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

Landscape of genomic alterations in cervical carcinomas.

Author information

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.

PMID:
24390348
PMCID:
PMC4161954
DOI:
10.1038/nature12881
[Indexed for MEDLINE]
Free PMC Article

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