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  • 1
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    Highly recurrent TERT promoter mutations in human melanoma (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-01-26
    Description: Systematic sequencing of human cancer genomes has identified many recurrent mutations in the protein-coding regions of genes but rarely in gene regulatory regions. Here, we describe two independent mutations within the core promoter of telomerase reverse transcriptase (TERT), the gene coding for the catalytic subunit of telomerase, which collectively occur in 50 of 70 (71%) melanomas examined. These mutations generate de novo consensus binding motifs for E-twenty-six (ETS) transcription factors, and in reporter assays, the mutations increased transcriptional activity from the TERT promoter by two- to fourfold. Examination of 150 cancer cell lines derived from diverse tumor types revealed the same mutations in 24 cases (16%), with preliminary evidence of elevated frequency in bladder and hepatocellular cancer cells. Thus, somatic mutations in regulatory regions of the genome may represent an important tumorigenic mechanism.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423787/" 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/PMC4423787/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Franklin W -- Hodis, Eran -- Xu, Mary Jue -- Kryukov, Gregory V -- Chin, Lynda -- Garraway, Levi A -- DP2 OD002750/OD/NIH HHS/ -- DP2OD002750/OD/NIH HHS/ -- R33 CA126674/CA/NCI NIH HHS/ -- R33CA126674/CA/NCI NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- T32GM07753/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 Feb 22;339(6122):957-9. doi: 10.1126/science.1229259. Epub 2013 Jan 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23348506" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Carcinoma, Hepatocellular/genetics ; Cell Line, Tumor ; Cell Transformation, Neoplastic ; *Gene Expression Regulation, Neoplastic ; Humans ; Liver Neoplasms/genetics ; Melanoma/*genetics ; *Mutation ; *Promoter Regions, Genetic ; Proto-Oncogene Proteins c-ets/metabolism ; Telomerase/chemistry/*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
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-03-31
    Description: The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320027/" 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/PMC3320027/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barretina, Jordi -- Caponigro, Giordano -- Stransky, Nicolas -- Venkatesan, Kavitha -- Margolin, Adam A -- Kim, Sungjoon -- Wilson, Christopher J -- Lehar, Joseph -- Kryukov, Gregory V -- Sonkin, Dmitriy -- Reddy, Anupama -- Liu, Manway -- Murray, Lauren -- Berger, Michael F -- Monahan, John E -- Morais, Paula -- Meltzer, Jodi -- Korejwa, Adam -- Jane-Valbuena, Judit -- Mapa, Felipa A -- Thibault, Joseph -- Bric-Furlong, Eva -- Raman, Pichai -- Shipway, Aaron -- Engels, Ingo H -- Cheng, Jill -- Yu, Guoying K -- Yu, Jianjun -- Aspesi, Peter Jr -- de Silva, Melanie -- Jagtap, Kalpana -- Jones, Michael D -- Wang, Li -- Hatton, Charles -- Palescandolo, Emanuele -- Gupta, Supriya -- Mahan, Scott -- Sougnez, Carrie -- Onofrio, Robert C -- Liefeld, Ted -- MacConaill, Laura -- Winckler, Wendy -- Reich, Michael -- Li, Nanxin -- Mesirov, Jill P -- Gabriel, Stacey B -- Getz, Gad -- Ardlie, Kristin -- Chan, Vivien -- Myer, Vic E -- Weber, Barbara L -- Porter, Jeff -- Warmuth, Markus -- Finan, Peter -- Harris, Jennifer L -- Meyerson, Matthew -- Golub, Todd R -- Morrissey, Michael P -- Sellers, William R -- Schlegel, Robert -- Garraway, Levi A -- DP2 OD002750/OD/NIH HHS/ -- DP2 OD002750-01/OD/NIH HHS/ -- R33 CA126674/CA/NCI NIH HHS/ -- R33 CA126674-04/CA/NCI NIH HHS/ -- R33 CA155554/CA/NCI NIH HHS/ -- R33 CA155554-02/CA/NCI NIH HHS/ -- England -- Nature. 2012 Mar 28;483(7391):603-7. doi: 10.1038/nature11003.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22460905" target="_blank"〉PubMed〈/a〉
    Keywords: Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Lineage ; Chromosomes, Human/genetics ; Clinical Trials as Topic/methods ; *Databases, Factual ; Drug Screening Assays, Antitumor/*methods ; *Encyclopedias as Topic ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Genes, ras/genetics ; Genome, Human/genetics ; Genomics ; Humans ; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors/metabolism ; *Models, Biological ; Neoplasms/*drug therapy/genetics/metabolism/*pathology ; Pharmacogenetics ; Plasma Cells/cytology/drug effects/metabolism ; Precision Medicine/methods ; Receptor, IGF Type 1/antagonists & inhibitors/metabolism ; Receptors, Aryl Hydrocarbon/genetics/metabolism ; Sequence Analysis, DNA ; Topoisomerase Inhibitors/pharmacology
    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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    MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-02-26
    Description: The discovery of cancer dependencies has the potential to inform therapeutic strategies and to identify putative drug targets. Integrating data from comprehensive genomic profiling of cancer cell lines and from functional characterization of cancer cell dependencies, we discovered that loss of the enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77. MTAP is frequently lost due to its proximity to the commonly deleted tumor suppressor gene, CDKN2A. We observed increased intracellular concentrations of methylthioadenosine (MTA, the metabolite cleaved by MTAP) in cells harboring MTAP deletions. Furthermore, MTA specifically inhibited PRMT5 enzymatic activity. Administration of either MTA or a small-molecule PRMT5 inhibitor showed a modest preferential impairment of cell viability for MTAP-null cancer cell lines compared with isogenic MTAP-expressing counterparts. Together, our findings reveal PRMT5 as a potential vulnerability across multiple cancer lineages augmented by a common "passenger" genomic alteration.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kryukov, Gregory V -- Wilson, Frederick H -- Ruth, Jason R -- Paulk, Joshiawa -- Tsherniak, Aviad -- Marlow, Sara E -- Vazquez, Francisca -- Weir, Barbara A -- Fitzgerald, Mark E -- Tanaka, Minoru -- Bielski, Craig M -- Scott, Justin M -- Dennis, Courtney -- Cowley, Glenn S -- Boehm, Jesse S -- Root, David E -- Golub, Todd R -- Clish, Clary B -- Bradner, James E -- Hahn, William C -- Garraway, Levi A -- KL2 TR001100/TR/NCATS NIH HHS/ -- U01 CA176058/CA/NCI NIH HHS/ -- U54 CA112962/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2016 Mar 11;351(6278):1214-8. doi: 10.1126/science.aad5214. Epub 2016 Feb 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. levi_garraway@dfci.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912360" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line, Tumor ; Deoxyadenosines/metabolism/pharmacology ; Enzyme Inhibitors/pharmacology ; Gene Deletion ; Humans ; Isoquinolines/pharmacology ; Neoplasms/*drug therapy/enzymology ; Protein-Arginine N-Methyltransferases/antagonists & ; inhibitors/genetics/*metabolism ; Purine-Nucleoside Phosphorylase/genetics/*metabolism ; Pyrimidines/pharmacology ; Thionucleosides/metabolism/pharmacology ; Transcription Factors
    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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