Integrated genomic analyses of ovarian carcinoma View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2011-06-29

AUTHORS

D. Bell, A. Berchuck, M. Birrer, J. Chien, D. W. Cramer, F. Dao, R. Dhir, P. DiSaia, H. Gabra, P. Glenn, A. K. Godwin, J. Gross, L. Hartmann, M. Huang, D. G. Huntsman, M. Iacocca, M. Imielinski, S. Kalloger, B. Y. Karlan, D. A. Levine, G. B. Mills, C. Morrison, D. Mutch, N. Olvera, S. Orsulic, K. Park, N. Petrelli, B. Rabeno, J. S. Rader, B. I. Sikic, K. Smith-McCune, A. K. Sood, D. Bowtell, R. Penny, J. R. Testa, K. Chang, C. J. Creighton, H. H. Dinh, J. A. Drummond, G. Fowler, P. Gunaratne, A. C. Hawes, C. L. Kovar, L. R. Lewis, M. B. Morgan, I. F. Newsham, J. Santibanez, J. G. Reid, L. R. Trevino, Y.-Q. Wu, M. Wang, D. M. Muzny, D. A. Wheeler, R. A. Gibbs, G. Getz, M. S. Lawrence, K. Cibulskis, A. Y. Sivachenko, C. Sougnez, D. Voet, J. Wilkinson, T. Bloom, K. Ardlie, T. Fennell, J. Baldwin, R. Nichol, S. Fisher, S. Gabriel, E. S. Lander, L. Ding, R. S. Fulton, D. C. Koboldt, M. D. McLellan, T. Wylie, J. Walker, M. O’Laughlin, D. J. Dooling, L. Fulton, R. Abbott, N. D. Dees, Q. Zhang, C. Kandoth, M. Wendl, W. Schierding, D. Shen, C. C. Harris, H. Schmidt, J. Kalicki, K. D. Delehaunty, C. C. Fronick, R. Demeter, L. Cook, J. W. Wallis, L. Lin, V. J. Magrini, J. S. Hodges, J. M. Eldred, S. M. Smith, C. S. Pohl, F. Vandin, E. Upfal, B. J. Raphael, G. M. Weinstock, E. R. Mardis, R. K. Wilson, M. Meyerson, W. Winckler, G. Getz, R. G. W. Verhaak, S. L. Carter, C. H. Mermel, G. Saksena, H. Nguyen, R. C. Onofrio, M. S. Lawrence, D. Hubbard, S. Gupta, A. Crenshaw, A. H. Ramos, K. Ardlie, L. Chin, A. Protopopov, Juinhua Zhang, T. M. Kim, I. Perna, Y. Xiao, H. Zhang, G. Ren, N. Sathiamoorthy, R. W. Park, E. Lee, P. J. Park, R. Kucherlapati, D. M. Absher, L. Waite, G. Sherlock, J. D. Brooks, J. Z. Li, J. Xu, R. M. Myers, P. W. Laird, L. Cope, J. G. Herman, H. Shen, D. J. Weisenberger, H. Noushmehr, F. Pan, T. Triche Jr, B. P. Berman, D. J. Van Den Berg, J. Buckley, S. B. Baylin, P. T. Spellman, E. Purdom, P. Neuvial, H. Bengtsson, L. R. Jakkula, S. Durinck, J. Han, S. Dorton, H. Marr, Y. G. Choi, V. Wang, N. J. Wang, J. Ngai, J. G. Conboy, B. Parvin, H. S. Feiler, T. P. Speed, J. W. Gray, D. A. Levine, N. D. Socci, Y. Liang, B. S. Taylor, N. Schultz, L. Borsu, A. E. Lash, C. Brennan, A. Viale, C. Sander, M. Ladanyi, K. A. Hoadley, S. Meng, Y. Du, Y. Shi, L. Li, Y. J. Turman, D. Zang, E. B. Helms, S. Balu, X. Zhou, J. Wu, M. D. Topal, D. N. Hayes, C. M. Perou, G. Getz, D. Voet, G. Saksena, Junihua Zhang, H. Zhang, C. J. Wu, S. Shukla, K. Cibulskis, M. S. Lawrence, A. Sivachenko, R. Jing, R. W. Park, Y. Liu, P. J. Park, M. Noble, L. Chin, H. Carter, D. Kim, J. Samayoa, R. Karchin, P. T. Spellman, E. Purdom, P. Neuvial, H. Bengtsson, S. Durinck, J. Han, J. E. Korkola, L. M. Heiser, R. J. Cho, Z. Hu, B. Parvin, T. P. Speed, J. W. Gray, N. Schultz, E. Cerami, B. S. Taylor, A. Olshen, B. Reva, Y. Antipin, R. Shen, P. Mankoo, R. Sheridan, G. Ciriello, W. K. Chang, J. A. Bernanke, L. Borsu, D. A. Levine, M. Ladanyi, C. Sander, D. Haussler, C. C. Benz, J. M. Stuart, S. C. Benz, J. Z. Sanborn, C. J. Vaske, J. Zhu, C. Szeto, G. K. Scott, C. Yau, K. A. Hoadley, Y. Du, S. Balu, D. N. Hayes, C. M. Perou, M. D. Wilkerson, N. Zhang, R. Akbani, K. A. Baggerly, W. K. Yung, G. B. Mills, J. N. Weinstein, R. Penny, T. Shelton, D. Grimm, M. Hatfield, S. Morris, P. Yena, P. Rhodes, M. Sherman, J. Paulauskis, S. Millis, A. Kahn, J. M. Greene, R. Sfeir, M. A. Jensen, J. Chen, J. Whitmore, S. Alonso, J. Jordan, A. Chu, Jinghui Zhang, A. Barker, C. Compton, G. Eley, M. Ferguson, P. Fielding, D. S. Gerhard, R. Myles, C. Schaefer, K. R. Mills Shaw, J. Vaught, J. G. Vockley, P. J. Good, M. S. Guyer, B. Ozenberger, J. Peterson, E. Thomson

ABSTRACT

A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients’ lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology. More... »

PAGES

609-615

Journal

TITLE

Nature

ISSUE

7353

VOLUME

474

Author Affiliations

  • Division of Anatomic Pathology, Mayo Clinic, 55905, Rochester, Minnesota, USA
  • Duke Institute for Genome Sciences and Policy, Duke University Medical Center, 27708, Durham, North Carolina, USA
  • Gynecologic Oncology, Massachusetts General Hospital, 02114, Boston, Massachusetts, USA
  • Division of Experimental Pathology, Mayo Clinic, 55905, Rochester, Minnesota, USA
  • Department of Obstetrics and Gynecology Epidemiology Center, Brigham and Women’s Hospital, 02115, Boston, Massachusetts, USA
  • Department of Surgery, Memorial Sloan-Kettering Cancer Center, 10065, New York, New York, USA
  • Department of Pathology, University of Pittsburgh, 15213, Pittsburgh, Pennsylvania, USA
  • Gynecologic Oncology Group, University of California Irvine, 92697, Irvine, California, USA
  • Department of Surgery and Cancer, Ovarian Cancer Action Research Centre, Imperial College London Hammersmith Campus, London W12 0NN, UK
  • Department of Obstetrics, Gynecology and Reproductive Services, University of California San Francisco, 94143, San Francisco, California, USA
  • Department of Medical Oncology, Women’s Cancer Program, Fox Chase Cancer Center, 19111, Philadelphia, Pennsylvania, USA
  • Women’s Cancer Research Institute at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Geffen School of Medicine at UCLA, 90048, Los Angeles, California, USA
  • Division of Medical Oncology, Mayo Clinic, 55905, Rochester, Minnesota, USA
  • Department of Pathology, Fox Chase Cancer Center, 19111, Philadelphia, Pennsylvania, USA
  • Center for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1G1, Canada
  • Department of Pathology, Christiana Care Health Services, 19718, Newark, Delaware, USA
  • Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Geffen School of Medicine at UCLA, 90048, Los Angeles, California, USA
  • Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, 77030, Houston, Texas, USA
  • Division of Molecular Pathology, Roswell Park Cancer Institute, 14263, Buffalo, New York, USA
  • Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Washington University School of Medicine in St Louis, 63110, St Louis, Missouri, USA
  • Department of Pathology, Memorial Sloan-Kettering Cancer Center, 10065, New York, New York, USA
  • Department of Surgery, Helen F Graham Cancer Center at Christina Care, 19713, Newark, Delaware, USA
  • Department of Obstetrics and Gynecology, Human and Molecular Genetics Center, Medical College of Wisconsin, 53226, Milwaukee, Wisconsin, USA
  • Division of Oncology, Department of Medicine, Stanford University School of Medicine, 94304, Palo Alto, California, USA
  • Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, 77230, Houston, Texas, USA
  • Research Division, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett St, 8006, Melbourne, Victoria, Australia
  • International Genomics Consortium, 85004, Phoenix, Arizona, USA
  • Cancer Biology Program, Fox Chase Cancer Center, 19111, Philadelphia, Pennsylvania, USA
  • Human Genome Sequencing Center, Baylor College of Medicine, 77030, Houston, Texas, USA
  • The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, 02142, Cambridge, Massachusetts, USA
  • Medical Sequencing Analysis and Informatics, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, 02142, Cambridge, Massachusetts, USA
  • Cancer Genome & Medical Resequencing Projects, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, 02142, Cambridge, Massachusetts, USA
  • Sequencing Platform, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, 02142, Cambridge, Massachusetts, USA
  • Sequencing Platform Informatics, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, 02142, Cambridge, Massachusetts, USA
  • Directed Sequencing Informatics, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, 02142, Cambridge, Massachusetts, USA
  • Genetic Analysis Platform, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, 02142, Cambridge, Massachusetts, USA
  • Department of Systems Biology, Harvard University, 02115, Boston, Massachusetts, USA
  • Department of Genetics, The Genome Center at Washington University, Washington University School of Medicine in St Louis, 63108, St Louis, Missouri, USA
  • Department of Computer Science and Center for Computational Molecular Biology, Brown University, 02912, Providence, Rhode Island, USA
  • Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, 02115, Boston, Massachusetts, USA
  • Department of Medical Oncology, Dana-Farber Cancer Institute, 02115, Boston, Massachusetts, USA
  • Department of Dermatology, Harvard Medical School, 02115, Boston, Massachusetts, USA
  • Department of Medical Oncology, Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, 02115, Boston, Massachusetts, USA
  • The Center for Biomedical Informatics, Harvard Medical School, 02115, Boston, Massachusetts, USA
  • Partners Center for Personalized Genetic Medicine, 02139, Cambridge, Massachusetts, USA
  • Informatics Program, Children’s Hospital, 02115, Boston, Massachusetts, USA
  • Department of Genetics, Harvard Medical School, 02115, Boston, Massachusetts, USA
  • HudsonAlpha Institute for Biotechnology, 35806, Huntsville, Alabama, USA
  • Department of Genetics, Stanford University School of Medicine, 94305, Stanford, California, USA
  • Department of Urology, Stanford University School of Medicine, 94305, Stanford, California, USA
  • Department of Human Genetics, University of Michigan, 48109, Ann Arbor, Michigan, USA
  • University of Southern California Epigenome Center, University of Southern California, 90089, Los Angeles, California, USA
  • Biometry and Clinical Trials Division, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, 21231, Baltimore, Maryland, USA
  • Cancer Biology Division, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, 21231, Baltimore, Maryland, USA
  • Life Sciences Division, Lawrence Berkeley National Laboratory, 94720, Berkeley, California, USA
  • Department of Statistics, University of California at Berkeley, 95720, Berkeley, California, USA
  • Department of Molecular and Cellular Biology, University of California at Berkeley, 95720, Berkeley, California, USA
  • Department of Biology and Biochemistry, University of Houston, 77004, Houston, Texas, USA
  • Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia
  • Computational Biology Center, Memorial-Sloan Kettering Cancer Center, 10065, New York, New York, USA
  • Department of Pathology, Human Oncology and Pathogenesis Program, Memorial-Sloan Kettering Cancer Center, 10065, New York, New York, USA
  • Department of Neurosurgery, Memorial-Sloan Kettering Cancer Center, 10065, New York, New York, USA
  • Genomics Core Laboratory, Memorial-Sloan Kettering Cancer Center, 10065, New York, New York, USA
  • Lineberger Comprehensive Cancer Center, 27599, Chapel Hill, North Carolina, USA
  • Department of Internal Medicine, Division of Medical Oncology, University of North Carolina at Chapel Hill, 27599, Chapel Hill, North Carolina, USA
  • Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, 21231, Baltimore, Maryland, USA
  • Department of Physiology and Biophysics, Weill Cornell Graduate School of Medical Sciences, 10065, New York, New York, USA
  • Weill Medical College of Cornell University, 1300 York Avenue, 10065, New York, New York, USA
  • Howard Hughes Medical Institute, University of California Santa Cruz, 95064, Santa Cruz, California, USA
  • Buck Institute for Age Research, 94945, Novato, California, USA
  • Department of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California Santa Cruz, 95064, Santa Cruz, California, USA
  • Lewis-Sigler Institute for Integrative Genomics, 08544, Princeton, New Jersey, USA
  • Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, 77030, Houston, Texas, USA
  • Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 77030, Houston, Texas, USA
  • SRA International, 22033, Fairfax, Virginia, USA
  • Department of Biotechnology, St Jude Children’s Research Hospital, 38105, Memphis, Tennessee, USA
  • MLF Consulting, 02474, Arlington, Massachusetts, USA
  • National Human Genome Research Institute, National Institutes of Health, 20892, Bethesda, Maryland, USA
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature10166

    DOI

    http://dx.doi.org/10.1038/nature10166

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1000736346

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/21720365


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    33 schema:description A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients’ lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.
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