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  • 1
    Publication Date: 2012-06-23
    Description: Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412905/" 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/PMC3412905/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Robinson, Giles -- Parker, Matthew -- Kranenburg, Tanya A -- Lu, Charles -- Chen, Xiang -- Ding, Li -- Phoenix, Timothy N -- Hedlund, Erin -- Wei, Lei -- Zhu, Xiaoyan -- Chalhoub, Nader -- Baker, Suzanne J -- Huether, Robert -- Kriwacki, Richard -- Curley, Natasha -- Thiruvenkatam, Radhika -- Wang, Jianmin -- Wu, Gang -- Rusch, Michael -- Hong, Xin -- Becksfort, Jared -- Gupta, Pankaj -- Ma, Jing -- Easton, John -- Vadodaria, Bhavin -- Onar-Thomas, Arzu -- Lin, Tong -- Li, Shaoyi -- Pounds, Stanley -- Paugh, Steven -- Zhao, David -- Kawauchi, Daisuke -- Roussel, Martine F -- Finkelstein, David -- Ellison, David W -- Lau, Ching C -- Bouffet, Eric -- Hassall, Tim -- Gururangan, Sridharan -- Cohn, Richard -- Fulton, Robert S -- Fulton, Lucinda L -- Dooling, David J -- Ochoa, Kerri -- Gajjar, Amar -- Mardis, Elaine R -- Wilson, Richard K -- Downing, James R -- Zhang, Jinghui -- Gilbertson, Richard J -- P01 CA096832/CA/NCI NIH HHS/ -- P01CA96832/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- P30CA021765/CA/NCI NIH HHS/ -- R01 CA129541/CA/NCI NIH HHS/ -- R01CA129541/CA/NCI NIH HHS/ -- England -- Nature. 2012 Aug 2;488(7409):43-8. doi: 10.1038/nature11213.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉St Jude Children's Research Hospital, Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722829" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CREB-Binding Protein/genetics ; Cadherins/genetics ; Cdh1 Proteins ; Cell Cycle Proteins/deficiency/genetics ; Cell Lineage ; Cerebellar Neoplasms/*classification/*genetics/pathology ; Child ; DEAD-box RNA Helicases/genetics ; DNA Copy Number Variations ; DNA Helicases/genetics ; DNA Mutational Analysis ; Disease Models, Animal ; Genome, Human/genetics ; Genomics ; Hedgehog Proteins/metabolism ; Histone Demethylases/genetics ; Histones/metabolism ; Humans ; Medulloblastoma/*classification/*genetics/pathology ; Methylation ; Mice ; Mutation/*genetics ; Nuclear Proteins/genetics ; Phosphatidylinositol 3-Kinases/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: 2014-02-21
    Description: Members of the nuclear factor-kappaB (NF-kappaB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-kappaB signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-kappaB activity in cancer. Here we show that more than two-thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-kappaB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-kappaB target genes, and rapidly transformed neural stem cells--the cell of origin of ependymoma--to form these tumours in mice. Our data identify a highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial ependymoma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050669/" 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/PMC4050669/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Parker, Matthew -- Mohankumar, Kumarasamypet M -- Punchihewa, Chandanamali -- Weinlich, Ricardo -- Dalton, James D -- Li, Yongjin -- Lee, Ryan -- Tatevossian, Ruth G -- Phoenix, Timothy N -- Thiruvenkatam, Radhika -- White, Elsie -- Tang, Bo -- Orisme, Wilda -- Gupta, Kirti -- Rusch, Michael -- Chen, Xiang -- Li, Yuxin -- Nagahawhatte, Panduka -- Hedlund, Erin -- Finkelstein, David -- Wu, Gang -- Shurtleff, Sheila -- Easton, John -- Boggs, Kristy -- Yergeau, Donald -- Vadodaria, Bhavin -- Mulder, Heather L -- Becksfort, Jared -- Gupta, Pankaj -- Huether, Robert -- Ma, Jing -- Song, Guangchun -- Gajjar, Amar -- Merchant, Thomas -- Boop, Frederick -- Smith, Amy A -- Ding, Li -- Lu, Charles -- Ochoa, Kerri -- Zhao, David -- Fulton, Robert S -- Fulton, Lucinda L -- Mardis, Elaine R -- Wilson, Richard K -- Downing, James R -- Green, Douglas R -- Zhang, Jinghui -- Ellison, David W -- Gilbertson, Richard J -- P01 CA096832/CA/NCI NIH HHS/ -- P01CA96832/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- P30CA021765/CA/NCI NIH HHS/ -- R01 CA129541/CA/NCI NIH HHS/ -- R01CA129541/CA/NCI NIH HHS/ -- England -- Nature. 2014 Feb 27;506(7489):451-5. doi: 10.1038/nature13109. Epub 2014 Feb 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [3]. ; 1] Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2]. ; 1] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2]. ; 1] Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2]. ; 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; 1] Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA [2] Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA. ; Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; MD Anderson Cancer Center Orlando, Pediatric Hematology/Oncology, 92 West Miller MP 318, Orlando, Florida 32806, USA. ; 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] The Genome Institute, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA [3] Department of Genetics, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA. ; 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] The Genome Institute, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA. ; 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] The Genome Institute, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA [3] Department of Genetics, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA [4] Siteman Cancer Center, Washington University School of Medicine in St Louis, St Louis, Missouri 63108, USA. ; Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; 1] St. Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA [2] Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24553141" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/genetics/metabolism ; Animals ; Base Sequence ; Brain Neoplasms/genetics/metabolism/pathology ; Cell Line ; Cell Nucleus/metabolism ; *Cell Transformation, Neoplastic/genetics ; Chromosomes, Human, Pair 11/genetics ; Ependymoma/*genetics/*metabolism/pathology ; Female ; Humans ; Mice ; Models, Genetic ; Molecular Sequence Data ; NF-kappa B/genetics/*metabolism ; Neural Stem Cells/metabolism/pathology ; Oncogene Proteins, Fusion/genetics/metabolism ; Phosphoproteins/genetics/metabolism ; Proteins/genetics/*metabolism ; *Signal Transduction ; Transcription Factor RelA/genetics/*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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  • 3
    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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