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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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    K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension (2011)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2011-02-12
    Description: Endocrine tumors such as aldosterone-producing adrenal adenomas (APAs), a cause of severe hypertension, feature constitutive hormone production and unrestrained cell proliferation; the mechanisms linking these events are unknown. We identify two recurrent somatic mutations in and near the selectivity filter of the potassium (K(+)) channel KCNJ5 that are present in 8 of 22 human APAs studied. Both produce increased sodium (Na(+)) conductance and cell depolarization, which in adrenal glomerulosa cells produces calcium (Ca(2+)) entry, the signal for aldosterone production and cell proliferation. Similarly, we identify an inherited KCNJ5 mutation that produces increased Na(+) conductance in a Mendelian form of severe aldosteronism and massive bilateral adrenal hyperplasia. These findings explain pathogenesis in a subset of patients with severe hypertension and implicate loss of K(+) channel selectivity in constitutive cell proliferation and hormone production.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371087/" 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/PMC3371087/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Choi, Murim -- Scholl, Ute I -- Yue, Peng -- Bjorklund, Peyman -- Zhao, Bixiao -- Nelson-Williams, Carol -- Ji, Weizhen -- Cho, Yoonsang -- Patel, Aniruddh -- Men, Clara J -- Lolis, Elias -- Wisgerhof, Max V -- Geller, David S -- Mane, Shrikant -- Hellman, Per -- Westin, Gunnar -- Akerstrom, Goran -- Wang, Wenhui -- Carling, Tobias -- Lifton, Richard P -- DK54983/DK/NIDDK NIH HHS/ -- K01 AR060300/AR/NIAMS NIH HHS/ -- T32 GM007205/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2011 Feb 11;331(6018):768-72. doi: 10.1126/science.1198785.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21311022" target="_blank"〉PubMed〈/a〉
    Keywords: Adrenal Cortex Neoplasms/*genetics/metabolism/pathology ; Adrenal Glands/pathology ; Adrenocortical Adenoma/*genetics/metabolism/pathology ; Aldosterone/*metabolism ; Cell Line ; Cell Proliferation ; Female ; G Protein-Coupled Inwardly-Rectifying Potassium ; Channels/chemistry/*genetics/metabolism ; Humans ; Hyperaldosteronism/*genetics/metabolism/pathology ; Hyperplasia ; Hypertension/*genetics/metabolism ; Male ; Mutant Proteins/chemistry/genetics/metabolism ; *Mutation ; Potassium/metabolism ; Protein Multimerization ; Sodium/metabolism ; Zona Glomerulosa/metabolism/pathology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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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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