title: Landscape of genomic alterations in cervical carcinomas.
abstract: 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.
authors.affiliation: 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].
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authors.affiliation: 1] The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA [2].
authors.forename: Lee
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authors.lastname: Lichtenstein
authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.
authors.forename: Samuel S
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authors.lastname: Freeman
authors.affiliation: 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.
authors.forename: Chandra Sekhar
authors.initials: CS
authors.lastname: Pedamallu
authors.affiliation: Instituto Nacional de Medicina Genomica, Mexico City 14610, Mexico.
authors.forename: Ivan
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authors.affiliation: 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.
authors.forename: Trevor J
authors.initials: TJ
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authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.
authors.forename: Andrew D
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authors.lastname: Cherniack
authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.
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authors.lastname: Ambrogio
authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.
authors.forename: Kristian
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authors.lastname: Cibulskis
authors.affiliation: Department of Pathology, Haukeland University Hospital, N5021 Bergen, Norway.
authors.forename: Bjørn
authors.initials: B
authors.lastname: Bertelsen
authors.affiliation: Instituto Nacional de Medicina Genomica, Mexico City 14610, Mexico.
authors.forename: Sandra
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authors.lastname: Romero-Cordoba
authors.affiliation: Tecnológico de Monterrey, Monterrey 64849, Mexico.
authors.forename: Victor
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authors.lastname: Treviño
authors.affiliation: Instituto Nacional de Medicina Genomica, Mexico City 14610, Mexico.
authors.forename: Karla
authors.initials: K
authors.lastname: Vazquez-Santillan
authors.affiliation: Instituto Nacional de Medicina Genomica, Mexico City 14610, Mexico.
authors.forename: Alberto Salido
authors.initials: AS
authors.lastname: Guadarrama
authors.affiliation: 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.
authors.forename: Alexi A
authors.initials: AA
authors.lastname: Wright
authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.
authors.forename: Mara W
authors.initials: MW
authors.lastname: Rosenberg
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Fujiko
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authors.affiliation: 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.
authors.forename: Bethany
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authors.affiliation: 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.
authors.forename: Rui
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authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.
authors.forename: Elizabeth
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authors.affiliation: Cancer Biology Program, Program in the Biomedical Sciences, Rackham Graduate School, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Heather M
authors.initials: HM
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authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.
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authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.
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authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.
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authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.
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authors.affiliation: Facultad de Medicina y Hospital Universitario 'Dr. José Eluterio González' de la Universidad Autónoma de Nuevo León, Monterrey, Nuevo León 64460, México.
authors.forename: Iram P
authors.initials: IP
authors.lastname: Rodriguez-Sanchez
authors.affiliation: Instituto Nacional de Medicina Genomica, Mexico City 14610, Mexico.
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authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, N5021 Bergen, Norway.
authors.forename: Kathrine
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authors.affiliation: 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.
authors.forename: Line
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authors.affiliation: 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.
authors.forename: Elisabeth
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authors.affiliation: 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.
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authors.initials: MK
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authors.affiliation: 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.
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authors.affiliation: 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.
authors.forename: Camilla
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authors.affiliation: Instituto Nacional de Medicina Genomica, Mexico City 14610, Mexico.
authors.forename: Nayeli Belem
authors.initials: NB
authors.lastname: Gabiño
authors.affiliation: Facultad de Medicina y Hospital Universitario 'Dr. José Eluterio González' de la Universidad Autónoma de Nuevo León, Monterrey, Nuevo León 64460, México.
authors.forename: Gabriela Sofia
authors.initials: GS
authors.lastname: Gómez-Macías
authors.affiliation: Facultad de Medicina y Hospital Universitario 'Dr. José Eluterio González' de la Universidad Autónoma de Nuevo León, Monterrey, Nuevo León 64460, México.
authors.forename: Lezmes D
authors.initials: LD
authors.lastname: Valdez-Chapa
authors.affiliation: Facultad de Medicina y Hospital Universitario 'Dr. José Eluterio González' de la Universidad Autónoma de Nuevo León, Monterrey, Nuevo León 64460, México.
authors.forename: María Lourdes
authors.initials: ML
authors.lastname: Garza-Rodríguez
authors.affiliation: Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico.
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authors.affiliation: Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico.
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authors.affiliation: Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico.
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authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.
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authors.affiliation: 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.
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authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
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authors.affiliation: Instituto Nacional de Medicina Genomica, Mexico City 14610, Mexico.
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authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.
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authors.affiliation: Facultad de Medicina y Hospital Universitario 'Dr. José Eluterio González' de la Universidad Autónoma de Nuevo León, Monterrey, Nuevo León 64460, México.
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authors.affiliation: Instituto Nacional de Medicina Genomica, Mexico City 14610, Mexico.
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authors.affiliation: 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.
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authors.forename: Helga B
authors.initials: HB
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authors.affiliation: 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].
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mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000821:virology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000821:virology; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics; D050658:Core Binding Factor beta Subunit / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D050881:E1A-Associated p300 Protein / Q000235:genetics; D059472:Exome / Q000235:genetics; D044783:F-Box Proteins / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D015235:HLA-B Antigens / Q000235:genetics; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D027383:Papillomaviridae / Q000235:genetics / Q000502:physiology; D030361:Papillomavirus Infections / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D050783:Proto-Oncogene Proteins c-ets; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D059467:Transcriptome / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000821:virology; D016662:Virus Integration / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D050658:Core Binding Factor beta Subunit; D004268:DNA-Binding Proteins; D050881:E1A-Associated p300 Protein; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D015235:HLA-B Antigens; D019950:Mitogen-Activated Protein Kinase 1; D051267:NF-E2-Related Factor 2; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; C493692:CBFB protein, human; C105529:ELF3 protein, human; C513273:FBXW7 protein, human; C495635:NFE2L2 protein, human; C495901:TP53 protein, human; C494360:EP300 protein, human; C508053:ERBB2 protein, human; C535150:MAPK1 protein, human