Maqola

Integrated genomic analyses of ovarian carcinoma

Debra BellMayo Clinic in ArizonaAndrew BerchuckDivision of Gynecologic Oncology/Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, 27708, North Carolina, USAMichael J. BirrerGynecologic Oncology, Massachusetts General Hospital, Boston, 02114, Massachusetts, USAMarcin ImielińskiHarvard University, Cambridge, United StatesJeremy ChienUniversity of Pittsburgh, Pittsburgh, United StatesD. W. CramerDepartment of Obstetrics and Gynecology Epidemiology Center, Brigham and Women’s Hospital, Boston, 02115, Massachusetts, USANarciso OlveraImperial College London, London, United KingdomFanny DaoUniversity of California, San Francisco, San Francisco, United StatesD. A. LevineFox Chase Cancer Center, Philadelphia, United StatesD. A. LevineDepartment of Surgery, Memorial Sloan-Kettering Cancer Center, New York, 10065, New York, USARajiv DhirWinnMedPhilip J. DiSaiaGynecologic Oncology Group, University of California Irvine, Irvine, 92697, California, USAHani GabraDepartment of Surgery and Cancer, Ovarian Cancer Action Research Centre, Imperial College London Hammersmith Campus, London W12 0NN, UKKaren Smith‐McCuneChristiana Care Health System, Wilmington, United StatesPat GlennDepartment of Obstetrics, Gynecology and Reproductive Services, University of California San Francisco, San Francisco, 94143, California, USAA. K. GodwinUniversity of British Columbia, Vancouver, CanadaSandra OršulićWomen’s Cancer Research Institute at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Geffen School of Medicine at UCLA, Los Angeles, 90048, California, USABeth Y. KarlanWomen’s Cancer Research Institute at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Geffen School of Medicine at UCLA, Los Angeles, 90048, California, USAJenny GrossWomen’s Cancer Research Institute at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Geffen School of Medicine at UCLA, Los Angeles, 90048, California, USAL HartmannRoswell Park Comprehensive Cancer Center, Buffalo, United StatesMei HuangDepartment of Pathology, Fox Chase Cancer Center, Philadelphia, 19111, Pennsylvania, USADavid G. HuntsmanMemorial Sloan Kettering Cancer Center, New York, United StatesSteve E. KallogerCedars-Sinai Medical Center, Los Angeles, United StatesBrenda RabenoMemorial Sloan Kettering Cancer Center, New York, United StatesMary IacoccaDepartment of Pathology, Christiana Care Health Services, Newark, 19718, Delaware, USABeth Y. KarlanWomen’s Cancer Research Institute at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Geffen School of Medicine at UCLA, Los Angeles, 90048, California, USAG.B. MillsDepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USAG. B. MillsDepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USAJ. N. WeinsteinDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USAG.B. MillsDepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USAG. B. MillsDepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USAC. MorrisonDivision of Molecular Pathology, Roswell Park Cancer Institute, Buffalo, 14263, New York, USAC. MorrisonThe Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, 14263, New York, USAD. MutchDepartment of Obstetrics and Gynecology, Division of Gynecologic Oncology, Washington University School of Medicine in St Louis, St Louis, 63110, Missouri, USAKay J. ParkDepartment of Pathology, Memorial Sloan-Kettering Cancer Center, New York, 10065, New York, USANicholas J. PetrelliHarvard University, Cambridge, United StatesJanet S. RaderDepartment of Obstetrics and Gynecology, Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, 53226, Wisconsin, USABranimir I. ŠikićDivision of Oncology, Department of Medicine, Stanford University School of Medicine, Palo Alto, 94304, California, USAAnil K. SoodCenter for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, 77230, Texas, USADavid D.L. BowtellMayo Clinic, Rochester, United StatesScott MorrisWinnMedPeggy YenaInternational Genomics Consortium, Phoenix, 85004, Arizona, USAMichael J HatfieldInternational Genomics Consortium, Phoenix, 85004, Arizona, USAJoseph PaulauskisHarvard University, Cambridge, United StatesTroy SheltonInternational Genomics Consortium, Phoenix, 85004, Arizona, USARobert PennyLawrence Berkeley National Laboratory, Berkeley, United StatesPaul RhodesBrown University, Providence, United StatesRobert PennyInternational Genomics Consortium, Phoenix, 85004, Arizona, USAMark E. ShermanHarvard University, Cambridge, United StatesDonata GrimmMassachusetts Institute of Technology, Cambridge, United StatesSherri Z. MillisMemorial Sloan Kettering Cancer Center, New York, United StatesJoseph R. TestaCancer Biology Program, Fox Chase Cancer Center, Philadelphia, 19111, Pennsylvania, USADavid A. WheelerHuman Genome Sequencing Center, Baylor College of Medicine, Houston, 77030, Texas, USALora LewisHuman Genome Sequencing Center, Baylor College of Medicine, Houston, 77030, Texas, USAY.-Q. WuStanford University, Stanford, United StatesJennifer DrummondStanford University, Stanford, United StatesIrene NewshamHuman Genome Sequencing Center, Baylor College of Medicine, Houston, 77030, Texas, USAM. B. MorganHuman Genome Sequencing Center, Baylor College of Medicine, Houston, 77030, Texas, USAJireh SantibanezHuman Genome Sequencing Center, Baylor College of Medicine, Houston, 77030, Texas, USAC. KovarDuke University, Durham, United StatesHuyen DinhHuman Genome Sequencing Center, Baylor College of Medicine, Houston, 77030, Texas, USAKuo-Ching ChangHuman Genome Sequencing Center, Baylor College of Medicine, Houston, 77030, Texas, USALisa R. TreviñoHuman Genome Sequencing Center, Baylor College of Medicine, Houston, 77030, Texas, USAC. J. CreightonStanford University, Stanford, United StatesRichard A. GibbsBrown University, Providence, United StatesPreethi H. GunaratneWashington University in St. Louis, St Louis, United StatesGerald FowlerHuman Genome Sequencing Center, Baylor College of Medicine, Houston, 77030, Texas, USAM. WangHarvard University, Cambridge, United StatesAlicia HawesHarvard University, Cambridge, United StatesDonna M. MuznyBrown University, Providence, United StatesJ. G. ReidHarvard University, Cambridge, United StatesG. GetzHarvard University, Cambridge, United StatesMatthew MeyersonThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, 02142, Massachusetts, USAAndrey SivachenkoEli and Edythe Broad FoundationC. H. MermelThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, 02142, Massachusetts, USAAlex H. RamosThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, 02142, Massachusetts, USAAndrey SivachenkoEli and Edythe Broad FoundationK. CibulskisUniversity of Houston, Houston, United StatesR. W. ParkUniversity of Houston, Houston, United StatesS. L. CarterHarvard University, Cambridge, United StatesRobert C. OnofrioThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, 02142, Massachusetts, USAGordon SaksenaEli and Edythe Broad FoundationEric S. LanderStanford UniversityL. ChinDepartment of Medical Oncology, Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USAAndrew CrenshawAnn Arbor Center for Independent LivingKristin ArdlieUniversity of Southern California, Los Angeles, United StatesGaddy GetzThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, 02142, Massachusetts, USAHuy NguyenJohns Hopkins University, Baltimore, United StatesR. G. W. VerhaakEli and Edythe Broad FoundationMichael S. LawrenceEli and Edythe Broad FoundationDouglas VoetUniversity of California, Berkeley, Berkeley, United StatesSumeet GuptaThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, 02142, Massachusetts, USARui JingUniversity of HoustonMike NobleWalter and Eliza Hall Institute of Medical Research, Melbourne, AustraliaDiana HubbardDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USAK. CibulskisMemorial Sloan Kettering Cancer Center, New York, United StatesKristian CibulskisMedical Sequencing Analysis and Informatics, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, 02142, Massachusetts, USA

2011en

ABI

Annotatsiya

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. The Cancer Genome Atlas (TCGA) project reports here its analysis of messenger RNA and microRNA expression, promoter methylation, DNA copy number and exome sequences in 489 high-grade serous ovarian adenocarcinomas. The analyses help establish new tumour subtypes. Among other insights is the finding that while the gene encoding p53 tumour suppressor is mutated in almost all tumours, nine other loci including NF1, BRCA1, BRCA2, RB1 and CDK12 carry recurrent albeit low-prevalence mutations. Homologous recombination is defective in about half of the tumours studied, and Notch and FOXM1 signalling are involved in the pathophysiology.

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Identifikatorlar

DOI: 10.1038/nature10166

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