Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA. ; 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] German Cancer Consortium (DKTK), Heidelberg 69120, Germany. ; 1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Division of Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. ; Department of Neurology, Harvard Medical School, Children's Hospital Boston, MIT, Boston, Massachusetts 02115, USA. ; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; 1] Ontario Cancer Institute, Princess Margaret Cancer Centre-University Health Network, Toronto, Ontario M5G 1L7, Canada [2] Ontario Institute for Cancer Research, Toronto, Ontario M5G 1L7, Canada. ; Cancer Epigenetics Discovery Performance Unit, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426, USA. ; Department of Oncogenomics, Academic Medical Center, Amsterdam 1105, The Netherlands. ; 1] Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany [2] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [3] CCU Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. ; 1] Centre for High-Throughput Biology, Department of Microbiology & Immunology, University of British Columbia, Vancouver, V6T 1Z4 British Columbia, Canada [2] Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada. ; 1] Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada. ; Department of Pediatrics and National Capital Consortium, Uniformed Services University, Bethesda, Maryland 20814, USA. ; Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA. ; Pediatric Neurosurgery, Catholic University Medical School, Gemelli Hospital, Rome 00168, Italy. ; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA. ; Department of Pediatrics, Virginia Commonwealth, Richmond, Virginia 23298-0646, USA. ; Department of Pathology, University of Warsaw, Children's Memorial Health Institute University of Warsaw, Warsaw 04-730, Poland. ; Division of Anatomical Pathology, Department of Pathology and Molecular Medicine, McMaster University, Hamilton General Hospital, Hamilton, Ontario L8S 4K1, Canada. ; 1] Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany [2] German Cancer Consortium (DKTK), Heidelberg 69120, Germany. ; 1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] Department of Neuropathology Ruprecht-Karls-University Heidelberg, Institute of Pathology, Heidelberg 69120, Germany. ; 1] University of Michigan Cell and Developmental Biology, Ann Arbor, Michigan 48109-2200, USA [2] Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; Department of Neurosurgery, University of California San Francisco, San Francisco, California 94143-0112, USA. ; Departments of Neurology, Pediatrics, and Neurosurgery, University of California, San Francisco, The Helen Diller Family Cancer Research Building, San Francisco, California 94158, USA. ; 1] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Department of Neuro-oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada. ; Department of Haematology and Oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada. ; 1] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada [3] Division of Neurosurgery, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Departments of Pediatrics and Human Genetics, McGill University and the McGill University Health Center Research Institute, Montreal, Quebec H3Z 2Z3, Canada. ; Department of Neuro-oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada. ; Genome Biology, European Molecular Biology, Laboratory Meyerhofstr. 1, Heidelberg 69117, Germany. ; 1] Ontario Cancer Institute, Princess Margaret Cancer Centre-University Health Network, Toronto, Ontario M5G 1L7, Canada [2] Ontario Institute for Cancer Research, Toronto, Ontario M5G 1L7, Canada [3] Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1X8, Canada. ; 1] Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada [2] Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada [3] Division of Neurosurgery, University of Toronto, Toronto, Ontario M5S 1A8, Canada [4] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; 1] Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [2] Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg 69120, Germany [3] German Cancer Consortium (DKTK), Heidelberg 69120, Germany. ; 1] German Cancer Consortium (DKTK), Heidelberg 69120, Germany [2] University of Michigan Cell and Developmental Biology, Ann Arbor, Michigan 48109-2200, USA [3] CCU Neuropathology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24553142" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain Neoplasms/drug therapy/genetics ; CpG Islands/*genetics ; DNA Methylation/drug effects ; Embryonic Stem Cells/metabolism ; Ependymoma/drug therapy/*genetics ; Epigenesis, Genetic/*genetics ; Epigenomics ; Female ; Gene Expression Regulation, Neoplastic ; Gene Silencing/drug effects ; Histones/drug effects/metabolism ; Humans ; Infant ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Mutation/genetics ; Phenotype ; Polycomb Repressive Complex 2/metabolism ; Prognosis ; Rhombencephalon/pathology ; Xenograft Model Antitumor Assays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2012-07-27
    Description: Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4alpha. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-beta signalling in Group 3, and NF-kappaB signalling in Group 4, suggest future avenues for rational, targeted therapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3683624/" 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/PMC3683624/" 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 -- Shih, David J H -- Peacock, John -- Garzia, Livia -- Morrissy, A Sorana -- Zichner, Thomas -- Stutz, Adrian M -- Korshunov, Andrey -- Reimand, Juri -- Schumacher, Steven E -- Beroukhim, Rameen -- Ellison, David W -- Marshall, Christian R -- Lionel, Anath C -- Mack, Stephen -- Dubuc, Adrian -- Yao, Yuan -- Ramaswamy, Vijay -- Luu, Betty -- Rolider, Adi -- Cavalli, Florence M G -- Wang, Xin -- Remke, Marc -- Wu, Xiaochong -- Chiu, Readman Y B -- Chu, Andy -- Chuah, Eric -- Corbett, Richard D -- Hoad, Gemma R -- Jackman, Shaun D -- Li, Yisu -- Lo, Allan -- Mungall, Karen L -- Nip, Ka Ming -- Qian, Jenny Q -- Raymond, Anthony G J -- Thiessen, Nina T -- Varhol, Richard J -- Birol, Inanc -- Moore, Richard A -- Mungall, Andrew J -- Holt, Robert -- Kawauchi, Daisuke -- Roussel, Martine F -- Kool, Marcel -- Jones, David T W -- Witt, Hendrick -- Fernandez-L, Africa -- Kenney, Anna M -- Wechsler-Reya, Robert J -- Dirks, Peter -- Aviv, Tzvi -- Grajkowska, Wieslawa A -- Perek-Polnik, Marta -- Haberler, Christine C -- Delattre, Olivier -- Reynaud, Stephanie S -- Doz, Francois F -- Pernet-Fattet, Sarah S -- Cho, Byung-Kyu -- Kim, Seung-Ki -- Wang, Kyu-Chang -- Scheurlen, Wolfram -- Eberhart, Charles G -- Fevre-Montange, Michelle -- Jouvet, Anne -- Pollack, Ian F -- Fan, Xing -- Muraszko, Karin M -- Gillespie, G Yancey -- Di Rocco, Concezio -- Massimi, Luca -- Michiels, Erna M C -- Kloosterhof, Nanne K -- French, Pim J -- Kros, Johan M -- Olson, James M -- Ellenbogen, Richard G -- Zitterbart, Karel -- Kren, Leos -- Thompson, Reid C -- Cooper, Michael K -- Lach, Boleslaw -- McLendon, Roger E -- Bigner, Darell D -- Fontebasso, Adam -- Albrecht, Steffen -- Jabado, Nada -- Lindsey, Janet C -- Bailey, Simon -- Gupta, Nalin -- Weiss, William A -- Bognar, Laszlo -- Klekner, Almos -- Van Meter, Timothy E -- Kumabe, Toshihiro -- Tominaga, Teiji -- Elbabaa, Samer K -- Leonard, Jeffrey R -- Rubin, Joshua B -- Liau, Linda M -- Van Meir, Erwin G -- Fouladi, Maryam -- Nakamura, Hideo -- Cinalli, Giuseppe -- Garami, Miklos -- Hauser, Peter -- Saad, Ali G -- Iolascon, Achille -- Jung, Shin -- Carlotti, Carlos G -- Vibhakar, Rajeev -- Ra, Young Shin -- Robinson, Shenandoah -- Zollo, Massimo -- Faria, Claudia C -- Chan, Jennifer A -- Levy, Michael L -- Sorensen, Poul H B -- Meyerson, Matthew -- Pomeroy, Scott L -- Cho, Yoon-Jae -- Bader, Gary D -- Tabori, Uri -- Hawkins, Cynthia E -- Bouffet, Eric -- Scherer, Stephen W -- Rutka, James T -- Malkin, David -- Clifford, Steven C -- Jones, Steven J M -- Korbel, Jan O -- Pfister, Stefan M -- Marra, Marco A -- Taylor, Michael D -- AT1-112286/Canadian Institutes of Health Research/Canada -- CA116804/CA/NCI NIH HHS/ -- CA138292/CA/NCI NIH HHS/ -- CA159859/CA/NCI NIH HHS/ -- CA86335/CA/NCI NIH HHS/ -- K08 NS059790/NS/NINDS NIH HHS/ -- P20 CA151129/CA/NCI NIH HHS/ -- P30 CA138292/CA/NCI NIH HHS/ -- P30 HD018655/HD/NICHD NIH HHS/ -- P41 GM103504/GM/NIGMS NIH HHS/ -- R01 CA086335/CA/NCI NIH HHS/ -- R01 CA109467/CA/NCI NIH HHS/ -- R01 CA114567/CA/NCI NIH HHS/ -- R01 CA116804/CA/NCI NIH HHS/ -- R01 CA148621/CA/NCI NIH HHS/ -- R01 CA155360/CA/NCI NIH HHS/ -- R01 CA159859/CA/NCI NIH HHS/ -- R01 CA163737/CA/NCI NIH HHS/ -- R01 NS061070/NS/NINDS NIH HHS/ -- England -- Nature. 2012 Aug 2;488(7409):49-56. doi: 10.1038/nature11327.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22832581" target="_blank"〉PubMed〈/a〉
    Keywords: Carrier Proteins/genetics ; Cerebellar Neoplasms/*classification/*genetics/metabolism ; Child ; DNA Copy Number Variations/genetics ; Gene Duplication/genetics ; Genes, myc/genetics ; Genome, Human/*genetics ; Genomic Structural Variation/*genetics ; Genomics ; Hedgehog Proteins/metabolism ; Humans ; Medulloblastoma/*classification/*genetics/metabolism ; NF-kappa B/metabolism ; Nerve Tissue Proteins/genetics ; Oncogene Proteins, Fusion/genetics ; Proteins/genetics ; RNA, Long Noncoding ; Signal Transduction ; Transforming Growth Factor beta/metabolism ; Translocation, Genetic/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2016-01-14
    Description: The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (〈5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (〈12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Morrissy, A Sorana -- Garzia, Livia -- Shih, David J H -- Zuyderduyn, Scott -- Huang, Xi -- Skowron, Patryk -- Remke, Marc -- Cavalli, Florence M G -- Ramaswamy, Vijay -- Lindsay, Patricia E -- Jelveh, Salomeh -- Donovan, Laura K -- Wang, Xin -- Luu, Betty -- Zayne, Kory -- Li, Yisu -- Mayoh, Chelsea -- Thiessen, Nina -- Mercier, Eloi -- Mungall, Karen L -- Ma, Yusanne -- Tse, Kane -- Zeng, Thomas -- Shumansky, Karey -- Roth, Andrew J L -- Shah, Sohrab -- Farooq, Hamza -- Kijima, Noriyuki -- Holgado, Borja L -- Lee, John J Y -- Matan-Lithwick, Stuart -- Liu, Jessica -- Mack, Stephen C -- Manno, Alex -- Michealraj, K A -- Nor, Carolina -- Peacock, John -- Qin, Lei -- Reimand, Juri -- Rolider, Adi -- Thompson, Yuan Y -- Wu, Xiaochong -- Pugh, Trevor -- Ally, Adrian -- Bilenky, Mikhail -- Butterfield, Yaron S N -- Carlsen, Rebecca -- Cheng, Young -- Chuah, Eric -- Corbett, Richard D -- Dhalla, Noreen -- He, An -- Lee, Darlene -- Li, Haiyan I -- Long, William -- Mayo, Michael -- Plettner, Patrick -- Qian, Jenny Q -- Schein, Jacqueline E -- Tam, Angela -- Wong, Tina -- Birol, Inanc -- Zhao, Yongjun -- Faria, Claudia C -- Pimentel, Jose -- Nunes, Sofia -- Shalaby, Tarek -- Grotzer, Michael -- Pollack, Ian F -- Hamilton, Ronald L -- Li, Xiao-Nan -- Bendel, Anne E -- Fults, Daniel W -- Walter, Andrew W -- Kumabe, Toshihiro -- Tominaga, Teiji -- Collins, V Peter -- Cho, Yoon-Jae -- Hoffman, Caitlin -- Lyden, David -- Wisoff, Jeffrey H -- Garvin, James H Jr -- Stearns, Duncan S -- Massimi, Luca -- Schuller, Ulrich -- Sterba, Jaroslav -- Zitterbart, Karel -- Puget, Stephanie -- Ayrault, Olivier -- Dunn, Sandra E -- Tirapelli, Daniela P C -- Carlotti, Carlos G -- Wheeler, Helen -- Hallahan, Andrew R -- Ingram, Wendy -- MacDonald, Tobey J -- Olson, Jeffrey J -- Van Meir, Erwin G -- Lee, Ji-Yeoun -- Wang, Kyu-Chang -- Kim, Seung-Ki -- Cho, Byung-Kyu -- Pietsch, Torsten -- Fleischhack, Gudrun -- Tippelt, Stephan -- Ra, Young Shin -- Bailey, Simon -- Lindsey, Janet C -- Clifford, Steven C -- Eberhart, Charles G -- Cooper, Michael K -- Packer, Roger J -- Massimino, Maura -- Garre, Maria Luisa -- Bartels, Ute -- Tabori, Uri -- Hawkins, Cynthia E -- Dirks, Peter -- Bouffet, Eric -- Rutka, James T -- Wechsler-Reya, Robert J -- Weiss, William A -- Collier, Lara S -- Dupuy, Adam J -- Korshunov, Andrey -- Jones, David T W -- Kool, Marcel -- Northcott, Paul A -- Pfister, Stefan M -- Largaespada, David A -- Mungall, Andrew J -- Moore, Richard A -- Jabado, Nada -- Bader, Gary D -- Jones, Steven J M -- Malkin, David -- Marra, Marco A -- Taylor, Michael D -- R01 CA163722/CA/NCI NIH HHS/ -- R01 NS096236/NS/NINDS NIH HHS/ -- R01CA148699/CA/NCI NIH HHS/ -- R01CA159859/CA/NCI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2016 Jan 21;529(7586):351-7. doi: 10.1038/nature16478. Epub 2016 Jan 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada. ; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. ; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 0A4, Canada. ; The Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada. ; Department of Pediatric Oncology, Hematology, and Clinical Immunology, University Hospital Dusseldorf, M5S 3E1, Germany. ; Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario M5S 3E1, Canada. ; Department of Radiation Oncology, University of Toronto, Toronto, Ontario M5G 2M9, Canada. ; Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada. ; Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada. ; Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada. ; Center for Stem Cell &Regenerative Medicine, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. ; Clinical Genomics Research Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario 44195, Canada. ; Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. ; School of Computing Science, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada. ; Division of Neurosurgery, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon 1649-035, Portugal. ; Divison of Pathology, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon 1649-035, Portugal. ; Unidade de Neuro-Oncologia Pediatrica, Instituto Portugues de Oncologia de Lisboa Francisco Gentil, Lisbon 1099-023, Portugal. ; Departments of Oncology and Neuro-Oncology, University Children's Hospital of Zurich, Zurich 8032, Switzerland. ; Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224, USA. ; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA. ; Brain Tumor Program, Children's Cancer Center and Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA. ; Pediatric Hematology-Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota 55404, USA. ; Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah 84132, USA. ; A I duPont Hospital for Children, Wilmington, Delaware 19803, USA. ; Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan. ; Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan. ; Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK. ; Departments of Neurosurgery, Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA. ; Departments of Pediatrics, Cell &Developmental Biology, Weill Medical College of Cornell University, New York, New York 10065, USA. ; Department of Neurosurgery, NYU Langone Medical Center, New York, New York 10016, USA. ; Department of Pediatrics, Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Columbia University, New York, New York 10032, USA. ; Department of Pediatrics-Hematology and Oncology, Rainbow Babies &Children's Hospital and Department of Pediatrics-Hematology and Oncology, Case Western Reserve, Cleveland, Ohio 44106, USA. ; Pediatric Neurosurgery, Catholic University Medical School, Rome 00198, Italy. ; Center for Neuropathology, Ludwig-Maximilians-Universitat, Munich 81377, Germany. ; Department of Pediatric Oncology, School of Medicine, Masaryk University, Brno 625 00, Czech Republic. ; AP-HP, Department of Neurosurgery, Necker-Enfants Malades Hospital, Universite Rene Descartes, Paris 75743, France. ; Signaling in Development and Brain Tumors, CNRS UMR 3347 / INSERM U1021, Institut Curie, Paris Cedex 5 91405, France. ; Division of Hematology/Oncology, British Columbia Children's Hospital, Vancouver, British Columbia V6H 3V4, Canada. ; Department of Surgery and Anatomy, Faculty of Medicine of Ribeirao Preto, Universidade de Sao Paulo, Brazil, Rebeirao Preto, Sao Paulo 14049-900, Brazil. ; Kolling Institute of Medical Research, The University of Sydney, Sydney, New South Wales 2065, Australia. ; Queensland Children's Medical Research Institute, Children's Health Queensland, Brisbane, Queensland 4029, Australia. ; Division of Oncology, Children's Health Queensland, Brisbane, Queensland 4029, Australia. ; UQ Child Health Research Centre, The University of Queensland, Brisbane 4029, Australia. ; Pediatric Neuro-Oncology Program, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia 30307, USA. ; Department of Neurosurgery, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA. ; Department of Hematology &Medical Oncology, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA. ; Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul 30322, South Korea. ; Institute for Neuropathology, University of Bonn D-53105, Germany. ; Children's University Hospital of Essen D-45147, Germany. ; Department of Neurosurgery, University of Ulsan, Asan Medical Center, Seoul 05505, South Korea. ; Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK. ; Departments of Pathology, Ophthalmology and Oncology, John Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Department of Neurology, Vanderbilt Medical Center, Nashville, Tennessee 37232-8550, USA. ; Department of Neurology, Children's National Medical Center, Washington DC 20010-2970, USA. ; Fondazione IRCCS Istituto Nazionale Tumori, Milan 20133, Italy. ; U.O. Neurochirurgia, Istituto Giannina Gaslini, Genova 16147, Italy. ; Department of Haematology &Oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada. ; Division of Pathology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada. ; Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA. ; Departments of Pediatrics, Neurology and Neurosurgery, University of California San Francisco, San Francisco, California 94158, USA. ; School of Pharmacology, University of Wisconsin, Madison, Wisconsin 53715, USA. ; Molecular &Cellular Biology Program, University of Iowa, Iowa City, Iowa 52242, USA. ; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. ; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. ; Department of Pediatric Oncology, University Hospital Heidelberg, Heidelberg 69120, Germany. ; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA. ; Division of Hematology/Oncology, McGill University, Montreal, Quebec H2W 1S6., Canada. ; McLaughlin Centre and Department of Molecular Genetics, Banting and Best Department of Medical Research and Samuel Lunenfeld Research Institute at Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1L7, Canada. ; Department of Molecular Biology &Biochemistry, Simon Fraser University, Burnaby, British Columbia M5G 1L7, Canada. ; Department of Pediatrics, University of Toronto, Toronto, Ontario M5G 1X8, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26760213" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    ISSN: 1432-0614
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Summary A process for l-phenylalanine production was studied using a tyrosine auxotrophic regulatory mutant of Escherichia coli, resistant to both β-2-thienyl-dl-alanine and p-fluoro-dl-phenylalanine. Fermentations were carried out in a 30-1 fermentor with intermittent feeding of glucose plus phosphate. The mutant accumulated l-phenylalanine in the fermentation broth up to 15 g/l at pH 7.0 and 33°C. Column chromatography on a strong cation exchanger was employed as the most effective step in the purification of l-phenyl-alanine from the broth. This step brought about 4-fold concentration of the product with 96% recovery.
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  • 10
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background  There are many reports of patients with a severe hydroa vacciniforme (HV)-like eruption in which cutaneous lesions occur in both sun-exposed and non-exposed areas, unlike in true HV. Several patients have died from a malignant haematological neoplasm. In most cases, a latent Epstein–Barr virus (EBV) infection has been detected in the skin lesions.Objectives  To describe the clinical and laboratory features of six additional patients with an EBV-associated HV-like eruption.Methods  The clinical, histological and immunohistochemical features were reviewed. T-cell receptor γ gene rearrangements were studied using polymerase chain reaction (PCR) and heteroduplex analysis. In-situ hybridization was performed to detect mRNA for EBV in skin biopsy specimens. PCR was performed to screen for EBV infection in the skin lesions of three patients and blood of two patients. Photoprovocation with repeated ultraviolet (UV) A exposure was performed in three patients.Results  The severity of the skin lesions and the clinical course varied among the patients. Skin lesions were induced by repeated UVA exposure in three patients and a latent EBV infection was demonstrated in the photoprovoked lesions.Conclusions  Three different clinical courses were found in six patients with an HV-like eruption associated with chronic EBV infection: (i) spontaneous remission; (ii) clearing after photoprotection; and (iii) continuous recurrence irrespective of sun exposure. It is possible that there are two patterns of HV-like eruption associated with chronic EBV infection. One is characterized by recurrent necrotic papulovesicles of the face and the other by nodules and facial swelling. It was demonstrated that the skin lesions could be triggered by repeated UVA exposure in the patients showing recurrent necrotic papulovesicles of the face.
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