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  • 1
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    Dissecting the genomic complexity underlying medulloblastoma (2012)
    Nature Publishing Group (NPG)
    Details
    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
    Published by Nature Publishing Group (NPG)
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  • 2
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    NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-12-21
    Description: Alzheimer's disease is the world's most common dementing illness. Deposition of amyloid-beta peptide drives cerebral neuroinflammation by activating microglia. Indeed, amyloid-beta activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1beta maturation and subsequent inflammatory events. However, it remains unknown whether NLRP3 activation contributes to Alzheimer's disease in vivo. Here we demonstrate strongly enhanced active caspase-1 expression in human mild cognitive impairment and brains with Alzheimer's disease, suggesting a role for the inflammasome in this neurodegenerative disease. Nlrp3(-/-) or Casp1(-/-) mice carrying mutations associated with familial Alzheimer's disease were largely protected from loss of spatial memory and other sequelae associated with Alzheimer's disease, and demonstrated reduced brain caspase-1 and interleukin-1beta activation as well as enhanced amyloid-beta clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-beta in the APP/PS1 model of Alzheimer's disease. These results show an important role for the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer's disease, and suggest that NLRP3 inflammasome inhibition represents a new therapeutic intervention for the disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812809/" 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/PMC3812809/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Heneka, Michael T -- Kummer, Markus P -- Stutz, Andrea -- Delekate, Andrea -- Schwartz, Stephanie -- Vieira-Saecker, Ana -- Griep, Angelika -- Axt, Daisy -- Remus, Anita -- Tzeng, Te-Chen -- Gelpi, Ellen -- Halle, Annett -- Korte, Martin -- Latz, Eicke -- Golenbock, Douglas T -- R01 AI083713/AI/NIAID NIH HHS/ -- R01 GM054060/GM/NIGMS NIH HHS/ -- R01 HL093262/HL/NHLBI NIH HHS/ -- U19 AI084048/AI/NIAID NIH HHS/ -- England -- Nature. 2013 Jan 31;493(7434):674-8. doi: 10.1038/nature11729. Epub 2012 Dec 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany. michael.Heneka@ukb.uni-bonn.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23254930" target="_blank"〉PubMed〈/a〉
    Keywords: Aged ; Aged, 80 and over ; Alzheimer Disease/enzymology/genetics/*pathology ; Amyloid beta-Peptides/metabolism ; Animals ; Behavior, Animal ; Brain/enzymology/*pathology ; Carrier Proteins/genetics/*metabolism ; Caspase 1/genetics/metabolism ; Gene Expression Regulation, Enzymologic ; Humans ; Inflammasomes/metabolism ; Interleukin-1beta/metabolism ; Memory ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mild Cognitive Impairment/enzymology/physiopathology ; Nitric Oxide Synthase Type II/metabolism ; Phagocytosis/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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  • 3
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    Subgroup-specific structural variation across 1,000 medulloblastoma genomes (2012)
    Nature Publishing Group (NPG)
    Details
    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
    Published by Nature Publishing Group (NPG)
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