Landscape of genomic alterations in cervical carcinomas

Akinyemi I Ojesina; Lee Lichtenstein; Samuel S Freeman; Chandra Sekhar Pedamallu; Ivan Imaz-Rosshandler; Trevor J Pugh; Andrew D Cherniack; Lauren Ambrogio; Kristian Cibulskis; Bjørn Bertelsen; Sandra Romero-Cordoba; Victor Treviño; Karla Vazquez-Santillan; Alberto Salido Guadarrama; Alexi A Wright; Mara W Rosenberg; Fujiko Duke; Bethany Kaplan; Rui Wang; Elizabeth Nickerson; Heather M Walline; Michael S Lawrence; Chip Stewart; Scott L Carter; Aaron McKenna; Iram P Rodriguez-Sanchez; Magali Espinosa-Castilla; Kathrine Woie; Line Bjorge; Elisabeth Wik; Mari K Halle; Erling A Hoivik; Camilla Krakstad; Nayeli Belem Gabiño; Gabriela Sofia Gómez-Macías; Lezmes D Valdez-Chapa; María Lourdes Garza-Rodríguez; German Maytorena; Jorge Vazquez; Carlos Rodea; Adrian Cravioto; Maria L Cortes; Heidi Greulich; Christopher P Crum; Donna S Neuberg; Alfredo Hidalgo-Miranda; Claudia Rangel Escareno; Lars A Akslen; Thomas E Carey; Olav K Vintermyr; Stacey B Gabriel; Hugo A Barrera-Saldaña; Jorge Melendez-Zajgla; Gad Getz; Helga B Salvesen; Matthew Meyerson

doi:10.1038/nature12881

Landscape of genomic alterations in cervical carcinomas

Nature. 2014 Feb 20;506(7488):371-5. doi: 10.1038/nature12881. Epub 2013 Dec 25.

Authors

Akinyemi I Ojesina¹, Lee Lichtenstein², Samuel S Freeman³, Chandra Sekhar Pedamallu⁴, Ivan Imaz-Rosshandler⁵, Trevor J Pugh⁴, Andrew D Cherniack³, Lauren Ambrogio³, Kristian Cibulskis³, Bjørn Bertelsen⁶, Sandra Romero-Cordoba⁵, Victor Treviño⁷, Karla Vazquez-Santillan⁵, Alberto Salido Guadarrama⁵, Alexi A Wright⁸, Mara W Rosenberg³, Fujiko Duke⁹, Bethany Kaplan⁴, Rui Wang¹⁰, Elizabeth Nickerson³, Heather M Walline¹¹, Michael S Lawrence³, Chip Stewart³, Scott L Carter³, Aaron McKenna³, Iram P Rodriguez-Sanchez¹², Magali Espinosa-Castilla⁵, Kathrine Woie¹³, Line Bjorge¹⁴, Elisabeth Wik¹⁴, Mari K Halle¹⁴, Erling A Hoivik¹⁴, Camilla Krakstad¹⁴, Nayeli Belem Gabiño⁵, Gabriela Sofia Gómez-Macías¹², Lezmes D Valdez-Chapa¹², María Lourdes Garza-Rodríguez¹², German Maytorena¹⁵, Jorge Vazquez¹⁵, Carlos Rodea¹⁵, Adrian Cravioto¹⁵, Maria L Cortes³, Heidi Greulich¹⁶, Christopher P Crum¹⁷, Donna S Neuberg¹⁸, Alfredo Hidalgo-Miranda⁵, Claudia Rangel Escareno¹⁹, Lars A Akslen²⁰, Thomas E Carey²¹, Olav K Vintermyr²⁰, Stacey B Gabriel³, Hugo A Barrera-Saldaña¹², Jorge Melendez-Zajgla⁵, Gad Getz²², Helga B Salvesen²³, Matthew Meyerson²⁴

Affiliations

¹ 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].
² 1] The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA [2].
³ The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.
⁴ 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.
⁵ Instituto Nacional de Medicina Genomica, Mexico City 14610, Mexico.
⁶ Department of Pathology, Haukeland University Hospital, N5021 Bergen, Norway.
⁷ Tecnológico de Monterrey, Monterrey 64849, Mexico.
⁸ 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.
⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
¹⁰ 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.
¹¹ Cancer Biology Program, Program in the Biomedical Sciences, Rackham Graduate School, University of Michigan, Ann Arbor, Michigan 48109, USA.
¹² Facultad de Medicina y Hospital Universitario 'Dr. José Eluterio González' de la Universidad Autónoma de Nuevo León, Monterrey, Nuevo León 64460, México.
¹³ Department of Obstetrics and Gynecology, Haukeland University Hospital, N5021 Bergen, Norway.
¹⁴ 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.
¹⁵ Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico.
¹⁶ 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.
¹⁷ Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
¹⁸ Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
¹⁹ 1] Instituto Nacional de Medicina Genomica, Mexico City 14610, Mexico [2] Claremont Graduate University, Claremont, California 91711, USA.
²⁰ 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.
²¹ Head and Neck Oncology Program and Department of Otolaryngology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 38109, USA.
²² 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.
²³ 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].
²⁴ 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].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / genetics
Adenocarcinoma / virology
Carcinoma, Squamous Cell / genetics
Carcinoma, Squamous Cell / 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
F-Box-WD Repeat-Containing Protein 7
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
Papillomaviridae / 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*
Uterine Cervical Neoplasms / virology
Virus Integration / genetics

Substances

CBFB protein, human
Cell Cycle Proteins
Core Binding Factor beta Subunit
DNA-Binding Proteins
ELF3 protein, human
F-Box Proteins
F-Box-WD Repeat-Containing Protein 7
FBXW7 protein, human
HLA-B Antigens
NF-E2-Related Factor 2
NFE2L2 protein, human
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-ets
TP53 protein, human
Transcription Factors
Tumor Suppressor Protein p53
E1A-Associated p300 Protein
EP300 protein, human
Ubiquitin-Protein Ligases
ERBB2 protein, human
Receptor, ErbB-2
MAPK1 protein, human
Mitogen-Activated Protein Kinase 1

Associated data

dbGaP/PHS000600

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding