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  • 1
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    The mutation spectrum revealed by paired genome sequences from a lung cancer patient (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-05-28
    Description: Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small-cell lung carcinomas in smokers being the predominant form of the disease. Although previous studies have identified important common somatic mutations in lung cancers, they have primarily focused on a limited set of genes and have thus provided a constrained view of the mutational spectrum. Recent cancer sequencing efforts have used next-generation sequencing technologies to provide a genome-wide view of mutations in leukaemia, breast cancer and cancer cell lines. Here we present the complete sequences of a primary lung tumour (60x coverage) and adjacent normal tissue (46x). Comparing the two genomes, we identify a wide variety of somatic variations, including 〉50,000 high-confidence single nucleotide variants. We validated 530 somatic single nucleotide variants in this tumour, including one in the KRAS proto-oncogene and 391 others in coding regions, as well as 43 large-scale structural variations. These constitute a large set of new somatic mutations and yield an estimated 17.7 per megabase genome-wide somatic mutation rate. Notably, we observe a distinct pattern of selection against mutations within expressed genes compared to non-expressed genes and in promoter regions up to 5 kilobases upstream of all protein-coding genes. Furthermore, we observe a higher rate of amino acid-changing mutations in kinase genes. We present a comprehensive view of somatic alterations in a single lung tumour, and provide the first evidence, to our knowledge, of distinct selective pressures present within the tumour environment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, William -- Jiang, Zhaoshi -- Liu, Jinfeng -- Haverty, Peter M -- Guan, Yinghui -- Stinson, Jeremy -- Yue, Peng -- Zhang, Yan -- Pant, Krishna P -- Bhatt, Deepali -- Ha, Connie -- Johnson, Stephanie -- Kennemer, Michael I -- Mohan, Sankar -- Nazarenko, Igor -- Watanabe, Colin -- Sparks, Andrew B -- Shames, David S -- Gentleman, Robert -- de Sauvage, Frederic J -- Stern, Howard -- Pandita, Ajay -- Ballinger, Dennis G -- Drmanac, Radoje -- Modrusan, Zora -- Seshagiri, Somasekar -- Zhang, Zemin -- England -- Nature. 2010 May 27;465(7297):473-7. doi: 10.1038/nature09004.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, California 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20505728" target="_blank"〉PubMed〈/a〉
    Keywords: Carcinoma, Non-Small-Cell Lung/*genetics ; DNA Mutational Analysis ; Genome, Human/*genetics ; Humans ; Lung Neoplasms/*genetics ; Male ; Middle Aged ; Models, Biological ; Point Mutation/*genetics ; Selection, 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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  • 2
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    Structures of APC/C(Cdh1) with substrates identify Cdh1 and Apc10 as the D-box co-receptor (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-11-26
    Description: The ubiquitylation of cell-cycle regulatory proteins by the large multimeric anaphase-promoting complex (APC/C) controls sister chromatid segregation and the exit from mitosis. Selection of APC/C targets is achieved through recognition of destruction motifs, predominantly the destruction (D)-box and KEN (Lys-Glu-Asn)-box. Although this process is known to involve a co-activator protein (either Cdc20 or Cdh1) together with core APC/C subunits, the structural basis for substrate recognition and ubiquitylation is not understood. Here we investigate budding yeast APC/C using single-particle electron microscopy and determine a cryo-electron microscopy map of APC/C in complex with the Cdh1 co-activator protein (APC/C(Cdh1)) bound to a D-box peptide at approximately 10 A resolution. We find that a combined catalytic and substrate-recognition module is located within the central cavity of the APC/C assembled from Cdh1, Apc10--a core APC/C subunit previously implicated in substrate recognition--and the cullin domain of Apc2. Cdh1 and Apc10, identified from difference maps, create a co-receptor for the D-box following repositioning of Cdh1 towards Apc10. Using NMR spectroscopy we demonstrate specific D-box-Apc10 interactions, consistent with a role for Apc10 in directly contributing towards D-box recognition by the APC/C(Cdh1) complex. Our results rationalize the contribution of both co-activator and core APC/C subunits to D-box recognition and provide a structural framework for understanding mechanisms of substrate recognition and catalysis by the APC/C.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037847/" 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/PMC3037847/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉da Fonseca, Paula C A -- Kong, Eric H -- Zhang, Ziguo -- Schreiber, Anne -- Williams, Mark A -- Morris, Edward P -- Barford, David -- A7403/Cancer Research UK/United Kingdom -- A8022/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2011 Feb 10;470(7333):274-8. doi: 10.1038/nature09625. Epub 2010 Nov 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Section of Structural Biology, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21107322" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Anaphase-Promoting Complex-Cyclosome ; Apc10 Subunit, Anaphase-Promoting Complex-Cyclosome ; Apc2 Subunit, Anaphase-Promoting Complex-Cyclosome ; Biocatalysis ; Cdh1 Proteins ; Cell Cycle Proteins/chemistry/*metabolism/ultrastructure ; Cryoelectron Microscopy ; Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular ; Peptides/*chemistry/*metabolism ; Protein Binding ; Protein Conformation ; Saccharomyces cerevisiae/*chemistry ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism/ultrastructure ; Substrate Specificity ; Ubiquitin-Protein Ligase Complexes/*chemistry/*metabolism/ultrastructure ; Ubiquitination
    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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    Diverse somatic mutation patterns and pathway alterations in human cancers (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-07-30
    Description: The systematic characterization of somatic mutations in cancer genomes is essential for understanding the disease and for developing targeted therapeutics. Here we report the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumours comprising breast, lung, ovarian and prostate cancer types and subtypes. We found that mutation rates and the sets of mutated genes varied substantially across tumour types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G-protein-coupled receptors such as GRM8, BAI3, AGTRL1 (also called APLNR) and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS, indicating an expanded role for galpha subunits in multiple cancer types. Furthermore, our experimental analyses demonstrate the functional roles of mutant GNAO1 (a Galpha subunit) and mutant MAP2K4 (a member of the JNK signalling pathway) in oncogenesis. Our study provides an overview of the mutational spectra across major human cancers and identifies several potential therapeutic targets.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kan, Zhengyan -- Jaiswal, Bijay S -- Stinson, Jeremy -- Janakiraman, Vasantharajan -- Bhatt, Deepali -- Stern, Howard M -- Yue, Peng -- Haverty, Peter M -- Bourgon, Richard -- Zheng, Jianbiao -- Moorhead, Martin -- Chaudhuri, Subhra -- Tomsho, Lynn P -- Peters, Brock A -- Pujara, Kanan -- Cordes, Shaun -- Davis, David P -- Carlton, Victoria E H -- Yuan, Wenlin -- Li, Li -- Wang, Weiru -- Eigenbrot, Charles -- Kaminker, Joshua S -- Eberhard, David A -- Waring, Paul -- Schuster, Stephan C -- Modrusan, Zora -- Zhang, Zemin -- Stokoe, David -- de Sauvage, Frederic J -- Faham, Malek -- Seshagiri, Somasekar -- England -- Nature. 2010 Aug 12;466(7308):869-73. doi: 10.1038/nature09208. Epub 2010 Jul 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20668451" target="_blank"〉PubMed〈/a〉
    Keywords: Breast Neoplasms/classification/genetics ; DNA Copy Number Variations/genetics ; DNA Mutational Analysis ; Female ; GTP-Binding Protein alpha Subunits/genetics ; Genes, Neoplasm/*genetics ; Humans ; Lung Neoplasms/classification/genetics ; MAP Kinase Kinase 4/genetics ; Male ; Mutation/*genetics ; Neoplasms/enzymology/*genetics/*metabolism/pathology ; Ovarian Neoplasms/classification/genetics ; Prostatic Neoplasms/classification/genetics ; Protein Kinases/genetics ; Receptors, G-Protein-Coupled/genetics ; Signal Transduction/*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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