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  • 1
    Publication Date: 2012-07-06
    Description: Drug resistance presents a challenge to the treatment of cancer patients. Many studies have focused on cell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour micro-environment confers innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. We found that stroma-mediated resistance is common, particularly to targeted agents. We characterized further the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibitors because most patients with this type of cancer show some degree of innate resistance. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)-AKT signalling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, this study indicates that the systematic dissection of interactions between tumours and their micro-environment can uncover important mechanisms underlying drug resistance.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711467/" 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/PMC3711467/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Straussman, Ravid -- Morikawa, Teppei -- Shee, Kevin -- Barzily-Rokni, Michal -- Qian, Zhi Rong -- Du, Jinyan -- Davis, Ashli -- Mongare, Margaret M -- Gould, Joshua -- Frederick, Dennie T -- Cooper, Zachary A -- Chapman, Paul B -- Solit, David B -- Ribas, Antoni -- Lo, Roger S -- Flaherty, Keith T -- Ogino, Shuji -- Wargo, Jennifer A -- Golub, Todd R -- P50CA093683/CA/NCI NIH HHS/ -- U54 CA112962/CA/NCI NIH HHS/ -- U54CA112962/CA/NCI NIH HHS/ -- UM1 CA186709/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jul 26;487(7408):500-4. doi: 10.1038/nature11183.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Eli and Edythe L. Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22763439" target="_blank"〉PubMed〈/a〉
    Keywords: Antineoplastic Agents/pharmacology/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; Cell Line, Tumor ; Coculture Techniques ; *Drug Resistance, Neoplasm/drug effects ; Hepatocyte Growth Factor/metabolism/*secretion ; Humans ; Indoles/pharmacology/therapeutic use ; Melanoma/drug therapy/genetics/*metabolism/pathology ; Molecular Targeted Therapy ; Mutation ; Phosphatidylinositol 3-Kinases/metabolism ; Prognosis ; Protein Kinase Inhibitors/pharmacology/therapeutic use ; Proteomics ; Proto-Oncogene Proteins B-raf/*antagonists & inhibitors/genetics ; Proto-Oncogene Proteins c-met/antagonists & inhibitors/metabolism ; Signal Transduction/drug effects ; Stromal Cells/cytology/drug effects/metabolism/secretion ; Sulfonamides/pharmacology/therapeutic use ; Tumor Microenvironment/*physiology
    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: 2012-06-23
    Description: Breast carcinoma is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.38 million new cases and 458,000 deaths in 2008 alone. This malignancy represents a heterogeneous group of tumours with characteristic molecular features, prognosis and responses to available therapy. Recurrent somatic alterations in breast cancer have been described, including mutations and copy number alterations, notably ERBB2 amplifications, the first successful therapy target defined by a genomic aberration. Previous DNA sequencing studies of breast cancer genomes have revealed additional candidate mutations and gene rearrangements. Here we report the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. Beyond confirming recurrent somatic mutations in PIK3CA, TP53, AKT1, GATA3 and MAP3K1, we discovered recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1. Furthermore, we have identified a recurrent MAGI3-AKT3 fusion enriched in triple-negative breast cancer lacking oestrogen and progesterone receptors and ERBB2 expression. The MAGI3-AKT3 fusion leads to constitutive activation of AKT kinase, which is abolished by treatment with an ATP-competitive AKT small-molecule inhibitor.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148686/" 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/PMC4148686/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Banerji, Shantanu -- Cibulskis, Kristian -- Rangel-Escareno, Claudia -- Brown, Kristin K -- Carter, Scott L -- Frederick, Abbie M -- Lawrence, Michael S -- Sivachenko, Andrey Y -- Sougnez, Carrie -- Zou, Lihua -- Cortes, Maria L -- Fernandez-Lopez, Juan C -- Peng, Shouyong -- Ardlie, Kristin G -- Auclair, Daniel -- Bautista-Pina, Veronica -- Duke, Fujiko -- Francis, Joshua -- Jung, Joonil -- Maffuz-Aziz, Antonio -- Onofrio, Robert C -- Parkin, Melissa -- Pho, Nam H -- Quintanar-Jurado, Valeria -- Ramos, Alex H -- Rebollar-Vega, Rosa -- Rodriguez-Cuevas, Sergio -- Romero-Cordoba, Sandra L -- Schumacher, Steven E -- Stransky, Nicolas -- Thompson, Kristin M -- Uribe-Figueroa, Laura -- Baselga, Jose -- Beroukhim, Rameen -- Polyak, Kornelia -- Sgroi, Dennis C -- Richardson, Andrea L -- Jimenez-Sanchez, Gerardo -- Lander, Eric S -- Gabriel, Stacey B -- Garraway, Levi A -- Golub, Todd R -- Melendez-Zajgla, Jorge -- Toker, Alex -- Getz, Gad -- Hidalgo-Miranda, Alfredo -- Meyerson, Matthew -- CA089393/CA/NCI NIH HHS/ -- CA122099/CA/NCI NIH HHS/ -- R01 CA122099/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jun 20;486(7403):405-9. doi: 10.1038/nature11154.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The 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/22722202" target="_blank"〉PubMed〈/a〉
    Keywords: Algorithms ; Breast Neoplasms/*classification/*genetics/pathology ; Core Binding Factor Alpha 2 Subunit/genetics ; Core Binding Factor beta Subunit/genetics ; DNA Mutational Analysis ; Exome/genetics ; Female ; Gene Fusion/genetics ; Humans ; Membrane Proteins/genetics ; Mexico ; Mutation/*genetics ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors/genetics/metabolism ; Translocation, Genetic/*genetics ; Vietnam
    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: 2014-01-07
    Description: Although a few cancer genes are mutated in a high proportion of tumours of a given type (〉20%), most are mutated at intermediate frequencies (2-20%). To explore the feasibility of creating a comprehensive catalogue of cancer genes, we analysed somatic point mutations in exome sequences from 4,742 human cancers and their matched normal-tissue samples across 21 cancer types. We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumour types. Our analysis also identified 33 genes that were not previously known to be significantly mutated in cancer, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies. We estimate that near-saturation may be achieved with 600-5,000 samples per tumour type, depending on background mutation frequency. The results may help to guide the next stage of cancer genomics.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048962/" 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/PMC4048962/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lawrence, Michael S -- Stojanov, Petar -- Mermel, Craig H -- Robinson, James T -- Garraway, Levi A -- Golub, Todd R -- Meyerson, Matthew -- Gabriel, Stacey B -- Lander, Eric S -- Getz, Gad -- R01 CA157304/CA/NCI NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jan 23;505(7484):495-501. doi: 10.1038/nature12912. Epub 2014 Jan 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA. ; 1] Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA. ; 1] Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Massachusetts General Hospital, Cancer Center and Department of Pathology, 55 Fruit Street, Boston, Massachusetts 02114, USA. ; 1] Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA [3] Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA. ; 1] Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA [3] Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA [4] Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, Maryland 20815, USA. ; 1] Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA [3] Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [4]. ; 1] Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Massachusetts General Hospital, Cancer Center and Department of Pathology, 55 Fruit Street, Boston, Massachusetts 02114, USA [3] Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA [4].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24390350" target="_blank"〉PubMed〈/a〉
    Keywords: Apoptosis/genetics ; Case-Control Studies ; Cell Proliferation ; Chromatin/genetics ; DNA Mutational Analysis ; Exome/genetics ; Genes, Neoplasm/*genetics ; Genome, Human/genetics ; Genomic Instability/genetics ; Genomics ; Humans ; Immune Evasion/genetics ; Mutation Rate ; Neoplasms/*classification/*genetics/pathology ; Point Mutation/genetics ; RNA Processing, Post-Transcriptional/genetics ; Sample Size
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2011-07-15
    Description: Malignant transformation, driven by gain-of-function mutations in oncogenes and loss-of-function mutations in tumour suppressor genes, results in cell deregulation that is frequently associated with enhanced cellular stress (for example, oxidative, replicative, metabolic and proteotoxic stress, and DNA damage). Adaptation to this stress phenotype is required for cancer cells to survive, and consequently cancer cells may become dependent upon non-oncogenes that do not ordinarily perform such a vital function in normal cells. Thus, targeting these non-oncogene dependencies in the context of a transformed genotype may result in a synthetic lethal interaction and the selective death of cancer cells. Here we used a cell-based small-molecule screening and quantitative proteomics approach that resulted in the unbiased identification of a small molecule that selectively kills cancer cells but not normal cells. Piperlongumine increases the level of reactive oxygen species (ROS) and apoptotic cell death in both cancer cells and normal cells engineered to have a cancer genotype, irrespective of p53 status, but it has little effect on either rapidly or slowly dividing primary normal cells. Significant antitumour effects are observed in piperlongumine-treated mouse xenograft tumour models, with no apparent toxicity in normal mice. Moreover, piperlongumine potently inhibits the growth of spontaneously formed malignant breast tumours and their associated metastases in mice. Our results demonstrate the ability of a small molecule to induce apoptosis selectively in cells that have a cancer genotype, by targeting a non-oncogene co-dependency acquired through the expression of the cancer genotype in response to transformation-induced oxidative stress.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316487/" 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/PMC3316487/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Raj, Lakshmi -- Ide, Takao -- Gurkar, Aditi U -- Foley, Michael -- Schenone, Monica -- Li, Xiaoyu -- Tolliday, Nicola J -- Golub, Todd R -- Carr, Steven A -- Shamji, Alykhan F -- Stern, Andrew M -- Mandinova, Anna -- Schreiber, Stuart L -- Lee, Sam W -- 5 RC2 CA148399-02/CA/NCI NIH HHS/ -- CA080058/CA/NCI NIH HHS/ -- CA085681/CA/NCI NIH HHS/ -- CA127247/CA/NCI NIH HHS/ -- CA142805/CA/NCI NIH HHS/ -- P01 CA080058/CA/NCI NIH HHS/ -- P01 CA080058-02/CA/NCI NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- R01 CA085681/CA/NCI NIH HHS/ -- R01 CA085681-06/CA/NCI NIH HHS/ -- R01 CA142805/CA/NCI NIH HHS/ -- R01 CA142805-01/CA/NCI NIH HHS/ -- RL1CA133834/CA/NCI NIH HHS/ -- RL1GM084437/GM/NIGMS NIH HHS/ -- RL1HG004671/HG/NHGRI NIH HHS/ -- UL1RR024924/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jul 13;475(7355):231-4. doi: 10.1038/nature10167.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Building 149 13th Street, Charlestown, Massachusetts 02129, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21753854" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis/*drug effects ; Breast Neoplasms/*drug therapy/genetics/metabolism/*pathology ; Cell Line ; Cell Line, Tumor ; Cell Transformation, Neoplastic ; Comet Assay ; DNA Damage/drug effects ; Dioxolanes/adverse effects/chemistry/*pharmacology ; Genotype ; Mice ; Neoplasm Metastasis/drug therapy/pathology ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/*metabolism ; Small Molecule Libraries/chemistry ; Xenograft Model Antitumor Assays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2011-02-04
    Description: Effective clinical management of prostate cancer (PCA) has been challenged by significant intratumoural heterogeneity on the genomic and pathological levels and limited understanding of the genetic elements governing disease progression. Here, we exploited the experimental merits of the mouse to test the hypothesis that pathways constraining progression might be activated in indolent Pten-null mouse prostate tumours and that inactivation of such progression barriers in mice would engender a metastasis-prone condition. Comparative transcriptomic and canonical pathway analyses, followed by biochemical confirmation, of normal prostate epithelium versus poorly progressive Pten-null prostate cancers revealed robust activation of the TGFbeta/BMP-SMAD4 signalling axis. The functional relevance of SMAD4 was further supported by emergence of invasive, metastatic and lethal prostate cancers with 100% penetrance upon genetic deletion of Smad4 in the Pten-null mouse prostate. Pathological and molecular analysis as well as transcriptomic knowledge-based pathway profiling of emerging tumours identified cell proliferation and invasion as two cardinal tumour biological features in the metastatic Smad4/Pten-null PCA model. Follow-on pathological and functional assessment confirmed cyclin D1 and SPP1 as key mediators of these biological processes, which together with PTEN and SMAD4, form a four-gene signature that is prognostic of prostate-specific antigen (PSA) biochemical recurrence and lethal metastasis in human PCA. This model-informed progression analysis, together with genetic, functional and translational studies, establishes SMAD4 as a key regulator of PCA progression in mice and humans.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753179/" 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/PMC3753179/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ding, Zhihu -- Wu, Chang-Jiun -- Chu, Gerald C -- Xiao, Yonghong -- Ho, Dennis -- Zhang, Jingfang -- Perry, Samuel R -- Labrot, Emma S -- Wu, Xiaoqiu -- Lis, Rosina -- Hoshida, Yujin -- Hiller, David -- Hu, Baoli -- Jiang, Shan -- Zheng, Hongwu -- Stegh, Alexander H -- Scott, Kenneth L -- Signoretti, Sabina -- Bardeesy, Nabeel -- Wang, Y Alan -- Hill, David E -- Golub, Todd R -- Stampfer, Meir J -- Wong, Wing H -- Loda, Massimo -- Mucci, Lorelei -- Chin, Lynda -- DePinho, Ronald A -- P50 CA090381/CA/NCI NIH HHS/ -- P50 CA090381-08/CA/NCI NIH HHS/ -- P50 CA90381/CA/NCI NIH HHS/ -- R01 5R01CA136578/CA/NCI NIH HHS/ -- R01 CA131945/CA/NCI NIH HHS/ -- R01CA131945/CA/NCI NIH HHS/ -- R01CA141298/CA/NCI NIH HHS/ -- U01-CA84313/CA/NCI NIH HHS/ -- England -- Nature. 2011 Feb 10;470(7333):269-73. doi: 10.1038/nature09677. Epub 2011 Feb 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21289624" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone Morphogenetic Proteins/metabolism ; Cell Proliferation ; Cyclin D1/genetics/metabolism ; *Disease Progression ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Genes, Tumor Suppressor/physiology ; Humans ; Lung Neoplasms/secondary ; Lymphatic Metastasis ; Male ; Mice ; Mice, Transgenic ; Models, Biological ; Neoplasm Invasiveness/genetics/pathology ; Neoplasm Metastasis/genetics/*pathology ; Osteopontin/genetics/metabolism ; PTEN Phosphohydrolase/deficiency/genetics ; Penetrance ; Prognosis ; Prostate/metabolism ; Prostate-Specific Antigen/metabolism ; Prostatic Neoplasms/diagnosis/genetics/*pathology ; Smad4 Protein/deficiency/genetics/*metabolism ; Transforming Growth Factor beta
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2011-07-30
    Description: Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), our analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (for example, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3415217/" 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/PMC3415217/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stransky, Nicolas -- Egloff, Ann Marie -- Tward, Aaron D -- Kostic, Aleksandar D -- Cibulskis, Kristian -- Sivachenko, Andrey -- Kryukov, Gregory V -- Lawrence, Michael S -- Sougnez, Carrie -- McKenna, Aaron -- Shefler, Erica -- Ramos, Alex H -- Stojanov, Petar -- Carter, Scott L -- Voet, Douglas -- Cortes, Maria L -- Auclair, Daniel -- Berger, Michael F -- Saksena, Gordon -- Guiducci, Candace -- Onofrio, Robert C -- Parkin, Melissa -- Romkes, Marjorie -- Weissfeld, Joel L -- Seethala, Raja R -- Wang, Lin -- Rangel-Escareno, Claudia -- Fernandez-Lopez, Juan Carlos -- Hidalgo-Miranda, Alfredo -- Melendez-Zajgla, Jorge -- Winckler, Wendy -- Ardlie, Kristin -- Gabriel, Stacey B -- Meyerson, Matthew -- Lander, Eric S -- Getz, Gad -- Golub, Todd R -- Garraway, Levi A -- Grandis, Jennifer R -- P50 CA097190/CA/NCI NIH HHS/ -- R01 CA077308/CA/NCI NIH HHS/ -- R01 CA098372/CA/NCI NIH HHS/ -- UL1 TR000005/TR/NCATS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2011 Aug 26;333(6046):1157-60. doi: 10.1126/science.1208130. Epub 2011 Jul 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21798893" target="_blank"〉PubMed〈/a〉
    Keywords: Algorithms ; Apoptosis ; Carcinoma/*genetics/metabolism/virology ; Carcinoma, Squamous Cell ; Cell Differentiation ; Exons ; Head and Neck Neoplasms/*genetics/metabolism/virology ; Humans ; *Mutation ; Neoplasms, Squamous Cell/*genetics/metabolism/virology ; Papillomaviridae/isolation & purification ; Papillomavirus Infections/virology ; Point Mutation ; Receptor, Notch1/*genetics/metabolism ; *Sequence Analysis, DNA ; Sequence Deletion ; Signal Transduction ; Smoking ; Tobacco
    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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  • 7
    Publication Date: 2013-07-23
    Description: The ribosome is centrally situated to sense metabolic states, but whether its activity, in turn, coherently rewires transcriptional responses is unknown. Here, through integrated chemical-genetic analyses, we found that a dominant transcriptional effect of blocking protein translation in cancer cells was inactivation of heat shock factor 1 (HSF1), a multifaceted transcriptional regulator of the heat-shock response and many other cellular processes essential for anabolic metabolism, cellular proliferation, and tumorigenesis. These analyses linked translational flux to the regulation of HSF1 transcriptional activity and to the modulation of energy metabolism. Targeting this link with translation initiation inhibitors such as rocaglates deprived cancer cells of their energy and chaperone armamentarium and selectively impaired the proliferation of both malignant and premalignant cells with early-stage oncogenic lesions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959726/" 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/PMC3959726/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Santagata, Sandro -- Mendillo, Marc L -- Tang, Yun-chi -- Subramanian, Aravind -- Perley, Casey C -- Roche, Stephane P -- Wong, Bang -- Narayan, Rajiv -- Kwon, Hyoungtae -- Koeva, Martina -- Amon, Angelika -- Golub, Todd R -- Porco, John A Jr -- Whitesell, Luke -- Lindquist, Susan -- 5U54HG006093/HG/NHGRI NIH HHS/ -- K08 NS064168/NS/NINDS NIH HHS/ -- K08NS064168/NS/NINDS NIH HHS/ -- R01 CA175744/CA/NCI NIH HHS/ -- R01 CA175744-01/CA/NCI NIH HHS/ -- R01 GM073855/GM/NIGMS NIH HHS/ -- R03 DA027713/DA/NIDA NIH HHS/ -- R03 DA027713-01/DA/NIDA NIH HHS/ -- R03 MH086465-01/MH/NIMH NIH HHS/ -- U54 HG006093/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Jul 19;341(6143):1238303. doi: 10.1126/science.1238303.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23869022" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents/chemistry/isolation & purification/pharmacology ; Benzofurans/pharmacology ; Cell Line, Tumor ; Cell Proliferation ; Cell Transformation, Neoplastic/drug effects/metabolism/pathology ; DNA-Binding Proteins/antagonists & inhibitors/*biosynthesis ; Energy Metabolism/drug effects ; Gene Expression Regulation, Neoplastic ; High-Throughput Screening Assays ; Humans ; Mice ; NIH 3T3 Cells ; Neoplasm Transplantation ; Neoplasms/genetics/*metabolism/*pathology ; Protein Biosynthesis/drug effects/genetics/*physiology ; Ribosomes/drug effects/*metabolism ; Transcription Factors/antagonists & inhibitors/*biosynthesis
    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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  • 8
    Publication Date: 2011-03-25
    Description: Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-kappaB signalling was indicated by mutations in 11 members of the NF-kappaB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3560292/" 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/PMC3560292/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chapman, Michael A -- Lawrence, Michael S -- Keats, Jonathan J -- Cibulskis, Kristian -- Sougnez, Carrie -- Schinzel, Anna C -- Harview, Christina L -- Brunet, Jean-Philippe -- Ahmann, Gregory J -- Adli, Mazhar -- Anderson, Kenneth C -- Ardlie, Kristin G -- Auclair, Daniel -- Baker, Angela -- Bergsagel, P Leif -- Bernstein, Bradley E -- Drier, Yotam -- Fonseca, Rafael -- Gabriel, Stacey B -- Hofmeister, Craig C -- Jagannath, Sundar -- Jakubowiak, Andrzej J -- Krishnan, Amrita -- Levy, Joan -- Liefeld, Ted -- Lonial, Sagar -- Mahan, Scott -- Mfuko, Bunmi -- Monti, Stefano -- Perkins, Louise M -- Onofrio, Robb -- Pugh, Trevor J -- Rajkumar, S Vincent -- Ramos, Alex H -- Siegel, David S -- Sivachenko, Andrey -- Stewart, A Keith -- Trudel, Suzanne -- Vij, Ravi -- Voet, Douglas -- Winckler, Wendy -- Zimmerman, Todd -- Carpten, John -- Trent, Jeff -- Hahn, William C -- Garraway, Levi A -- Meyerson, Matthew -- Lander, Eric S -- Getz, Gad -- Golub, Todd R -- K12 CA133250/CA/NCI NIH HHS/ -- R01 AG020686/AG/NIA NIH HHS/ -- R01 AG020686-07/AG/NIA NIH HHS/ -- R01 CA133115/CA/NCI NIH HHS/ -- R01 CA133115-04/CA/NCI NIH HHS/ -- R01 CA133966/CA/NCI NIH HHS/ -- R01 CA133966-03/CA/NCI NIH HHS/ -- England -- Nature. 2011 Mar 24;471(7339):467-72. doi: 10.1038/nature09837.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Eli and Edythe L. Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02412, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21430775" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Blood Coagulation/genetics ; CpG Islands/genetics ; DNA Mutational Analysis ; DNA Repair/genetics ; Exons/genetics ; Exosome Multienzyme Ribonuclease Complex ; Genome, Human/*genetics ; Genomics ; Histones/metabolism ; Homeodomain Proteins/genetics ; Homeostasis/genetics ; Humans ; Methylation ; Models, Molecular ; Molecular Sequence Data ; Multiple Myeloma/drug therapy/enzymology/*genetics/metabolism ; Mutation/*genetics ; NF-kappa B/metabolism ; Oncogenes/genetics ; Open Reading Frames/genetics ; Protein Biosynthesis/genetics ; Protein Conformation ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors/genetics/metabolism ; RNA Processing, Post-Transcriptional/genetics ; Ribonucleases/chemistry/genetics ; Signal Transduction/genetics ; Transcription, 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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  • 9
    Publication Date: 2012-05-25
    Description: Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. To obtain a comprehensive genomic view of melanoma in humans, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome), intermediate in those originating from hair-bearing skin of the trunk (5-55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)--a PTEN-interacting protein and negative regulator of PTEN in breast cancer--as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumours revealed genomic evidence of ultraviolet pathogenesis and discovered a new recurrently mutated gene in melanoma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367798/" 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/PMC3367798/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Berger, Michael F -- Hodis, Eran -- Heffernan, Timothy P -- Deribe, Yonathan Lissanu -- Lawrence, Michael S -- Protopopov, Alexei -- Ivanova, Elena -- Watson, Ian R -- Nickerson, Elizabeth -- Ghosh, Papia -- Zhang, Hailei -- Zeid, Rhamy -- Ren, Xiaojia -- Cibulskis, Kristian -- Sivachenko, Andrey Y -- Wagle, Nikhil -- Sucker, Antje -- Sougnez, Carrie -- Onofrio, Robert -- Ambrogio, Lauren -- Auclair, Daniel -- Fennell, Timothy -- Carter, Scott L -- Drier, Yotam -- Stojanov, Petar -- Singer, Meredith A -- Voet, Douglas -- Jing, Rui -- Saksena, Gordon -- Barretina, Jordi -- Ramos, Alex H -- Pugh, Trevor J -- Stransky, Nicolas -- Parkin, Melissa -- Winckler, Wendy -- Mahan, Scott -- Ardlie, Kristin -- Baldwin, Jennifer -- Wargo, Jennifer -- Schadendorf, Dirk -- Meyerson, Matthew -- Gabriel, Stacey B -- Golub, Todd R -- Wagner, Stephan N -- Lander, Eric S -- Getz, Gad -- Chin, Lynda -- Garraway, Levi A -- DP2 OD002750/OD/NIH HHS/ -- DP2 OD002750-01/OD/NIH HHS/ -- R33 CA126674/CA/NCI NIH HHS/ -- R33 CA126674-03/CA/NCI NIH HHS/ -- R33 CA126674-04/CA/NCI NIH HHS/ -- R33 CA155554/CA/NCI NIH HHS/ -- R33 CA155554-01/CA/NCI NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 May 9;485(7399):502-6. doi: 10.1038/nature11071.〈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/22622578" target="_blank"〉PubMed〈/a〉
    Keywords: Chromosome Breakpoints/radiation effects ; DNA Damage ; DNA Mutational Analysis ; Gene Expression Regulation, Neoplastic ; Genome, Human/*genetics ; Guanine Nucleotide Exchange Factors/*genetics/metabolism ; Humans ; Melanocytes/metabolism/pathology ; Melanoma/*genetics/pathology ; Mutagenesis/radiation effects ; Mutation/*genetics/radiation effects ; Oncogenes/genetics ; Sunlight/*adverse effects ; Ultraviolet Rays/adverse effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2013-06-19
    Description: Major international projects are underway that are aimed at creating a comprehensive catalogue of all the genes responsible for the initiation and progression of cancer. These studies involve the sequencing of matched tumour-normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false-positive findings that overshadow true driver events. We show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumour-normal pairs and discover extraordinary variation in mutation frequency and spectrum within cancer types, which sheds light on mutational processes and disease aetiology, and in mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and enable the identification of genes truly associated with cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919509/" 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/PMC3919509/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lawrence, Michael S -- Stojanov, Petar -- Polak, Paz -- Kryukov, Gregory V -- Cibulskis, Kristian -- Sivachenko, Andrey -- Carter, Scott L -- Stewart, Chip -- Mermel, Craig H -- Roberts, Steven A -- Kiezun, Adam -- Hammerman, Peter S -- McKenna, Aaron -- Drier, Yotam -- Zou, Lihua -- Ramos, Alex H -- Pugh, Trevor J -- Stransky, Nicolas -- Helman, Elena -- Kim, Jaegil -- Sougnez, Carrie -- Ambrogio, Lauren -- Nickerson, Elizabeth -- Shefler, Erica -- Cortes, Maria L -- Auclair, Daniel -- Saksena, Gordon -- Voet, Douglas -- Noble, Michael -- DiCara, Daniel -- Lin, Pei -- Lichtenstein, Lee -- Heiman, David I -- Fennell, Timothy -- Imielinski, Marcin -- Hernandez, Bryan -- Hodis, Eran -- Baca, Sylvan -- Dulak, Austin M -- Lohr, Jens -- Landau, Dan-Avi -- Wu, Catherine J -- Melendez-Zajgla, Jorge -- Hidalgo-Miranda, Alfredo -- Koren, Amnon -- McCarroll, Steven A -- Mora, Jaume -- Lee, Ryan S -- Crompton, Brian -- Onofrio, Robert -- Parkin, Melissa -- Winckler, Wendy -- Ardlie, Kristin -- Gabriel, Stacey B -- Roberts, Charles W M -- Biegel, Jaclyn A -- Stegmaier, Kimberly -- Bass, Adam J -- Garraway, Levi A -- Meyerson, Matthew -- Golub, Todd R -- Gordenin, Dmitry A -- Sunyaev, Shamil -- Lander, Eric S -- Getz, Gad -- ES065073/ES/NIEHS NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- T32 CA009216/CA/NCI NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- U24 CA143845/CA/NCI NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2013 Jul 11;499(7457):214-8. doi: 10.1038/nature12213. Epub 2013 Jun 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02141, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23770567" target="_blank"〉PubMed〈/a〉
    Keywords: Artifacts ; DNA Replication Timing ; Exome/genetics ; False Positive Reactions ; Gene Expression ; *Genetic Heterogeneity ; Genome, Human/genetics ; Humans ; Lung Neoplasms/genetics ; Mutation/*genetics ; Mutation Rate ; Neoplasms/classification/*genetics/pathology ; Neoplasms, Squamous Cell/genetics ; Oncogenes/*genetics ; Reproducibility of Results ; Sample Size
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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