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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: 2011-07-30
    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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  • 3
    Publication Date: 2011-02-11
    Description: Prostate cancer is the second most common cause of male cancer deaths in the United States. However, the full range of prostate cancer genomic alterations is incompletely characterized. Here we present the complete sequence of seven primary human prostate cancers and their paired normal counterparts. Several tumours contained complex chains of balanced (that is, 'copy-neutral') rearrangements that occurred within or adjacent to known cancer genes. Rearrangement breakpoints were enriched near open chromatin, androgen receptor and ERG DNA binding sites in the setting of the ETS gene fusion TMPRSS2-ERG, but inversely correlated with these regions in tumours lacking ETS fusions. This observation suggests a link between chromatin or transcriptional regulation and the genesis of genomic aberrations. Three tumours contained rearrangements that disrupted CADM2, and four harboured events disrupting either PTEN (unbalanced events), a prostate tumour suppressor, or MAGI2 (balanced events), a PTEN interacting protein not previously implicated in prostate tumorigenesis. Thus, genomic rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3075885/" 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/PMC3075885/" 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 -- Lawrence, Michael S -- Demichelis, Francesca -- Drier, Yotam -- Cibulskis, Kristian -- Sivachenko, Andrey Y -- Sboner, Andrea -- Esgueva, Raquel -- Pflueger, Dorothee -- Sougnez, Carrie -- Onofrio, Robert -- Carter, Scott L -- Park, Kyung -- Habegger, Lukas -- Ambrogio, Lauren -- Fennell, Timothy -- Parkin, Melissa -- Saksena, Gordon -- Voet, Douglas -- Ramos, Alex H -- Pugh, Trevor J -- Wilkinson, Jane -- Fisher, Sheila -- Winckler, Wendy -- Mahan, Scott -- Ardlie, Kristin -- Baldwin, Jennifer -- Simons, Jonathan W -- Kitabayashi, Naoki -- MacDonald, Theresa Y -- Kantoff, Philip W -- Chin, Lynda -- Gabriel, Stacey B -- Gerstein, Mark B -- Golub, Todd R -- Meyerson, Matthew -- Tewari, Ashutosh -- Lander, Eric S -- Getz, Gad -- Rubin, Mark A -- Garraway, Levi A -- 2 P50 CA090381-11/CA/NCI NIH HHS/ -- DP2 OD002750/OD/NIH HHS/ -- DP2 OD002750-01/OD/NIH HHS/ -- R33 CA126674/CA/NCI NIH HHS/ -- R33 CA126674-03/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Feb 10;470(7333):214-20. doi: 10.1038/nature09744.〈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/21307934" target="_blank"〉PubMed〈/a〉
    Keywords: Carrier Proteins/genetics ; Case-Control Studies ; Cell Adhesion Molecules/genetics ; Chromatin/genetics/metabolism ; Chromosome Aberrations ; Chromosome Breakpoints ; Epigenesis, Genetic/genetics ; Gene Expression Regulation, Neoplastic ; Genome, Human/*genetics ; Humans ; Male ; PTEN Phosphohydrolase/genetics/metabolism ; Prostatic Neoplasms/*genetics ; Recombination, Genetic/genetics ; Signal Transduction/genetics ; Transcription, Genetic
    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: 2014-01-07
    Description: Cervical cancer is responsible for 10-15% of cancer-related deaths in women worldwide. The aetiological role of infection with high-risk human papilloma viruses (HPVs) in cervical carcinomas is well established. Previous studies have also implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as several copy-number alterations in the pathogenesis of cervical carcinomas. Here we report whole-exome sequencing analysis of 115 cervical carcinoma-normal paired samples, transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumour-normal pairs. Previously unknown somatic mutations in 79 primary squamous cell carcinomas include recurrent E322K substitutions in the MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in EP300 (16%), FBXW7 (15%), NFE2L2 (4%), TP53 (5%) and ERBB2 (6%). We also observe somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. Squamous cell carcinomas have higher frequencies of somatic nucleotide substitutions occurring at cytosines preceded by thymines (Tp*C sites) than adenocarcinomas. Gene expression levels at HPV integration sites were statistically significantly higher in tumours with HPV integration compared with expression of the same genes in tumours without viral integration at the same site. These data demonstrate several recurrent genomic alterations in cervical carcinomas that suggest new strategies to combat this disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161954/" 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/PMC4161954/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ojesina, Akinyemi I -- Lichtenstein, Lee -- Freeman, Samuel S -- Pedamallu, Chandra Sekhar -- Imaz-Rosshandler, Ivan -- Pugh, Trevor J -- Cherniack, Andrew D -- Ambrogio, Lauren -- Cibulskis, Kristian -- Bertelsen, Bjorn -- Romero-Cordoba, Sandra -- Trevino, Victor -- Vazquez-Santillan, Karla -- Guadarrama, Alberto Salido -- Wright, Alexi A -- Rosenberg, Mara W -- Duke, Fujiko -- Kaplan, Bethany -- Wang, Rui -- Nickerson, Elizabeth -- Walline, Heather M -- Lawrence, Michael S -- Stewart, Chip -- Carter, Scott L -- McKenna, Aaron -- Rodriguez-Sanchez, Iram P -- Espinosa-Castilla, Magali -- Woie, Kathrine -- Bjorge, Line -- Wik, Elisabeth -- Halle, Mari K -- Hoivik, Erling A -- Krakstad, Camilla -- Gabino, Nayeli Belem -- Gomez-Macias, Gabriela Sofia -- Valdez-Chapa, Lezmes D -- Garza-Rodriguez, Maria Lourdes -- Maytorena, German -- Vazquez, Jorge -- Rodea, Carlos -- Cravioto, Adrian -- Cortes, Maria L -- Greulich, Heidi -- Crum, Christopher P -- Neuberg, Donna S -- Hidalgo-Miranda, Alfredo -- Escareno, Claudia Rangel -- Akslen, Lars A -- Carey, Thomas E -- Vintermyr, Olav K -- Gabriel, Stacey B -- Barrera-Saldana, Hugo A -- Melendez-Zajgla, Jorge -- Getz, Gad -- Salvesen, Helga B -- Meyerson, Matthew -- K07 CA166210/CA/NCI NIH HHS/ -- T32 CA009676/CA/NCI NIH HHS/ -- England -- Nature. 2014 Feb 20;506(7488):371-5. doi: 10.1038/nature12881. Epub 2013 Dec 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA [3]. ; 1] The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA [2]. ; The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA. ; 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA. ; Instituto Nacional de Medicina Genomica, Mexico City 14610, Mexico. ; Department of Pathology, Haukeland University Hospital, N5021 Bergen, Norway. ; Tecnologico de Monterrey, Monterrey 64849, Mexico. ; 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China. ; Cancer Biology Program, Program in the Biomedical Sciences, Rackham Graduate School, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Facultad de Medicina y Hospital Universitario 'Dr. Jose Eluterio Gonzalez' de la Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon 64460, Mexico. ; Department of Obstetrics and Gynecology, Haukeland University Hospital, N5021 Bergen, Norway. ; 1] Department of Obstetrics and Gynecology, Haukeland University Hospital, N5021 Bergen, Norway [2] Department of Clinical Science, Centre for Cancer Biomarkers, University of Bergen, N5020 Bergen, Norway. ; Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico. ; 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA [3] Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; 1] Instituto Nacional de Medicina Genomica, Mexico City 14610, Mexico [2] Claremont Graduate University, Claremont, California 91711, USA. ; 1] Department of Pathology, Haukeland University Hospital, N5021 Bergen, Norway [2] Centre for Cancer Biomarkers, Department of Clinical Medicine, University of Bergen, N5020 Bergen, Norway. ; Head and Neck Oncology Program and Department of Otolaryngology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 38109, USA. ; 1] The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA [2] Massachusetts General Hospital Cancer Center and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. ; 1] Department of Obstetrics and Gynecology, Haukeland University Hospital, N5021 Bergen, Norway [2] Department of Clinical Science, Centre for Cancer Biomarkers, University of Bergen, N5020 Bergen, Norway [3]. ; 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA [3] Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [4].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24390348" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/genetics/virology ; Carcinoma, Squamous Cell/genetics/virology ; Case-Control Studies ; Cell Cycle Proteins/genetics ; Core Binding Factor beta Subunit/genetics ; DNA Copy Number Variations/genetics ; DNA Mutational Analysis ; DNA-Binding Proteins/genetics ; E1A-Associated p300 Protein/genetics ; Exome/genetics ; F-Box Proteins/genetics ; Female ; Gene Expression Regulation, Neoplastic/genetics ; Genome, Human/*genetics ; Genomics ; HLA-B Antigens/genetics ; Humans ; Mitogen-Activated Protein Kinase 1/genetics ; Mutation/*genetics ; NF-E2-Related Factor 2/genetics ; Papillomaviridae/genetics/physiology ; Papillomavirus Infections/genetics ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins c-ets ; Receptor, ErbB-2/genetics ; Transcription Factors/genetics ; Transcriptome/genetics ; Tumor Suppressor Protein p53/genetics ; Ubiquitin-Protein Ligases/genetics ; Uterine Cervical Neoplasms/*genetics/virology ; Virus Integration/genetics
    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: 2011-03-25
    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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  • 6
    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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  • 7
    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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  • 8
    Publication Date: 2015-05-09
    Description: Transcriptional regulation and posttranscriptional processing underlie many cellular and organismal phenotypes. We used RNA sequence data generated by Genotype-Tissue Expression (GTEx) project to investigate the patterns of transcriptome variation across individuals and tissues. Tissues exhibit characteristic transcriptional signatures that show stability in postmortem samples. These signatures are dominated by a relatively small number of genes-which is most clearly seen in blood-though few are exclusive to a particular tissue and vary more across tissues than individuals. Genes exhibiting high interindividual expression variation include disease candidates associated with sex, ethnicity, and age. Primary transcription is the major driver of cellular specificity, with splicing playing mostly a complementary role; except for the brain, which exhibits a more divergent splicing program. Variation in splicing, despite its stochasticity, may play in contrast a comparatively greater role in defining individual phenotypes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4547472/" 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/PMC4547472/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mele, Marta -- Ferreira, Pedro G -- Reverter, Ferran -- DeLuca, David S -- Monlong, Jean -- Sammeth, Michael -- Young, Taylor R -- Goldmann, Jakob M -- Pervouchine, Dmitri D -- Sullivan, Timothy J -- Johnson, Rory -- Segre, Ayellet V -- Djebali, Sarah -- Niarchou, Anastasia -- GTEx Consortium -- Wright, Fred A -- Lappalainen, Tuuli -- Calvo, Miquel -- Getz, Gad -- Dermitzakis, Emmanouil T -- Ardlie, Kristin G -- Guigo, Roderic -- HHSN261200800001E/PHS HHS/ -- HHSN268201000029C/HL/NHLBI NIH HHS/ -- HHSN268201000029C/PHS HHS/ -- R01 DA006227-17/DA/NIDA NIH HHS/ -- R01 MH090936/MH/NIMH NIH HHS/ -- R01 MH090941/MH/NIMH NIH HHS/ -- New York, N.Y. -- Science. 2015 May 8;348(6235):660-5. doi: 10.1126/science.aaa0355.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain. Harvard Department of stem cell and regenerative biology, Harvard University, Cambridge, MA, USA. ; Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain. Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland. Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. Swiss Institute of Bioinformatics, Geneva, Switzerland. ; Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain. Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Catalonia, Spain. Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. ; Broad Institute of MIT and Harvard, Cambridge, MA, USA. ; Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain. Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. McGill University, Montreal, Canada. ; Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain. Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. National Institute for Scientific Computing (LNCC), Petropolis, Rio de Janeiro, Brazil. ; Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain. Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. Radboud University, Nijmegen, Netherlands. ; Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain. Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. Faculty of Bioengineering and Bioinformatics, Moscow State University, Leninskie Gory 1-73, 119992 Moscow, Russia. ; Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain. Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. ; Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland. Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. Swiss Institute of Bioinformatics, Geneva, Switzerland. ; Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain. Harvard Department of stem cell and regenerative biology, Harvard University, Cambridge, MA, USA. Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland. Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. Swiss Institute of Bioinformatics, Geneva, Switzerland. Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Catalonia, Spain. Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. Broad Institute of MIT and Harvard, Cambridge, MA, USA. McGill University, Montreal, Canada. National Institute for Scientific Computing (LNCC), Petropolis, Rio de Janeiro, Brazil. Radboud University, Nijmegen, Netherlands. Faculty of Bioengineering and Bioinformatics, Moscow State University, Leninskie Gory 1-73, 119992 Moscow, Russia. North Carolina State University, Raleigh, NC, USA. New York Genome Center, New York, NY, USA. Department of Systems Biology, Columbia University, New York, NY, USA. Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Institut Hospital del Mar d'Investigacions Mediques (IMIM), Barcelona, Catalonia, Spain. Joint CRG-Barcelona Super Computing Center (BSC)-Institut de Recerca Biomedica (IRB) Program in Computational Biology, Barcelona, Catalonia, Spain. ; North Carolina State University, Raleigh, NC, USA. ; Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland. Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland. Swiss Institute of Bioinformatics, Geneva, Switzerland. New York Genome Center, New York, NY, USA. Department of Systems Biology, Columbia University, New York, NY, USA. ; Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Catalonia, Spain. ; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. ; Broad Institute of MIT and Harvard, Cambridge, MA, USA. kardlie@broadinstitute.org roderic.guigo@crg.cat. ; Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain. Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain. Institut Hospital del Mar d'Investigacions Mediques (IMIM), Barcelona, Catalonia, Spain. Joint CRG-Barcelona Super Computing Center (BSC)-Institut de Recerca Biomedica (IRB) Program in Computational Biology, Barcelona, Catalonia, Spain. kardlie@broadinstitute.org roderic.guigo@crg.cat.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25954002" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing ; Female ; Gene Expression Profiling ; *Gene Expression Regulation ; Genome, Human/*genetics ; Humans ; Male ; Organ Specificity/genetics ; Phenotype ; Polymorphism, Single Nucleotide ; Sequence Analysis, RNA ; Sex Factors ; *Transcriptome
    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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