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  • 1
    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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  • 2
    Publication Date: 2011-04-23
    Description: The fission yeast clade--comprising Schizosaccharomyces pombe, S. octosporus, S. cryophilus, and S. japonicus--occupies the basal branch of Ascomycete fungi and is an important model of eukaryote biology. A comparative annotation of these genomes identified a near extinction of transposons and the associated innovation of transposon-free centromeres. Expression analysis established that meiotic genes are subject to antisense transcription during vegetative growth, which suggests a mechanism for their tight regulation. In addition, trans-acting regulators control new genes within the context of expanded functional modules for meiosis and stress response. Differences in gene content and regulation also explain why, unlike the budding yeast of Saccharomycotina, fission yeasts cannot use ethanol as a primary carbon source. These analyses elucidate the genome structure and gene regulation of fission yeast and provide tools for investigation across the Schizosaccharomyces clade.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131103/" 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/PMC3131103/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rhind, Nicholas -- Chen, Zehua -- Yassour, Moran -- Thompson, Dawn A -- Haas, Brian J -- Habib, Naomi -- Wapinski, Ilan -- Roy, Sushmita -- Lin, Michael F -- Heiman, David I -- Young, Sarah K -- Furuya, Kanji -- Guo, Yabin -- Pidoux, Alison -- Chen, Huei Mei -- Robbertse, Barbara -- Goldberg, Jonathan M -- Aoki, Keita -- Bayne, Elizabeth H -- Berlin, Aaron M -- Desjardins, Christopher A -- Dobbs, Edward -- Dukaj, Livio -- Fan, Lin -- FitzGerald, Michael G -- French, Courtney -- Gujja, Sharvari -- Hansen, Klavs -- Keifenheim, Dan -- Levin, Joshua Z -- Mosher, Rebecca A -- Muller, Carolin A -- Pfiffner, Jenna -- Priest, Margaret -- Russ, Carsten -- Smialowska, Agata -- Swoboda, Peter -- Sykes, Sean M -- Vaughn, Matthew -- Vengrova, Sonya -- Yoder, Ryan -- Zeng, Qiandong -- Allshire, Robin -- Baulcombe, David -- Birren, Bruce W -- Brown, William -- Ekwall, Karl -- Kellis, Manolis -- Leatherwood, Janet -- Levin, Henry -- Margalit, Hanah -- Martienssen, Rob -- Nieduszynski, Conrad A -- Spatafora, Joseph W -- Friedman, Nir -- Dalgaard, Jacob Z -- Baumann, Peter -- Niki, Hironori -- Regev, Aviv -- Nusbaum, Chad -- BB/E023754/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- DP1 OD003958/OD/NIH HHS/ -- R01 GM069957/GM/NIGMS NIH HHS/ -- R01 GM076396/GM/NIGMS NIH HHS/ -- R01 HG004037/HG/NHGRI NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- U54 HG003067-06/HG/NHGRI NIH HHS/ -- Biotechnology and Biological Sciences Research Council/United Kingdom -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2011 May 20;332(6032):930-6. doi: 10.1126/science.1203357. Epub 2011 Apr 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA. nick.rhind@umassmed.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21511999" target="_blank"〉PubMed〈/a〉
    Keywords: Centromere/genetics/physiology/ultrastructure ; DNA Transposable Elements ; Evolution, Molecular ; Gene Expression Profiling ; Gene Expression Regulation, Fungal ; Genes, Mating Type, Fungal ; *Genome, Fungal ; Genomics ; Glucose/metabolism ; Meiosis ; Molecular Sequence Annotation ; Molecular Sequence Data ; Phylogeny ; RNA, Antisense/genetics ; RNA, Fungal/genetics ; RNA, Small Interfering/genetics ; RNA, Untranslated/genetics ; Regulatory Elements, Transcriptional ; Schizosaccharomyces/*genetics/growth & development/metabolism ; Schizosaccharomyces pombe Proteins/genetics/metabolism ; Sequence Analysis, DNA ; Species Specificity ; Transcription Factors/genetics/metabolism ; Transcription, Genetic
    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: 2012-01-28
    Description: Neighboring genes are often coordinately expressed within cis-regulatory modules, but evidence that nonparalogous genes share functions in mammals is lacking. Here, we report that mutation of either TMEM138 or TMEM216 causes a phenotypically indistinguishable human ciliopathy, Joubert syndrome. Despite a lack of sequence homology, the genes are aligned in a head-to-tail configuration and joined by chromosomal rearrangement at the amphibian-to-reptile evolutionary transition. Expression of the two genes is mediated by a conserved regulatory element in the noncoding intergenic region. Coordinated expression is important for their interdependent cellular role in vesicular transport to primary cilia. Hence, during vertebrate evolution of genes involved in ciliogenesis, nonparalogous genes were arranged to a functional gene cluster with shared regulatory elements.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3671610/" 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/PMC3671610/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Jeong Ho -- Silhavy, Jennifer L -- Lee, Ji Eun -- Al-Gazali, Lihadh -- Thomas, Sophie -- Davis, Erica E -- Bielas, Stephanie L -- Hill, Kiley J -- Iannicelli, Miriam -- Brancati, Francesco -- Gabriel, Stacey B -- Russ, Carsten -- Logan, Clare V -- Sharif, Saghira Malik -- Bennett, Christopher P -- Abe, Masumi -- Hildebrandt, Friedhelm -- Diplas, Bill H -- Attie-Bitach, Tania -- Katsanis, Nicholas -- Rajab, Anna -- Koul, Roshan -- Sztriha, Laszlo -- Waters, Elizabeth R -- Ferro-Novick, Susan -- Woods, C Geoffrey -- Johnson, Colin A -- Valente, Enza Maria -- Zaki, Maha S -- Gleeson, Joseph G -- DK068306/DK/NIDDK NIH HHS/ -- DK072301/DK/NIDDK NIH HHS/ -- DK075972/DK/NIDDK NIH HHS/ -- DK090917/DK/NIDDK NIH HHS/ -- EY021872/EY/NEI NIH HHS/ -- G0700073/Medical Research Council/United Kingdom -- GGP08145/Telethon/Italy -- HD042601/HD/NICHD NIH HHS/ -- NS04843/NS/NINDS NIH HHS/ -- NS052455/NS/NINDS NIH HHS/ -- P30 CA023100/CA/NCI NIH HHS/ -- P30NS047101/NS/NINDS NIH HHS/ -- R01 DK068306/DK/NIDDK NIH HHS/ -- R01 DK072301/DK/NIDDK NIH HHS/ -- R01 DK075972/DK/NIDDK NIH HHS/ -- R01 EY021872/EY/NEI NIH HHS/ -- R01 HD042601/HD/NICHD NIH HHS/ -- R01 NS048453/NS/NINDS NIH HHS/ -- R01 NS052455/NS/NINDS NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2012 Feb 24;335(6071):966-9. doi: 10.1126/science.1213506. Epub 2012 Jan 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Neurogenetics Laboratory, Howard Hughes Medical Institute (HHMI), Department of Neurosciences, University of California, San Diego, CA, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22282472" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Cell Line ; Cerebellar Diseases/*genetics/metabolism/pathology ; Cilia/metabolism/*ultrastructure ; Conserved Sequence ; DNA, Intergenic ; *Evolution, Molecular ; Eye Abnormalities/*genetics/metabolism/pathology ; Gene Expression Profiling ; *Gene Expression Regulation ; Genetic Heterogeneity ; *Genetic Loci ; Humans ; Kidney Diseases, Cystic/*genetics/metabolism/pathology ; Membrane Proteins/chemistry/*genetics/metabolism ; Molecular Sequence Data ; Multigene Family ; Mutation ; Mutation, Missense ; Phenotype ; Protein Transport ; *Regulatory Sequences, Nucleic Acid ; Retina/abnormalities/metabolism/pathology ; Transport Vesicles/metabolism/ultrastructure
    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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  • 4
    Keywords: PATHWAY ; COMPLEX ; leukemia ; CHILDHOOD ; STRUCTURAL BASIS ; cancer genes ; LANDSCAPE
    Abstract: Medulloblastomas are themost commonmalignant brain tumours in children(1). 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 ofmedulloblastoma on the basis of transcriptional and copy number profiles(2-5). 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 andTP53. 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 ofWNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates theRNA helicase DDX3X as a component of pathogenic b-catenin signalling in medulloblastoma.
    Type of Publication: Journal article published
    PubMed ID: 22820256
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  • 5
    ISSN: 0021-9991
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Computer Science , Physics
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 0570-0833
    Keywords: Chemistry ; General Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 0570-0833
    Keywords: Chemistry ; General Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Weinheim : Wiley-Blackwell
    ISSN: 0044-8249
    Keywords: Chemistry ; General Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Weinheim : Wiley-Blackwell
    ISSN: 0044-8249
    Keywords: Chemistry ; General Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Journal of ornithology 21 (1873), S. 31-35 
    ISSN: 1439-0361
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Type of Medium: Electronic Resource
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