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  • 1
    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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  • 2
    Publication Date: 2013-07-23
    Description: Stable isotope ratios of H, C, and O are powerful indicators of a wide variety of planetary geophysical processes, and for Mars they reveal the record of loss of its atmosphere and subsequent interactions with its surface such as carbonate formation. We report in situ measurements of the isotopic ratios of D/H and (18)O/(16)O in water and (13)C/(12)C, (18)O/(16)O, (17)O/(16)O, and (13)C(18)O/(12)C(16)O in carbon dioxide, made in the martian atmosphere at Gale Crater from the Curiosity rover using the Sample Analysis at Mars (SAM)'s tunable laser spectrometer (TLS). Comparison between our measurements in the modern atmosphere and those of martian meteorites such as ALH 84001 implies that the martian reservoirs of CO2 and H2O were largely established ~4 billion years ago, but that atmospheric loss or surface interaction may be still ongoing.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Webster, Chris R -- Mahaffy, Paul R -- Flesch, Gregory J -- Niles, Paul B -- Jones, John H -- Leshin, Laurie A -- Atreya, Sushil K -- Stern, Jennifer C -- Christensen, Lance E -- Owen, Tobias -- Franz, Heather -- Pepin, Robert O -- Steele, Andrew -- MSL Science Team -- Achilles, Cherie -- Agard, Christophe -- Alves Verdasca, Jose Alexandre -- Anderson, Robert -- Anderson, Ryan -- Archer, Doug -- Armiens-Aparicio, Carlos -- Arvidson, Ray -- Atlaskin, Evgeny -- Aubrey, Andrew -- Baker, Burt -- Baker, Michael -- Balic-Zunic, Tonci -- Baratoux, David -- Baroukh, Julien -- Barraclough, Bruce -- Bean, Keri -- Beegle, Luther -- Behar, Alberto -- Bell, James -- Bender, Steve -- Benna, Mehdi -- Bentz, Jennifer -- Berger, Gilles -- Berger, Jeff -- Berman, Daniel -- Bish, David -- Blake, David F -- Blanco Avalos, Juan J -- Blaney, Diana -- Blank, Jen -- Blau, Hannah -- Bleacher, Lora -- Boehm, Eckart -- Botta, Oliver -- Bottcher, Stephan -- Boucher, Thomas -- Bower, Hannah -- Boyd, Nick -- Boynton, Bill -- Breves, Elly -- Bridges, John -- Bridges, Nathan -- Brinckerhoff, William -- Brinza, David -- Bristow, Thomas -- Brunet, Claude -- Brunner, Anna -- Brunner, Will -- Buch, Arnaud -- Bullock, Mark -- Burmeister, Sonke -- Cabane, Michel -- Calef, Fred -- Cameron, James -- Campbell, John -- Cantor, Bruce -- Caplinger, Michael -- Caride Rodriguez, Javier -- Carmosino, Marco -- Carrasco Blazquez, Isaias -- Charpentier, Antoine -- Chipera, Steve -- Choi, David -- Clark, Benton -- Clegg, Sam -- Cleghorn, Timothy -- Cloutis, Ed -- Cody, George -- Coll, Patrice -- Conrad, Pamela -- Coscia, David -- Cousin, Agnes -- Cremers, David -- Crisp, Joy -- Cros, Alain -- Cucinotta, Frank -- d'Uston, Claude -- Davis, Scott -- Day, Mackenzie -- de la Torre Juarez, Manuel -- DeFlores, Lauren -- DeLapp, Dorothea -- DeMarines, Julia -- DesMarais, David -- Dietrich, William -- Dingler, Robert -- Donny, Christophe -- Downs, Bob -- Drake, Darrell -- Dromart, Gilles -- Dupont, Audrey -- Duston, Brian -- Dworkin, Jason -- Dyar, M Darby -- Edgar, Lauren -- Edgett, Kenneth -- Edwards, Christopher -- Edwards, Laurence -- Ehlmann, Bethany -- Ehresmann, Bent -- Eigenbrode, Jen -- Elliott, Beverley -- Elliott, Harvey -- Ewing, Ryan -- Fabre, Cecile -- Fairen, Alberto -- Farley, Ken -- Farmer, Jack -- Fassett, Caleb -- Favot, Laurent -- Fay, Donald -- Fedosov, Fedor -- Feldman, Jason -- Feldman, Sabrina -- Fisk, Marty -- Fitzgibbon, Mike -- Floyd, Melissa -- Fluckiger, Lorenzo -- Forni, Olivier -- Fraeman, Abby -- Francis, Raymond -- Francois, Pascaline -- Freissinet, Caroline -- French, Katherine Louise -- Frydenvang, Jens -- Gaboriaud, Alain -- Gailhanou, Marc -- Garvin, James -- Gasnault, Olivier -- Geffroy, Claude -- Gellert, Ralf -- Genzer, Maria -- Glavin, Daniel -- Godber, Austin -- Goesmann, Fred -- Goetz, Walter -- Golovin, Dmitry -- Gomez Gomez, Felipe -- Gomez-Elvira, Javier -- Gondet, Brigitte -- Gordon, Suzanne -- Gorevan, Stephen -- Grant, John -- Griffes, Jennifer -- Grinspoon, David -- Grotzinger, John -- Guillemot, Philippe -- Guo, Jingnan -- Gupta, Sanjeev -- Guzewich, Scott -- Haberle, Robert -- Halleaux, Douglas -- Hallet, Bernard -- Hamilton, Vicky -- Hardgrove, Craig -- Harker, David -- Harpold, Daniel -- Harri, Ari-Matti -- Harshman, Karl -- Hassler, Donald -- Haukka, Harri -- Hayes, Alex -- Herkenhoff, Ken -- Herrera, Paul -- Hettrich, Sebastian -- Heydari, Ezat -- Hipkin, Victoria -- Hoehler, Tori -- Hollingsworth, Jeff -- Hudgins, Judy -- Huntress, Wesley -- Hurowitz, Joel -- Hviid, Stubbe -- Iagnemma, Karl -- Indyk, Steve -- Israel, Guy -- Jackson, Ryan -- Jacob, Samantha -- Jakosky, Bruce -- Jensen, Elsa -- Jensen, Jaqueline Klovgaard -- Johnson, Jeffrey -- Johnson, Micah -- Johnstone, Steve -- Jones, Andrea -- Joseph, Jonathan -- Jun, Insoo -- Kah, Linda -- Kahanpaa, Henrik -- Kahre, Melinda -- Karpushkina, Natalya -- Kasprzak, Wayne -- Kauhanen, Janne -- Keely, Leslie -- Kemppinen, Osku -- Keymeulen, Didier -- Kim, Myung-Hee -- Kinch, Kjartan -- King, Penny -- Kirkland, Laurel -- Kocurek, Gary -- Koefoed, Asmus -- Kohler, Jan -- Kortmann, Onno -- Kozyrev, Alexander -- Krezoski, Jill -- Krysak, Daniel -- Kuzmin, Ruslan -- Lacour, Jean Luc -- Lafaille, Vivian -- Langevin, Yves -- Lanza, Nina -- Lasue, Jeremie -- Le Mouelic, Stephane -- Lee, Ella Mae -- Lee, Qiu-Mei -- Lees, David -- Lefavor, Matthew -- Lemmon, Mark -- Lepinette Malvitte, Alain -- Leveille, Richard -- Lewin-Carpintier, Eric -- Lewis, Kevin -- Li, Shuai -- Lipkaman, Leslie -- Little, Cynthia -- Litvak, Maxim -- Lorigny, Eric -- Lugmair, Guenter -- Lundberg, Angela -- Lyness, Eric -- Madsen, Morten -- Maki, Justin -- Malakhov, Alexey -- Malespin, Charles -- Malin, Michael -- Mangold, Nicolas -- Manhes, Gerard -- Manning, Heidi -- Marchand, Genevieve -- Marin Jimenez, Mercedes -- Martin Garcia, Cesar -- Martin, Dave -- Martin, Mildred -- Martinez-Frias, Jesus -- Martin-Soler, Javier -- Martin-Torres, F Javier -- Mauchien, Patrick -- Maurice, Sylvestre -- McAdam, Amy -- McCartney, Elaina -- McConnochie, Timothy -- McCullough, Emily -- McEwan, Ian -- McKay, Christopher -- McLennan, Scott -- McNair, Sean -- Melikechi, Noureddine -- Meslin, Pierre-Yves -- Meyer, Michael -- Mezzacappa, Alissa -- Miller, Hayden -- Miller, Kristen -- Milliken, Ralph -- Ming, Douglas -- Minitti, Michelle -- Mischna, Michael -- Mitrofanov, Igor -- Moersch, Jeff -- Mokrousov, Maxim -- Molina Jurado, Antonio -- Moores, John -- Mora-Sotomayor, Luis -- Morookian, John Michael -- Morris, Richard -- Morrison, Shaunna -- Mueller-Mellin, Reinhold -- Muller, Jan-Peter -- Munoz Caro, Guillermo -- Nachon, Marion -- Navarro Lopez, Sara -- Navarro-Gonzalez, Rafael -- Nealson, Kenneth -- Nefian, Ara -- Nelson, Tony -- Newcombe, Megan -- Newman, Claire -- Newsom, Horton -- Nikiforov, Sergey -- Nixon, Brian -- Noe Dobrea, Eldar -- Nolan, Thomas -- Oehler, Dorothy -- Ollila, Ann -- Olson, Timothy -- de Pablo Hernandez, Miguel Angel -- Paillet, Alexis -- Pallier, Etienne -- Palucis, Marisa -- Parker, Timothy -- Parot, Yann -- Patel, Kiran -- Paton, Mark -- Paulsen, Gale -- Pavlov, Alex -- Pavri, Betina -- Peinado-Gonzalez, Veronica -- Peret, Laurent -- Perez, Rene -- Perrett, Glynis -- Peterson, Joe -- Pilorget, Cedric -- Pinet, Patrick -- Pla-Garcia, Jorge -- Plante, Ianik -- Poitrasson, Franck -- Polkko, Jouni -- Popa, Radu -- Posiolova, Liliya -- Posner, Arik -- Pradler, Irina -- Prats, Benito -- Prokhorov, Vasily -- Purdy, Sharon Wilson -- Raaen, Eric -- Radziemski, Leon -- Rafkin, Scot -- Ramos, Miguel -- Rampe, Elizabeth -- Raulin, Francois -- Ravine, Michael -- Reitz, Gunther -- Renno, Nilton -- Rice, Melissa -- Richardson, Mark -- Robert, Francois -- Robertson, Kevin -- Rodriguez Manfredi, Jose Antonio -- Romeral-Planello, Julio J -- Rowland, Scott -- Rubin, David -- Saccoccio, Muriel -- Salamon, Andrew -- Sandoval, Jennifer -- Sanin, Anton -- Sans Fuentes, Sara Alejandra -- Saper, Lee -- Sarrazin, Philippe -- Sautter, Violaine -- Savijarvi, Hannu -- Schieber, Juergen -- Schmidt, Mariek -- Schmidt, Walter -- Scholes, Daniel -- Schoppers, Marcel -- Schroder, Susanne -- Schwenzer, Susanne -- Sebastian Martinez, Eduardo -- Sengstacken, Aaron -- Shterts, Ruslan -- Siebach, Kirsten -- Siili, Tero -- Simmonds, Jeff -- Sirven, Jean-Baptiste -- Slavney, Susie -- Sletten, Ronald -- Smith, Michael -- Sobron Sanchez, Pablo -- Spanovich, Nicole -- Spray, John -- Squyres, Steven -- Stack, Katie -- Stalport, Fabien -- Stein, Thomas -- Stewart, Noel -- Stipp, Susan Louise Svane -- Stoiber, Kevin -- Stolper, Ed -- Sucharski, Bob -- Sullivan, Rob -- Summons, Roger -- Sumner, Dawn -- Sun, Vivian -- Supulver, Kimberley -- Sutter, Brad -- Szopa, Cyril -- Tan, Florence -- Tate, Christopher -- Teinturier, Samuel -- ten Kate, Inge -- Thomas, Peter -- Thompson, Lucy -- Tokar, Robert -- Toplis, Mike -- Torres Redondo, Josefina -- Trainer, Melissa -- Treiman, Allan -- Tretyakov, Vladislav -- Urqui-O'Callaghan, Roser -- Van Beek, Jason -- Van Beek, Tessa -- VanBommel, Scott -- Vaniman, David -- Varenikov, Alexey -- Vasavada, Ashwin -- Vasconcelos, Paulo -- Vicenzi, Edward -- Vostrukhin, Andrey -- Voytek, Mary -- Wadhwa, Meenakshi -- Ward, Jennifer -- Weigle, Eddie -- Wellington, Danika -- Westall, Frances -- Wiens, Roger Craig -- Wilhelm, Mary Beth -- Williams, Amy -- Williams, Joshua -- Williams, Rebecca -- Williams, Richard B -- Wilson, Mike -- Wimmer-Schweingruber, Robert -- Wolff, Mike -- Wong, Mike -- Wray, James -- Wu, Megan -- Yana, Charles -- Yen, Albert -- Yingst, Aileen -- Zeitlin, Cary -- Zimdar, Robert -- Zorzano Mier, Maria-Paz -- New York, N.Y. -- Science. 2013 Jul 19;341(6143):260-3. doi: 10.1126/science.1237961.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Jet Propulsion Laboratory, California Institute of Technology, Pasadena, CA 91109, USA. chris.r.webster@jpl.nasa.gov〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23869013" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    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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  • 4
    Publication Date: 2013-09-28
    Description: The ChemCam instrument, which provides insight into martian soil chemistry at the submillimeter scale, identified two principal soil types along the Curiosity rover traverse: a fine-grained mafic type and a locally derived, coarse-grained felsic type. The mafic soil component is representative of widespread martian soils and is similar in composition to the martian dust. It possesses a ubiquitous hydrogen signature in ChemCam spectra, corresponding to the hydration of the amorphous phases found in the soil by the CheMin instrument. This hydration likely accounts for an important fraction of the global hydration of the surface seen by previous orbital measurements. ChemCam analyses did not reveal any significant exchange of water vapor between the regolith and the atmosphere. These observations provide constraints on the nature of the amorphous phases and their hydration.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Meslin, P-Y -- Gasnault, O -- Forni, O -- Schroder, S -- Cousin, A -- Berger, G -- Clegg, S M -- Lasue, J -- Maurice, S -- Sautter, V -- Le Mouelic, S -- Wiens, R C -- Fabre, C -- Goetz, W -- Bish, D -- Mangold, N -- Ehlmann, B -- Lanza, N -- Harri, A-M -- Anderson, R -- Rampe, E -- McConnochie, T H -- Pinet, P -- Blaney, D -- Leveille, R -- Archer, D -- Barraclough, B -- Bender, S -- Blake, D -- Blank, J G -- Bridges, N -- Clark, B C -- DeFlores, L -- Delapp, D -- Dromart, G -- Dyar, M D -- Fisk, M -- Gondet, B -- Grotzinger, J -- Herkenhoff, K -- Johnson, J -- Lacour, J-L -- Langevin, Y -- Leshin, L -- Lewin, E -- Madsen, M B -- Melikechi, N -- Mezzacappa, A -- Mischna, M A -- Moores, J E -- Newsom, H -- Ollila, A -- Perez, R -- Renno, N -- Sirven, J-B -- Tokar, R -- de la Torre, M -- d'Uston, L -- Vaniman, D -- Yingst, A -- MSL Science Team -- New York, N.Y. -- Science. 2013 Sep 27;341(6153):1238670. doi: 10.1126/science.1238670.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Universite de Toulouse, UPS-OMP, IRAP, 31028 Toulouse, France. pmeslin@irap.omp.eu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24072924" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
    Keywords: EXPRESSION ; tumor ; IDENTIFICATION ; PROGRESSION ; OVARIAN-CANCER ; PROGNOSTIC-FACTORS ; CHILDHOOD MEDULLOBLASTOMA ; STEM-CELL ; BREAST-CANCER CELLS ; INFLUENCES ZYXIN LOCALIZATION
    Abstract: Medulloblastoma is the most common malignant pediatric brain tumor and is one of the leading causes of cancer-related mortality in children. Treatment failure mainly occurs in children harboring metastatic tumors, which typically carry an isochromosome 17 or gain of 17q, a common hallmark of intermediate and high-risk medulloblastoma. Through mRNA expression profiling, we identified LIM and SH3 protein 1 (LASP1) as one of the most upregulated genes on chromosome 17q in tumors with 17q gain. In an independent validation cohort of 101 medulloblastoma samples, the abundance of LASP1 mRNA was significantly associated with 17q gain, metastatic dissemination, and unfavorable outcome. LASP1 protein expression was analyzed by immunohistochemistry in a large cohort of patients (n = 207), and high protein expression levels were found to be strongly correlated with 17q gain, metastatic dissemination, and inferior overall and progression-free survival. In vitro experiments in medulloblastoma cell lines showed a strong reduction of cell migration, increased adhesion, and decreased proliferation upon LASP1 knockdown by small interfering RNA-mediated silencing, further indicating a functional role for LASP1 in the progression and metastatic dissemination of medulloblastoma.
    Type of Publication: Journal article published
    PubMed ID: 20924110
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  • 6
    Keywords: CANCER ; EXPRESSION ; SURVIVAL ; GENES ; PROTEIN ; transcription ; TRANSCRIPTION FACTOR ; IDENTIFICATION ; PROMOTER ; chemotherapy ; MUTATIONS ; LOCALIZATION ; METHYLATION ; BRAIN-TUMORS ; ACUTE MYELOID-LEUKEMIA ; INTRACRANIAL EPENDYMOMAS ; MDS1/EVI1
    Abstract: Purpose: Ependymomas are glial tumors of presumably radial glial origin that share morphologic similarities with ependymal cells. The molecular genetics of ependymomas of supratentorial, infratentorial, and spinal location is heterogeneous. We aimed at identifying pathways operative in the development of infratentorial ependymomas. Experimental Design: To do so, gene expression profiles of tumor cells laser microdissected from infratentorial ependymomas (n = 15) were compared with that of nonneoplastic ependymal cells laser microdissected from autopsy tissue (n = 7). Results: Among 31 genes significantly overexpressed (〉5-fold) in ependymomas, transcription factor EVI1 (ecotropic viral integration site 1) showed the highest overexpression (35-fold). Evi-1 protein expression could be confirmed in formalin-fixed, paraffin-embedded samples of 26 of 28 infratentorial ependymomas but only in 7 of 47 nonependymal glial tumors (P 〈 0.001). Furthermore, MDS1/EVI1 fusion transcripts were detectable in 17 of 28 infratentorial ependymomas and significantly correlated with MGMT (O6-methylguanine-DNA-methyltransferase) promoter hypermethylation (P 〈 0.05). In primary infratentorial ependymoma cells, transfection with EVI1-specific siRNAs resulted in significant growth inhibition [48 hours: 87% +/- 2% and 74% +/- 10% as compared with control (mean +/- SD; P 〈 0.001)]. The prognostic role of EVI1 could further be validated in an independent cohort of 39 infratentorial and 26 supratentorial ependymomas on the basis of mRNA expression profiling. Although in supratentorial ependymomas EVI1 expression status had no prognostic impact, in infratentorial ependymomas, high EVI1 expression was associated with shorter overall survival and progression-free survival. Conclusions: To conclude, the transcription factor Evi-1 is overexpressed in infratentorial ependymomas, promotes proliferation of ependymal tumor cells, and is prognostically unfavorable.
    Type of Publication: Journal article published
    PubMed ID: 21493867
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  • 7
    Keywords: DISTINCT ; GENE ; BREAST-CANCER ; COPY-NUMBER ; SONIC HEDGEHOG ; GERMLINE ; LI-FRAUMENI-SYNDROME ; ACUTE MYELOID-LEUKEMIA ; telomere length ; FAMILIAL SYNDROME
    Abstract: Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acutemyeloid leukemia. These findings connect p53 status and chr
    Type of Publication: Journal article published
    PubMed ID: 22265402
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  • 8
    Keywords: CANCER ; PATHWAY ; GENES ; ACTIVATION ; MUTATIONS ; SUBGROUPS ; LANDSCAPE ; TETRAPLOID TUMOR-CELLS ; TBR1
    Abstract: 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.
    Type of Publication: Journal article published
    PubMed ID: 22832583
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  • 9
    Keywords: CANCER ; GROWTH ; TUMORS ; NERVOUS-SYSTEM ; ADULT ; MOUSE MODELS ; PEDIATRIC MEDULLOBLASTOMA ; HEDGEHOG PATHWAY INHIBITOR ; TERT PROMOTER MUTATIONS ; ITRACONAZOLE
    Abstract: Smoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children 〉3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant.
    Type of Publication: Journal article published
    PubMed ID: 24651015
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  • 10
    Keywords: APOPTOSIS ; PATHWAY ; GENES ; POOR-PROGNOSIS ; INCREASED EXPRESSION ; MICE LACKING ; high-throughput analysis ; ISLAND METHYLATOR PHENOTYPE ; D-DEPENDENT KINASES ; INK4 FAMILY
    Abstract: Uncontrolled cell cycle entry, resulting from deregulated CDK-RB1-E2F pathway activity, is a crucial determinant of neuroblastoma cell malignancy. Here we identify neuroblastoma-suppressive functions of the p19-INK4d CDK inhibitor and uncover mechanisms of its repression in high-risk neuroblastomas. Reduced p19-INK4d expression was associated with poor event-free and overall survival and neuroblastoma risk factors including amplified MYCN in a set of 478 primary neuroblastomas. High MYCN expression repressed p19-INK4d mRNA and protein levels in different neuroblastoma cell models with conditional MYCN expression. MassARRAY and 450K methylation analyses of 105 primary neuroblastomas uncovered a differentially methylated region within p19-INK4d. Hypermethylation of this region was associated with reduced p19-INK4d expression. In accordance, p19-INK4d expression was activated upon treatment with the demethylating agent, 2'-deoxy-5-azacytidine, in neuroblastoma cell lines. Ectopic p19-INK4d expression decreased viability, clonogenicity and the capacity for anchorage-independent growth of neuroblastoma cells, and shifted the cell cycle towards the G1/0 phase. p19-INK4d also induced neurite-like processes and markers of neuronal differentiation. Moreover, neuroblastoma cell differentiation, induced by all-trans retinoic acid or NGF-NTRK1-signaling, activated p19-/NK4dexpression. Our findings pinpoint p19-INK4d as a neuroblastoma suppressor and provide evidence for MYCN-mediated repression and for epigenetic silencing of p19-INK4d by DNA hypermethylation in high-risk neuroblastomas.
    Type of Publication: Journal article published
    PubMed ID: 25104850
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