Journal Article

Landscape of genomic alterations in cervical carcinomas

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

2014

Overview

Whole-exome sequencing and analysis of 115 cervical carcinoma–normal paired samples, in addition to transcriptome and whole-genome sequencing for a subset of these tumours, reveal novel genes mutated at significant levels within this cohort and provide evidence that HPV integration is a common mechanism for target gene overexpression; results also compare mutational landscapes between squamous cell carcinomas and adenocarcinomas. A genomic survey of cervical cancer To provide an overview of the genomic aberrations that contribute to cervical cancer these authors performed whole-exome sequencing and analysis of 115 cervical cancer–normal pairs, transcriptome sequences of 79 cervical carcinomas and whole-genomes from 14 cervical cancer–normal pairs. Analyses identify MAPK1 , HLA-B and ELF3 as novel significantly mutated genes and provide evidence that human papilloma virus integration is a common mechanism for target gene overexpression in cervical cancer. The results also provide a comparison of the mutational landscapes of squamous cell carcinomas and adenocarcinomas. Cervical cancer is responsible for 10–15% of cancer-related deaths in women worldwide 1 , 2 . The aetiological role of infection with high-risk human papilloma viruses (HPVs) in cervical carcinomas is well established 3 . Previous studies have also implicated somatic mutations in PIK3CA , PTEN , TP53 , STK11 and KRAS 4 , 5 , 6 , 7 as well as several copy-number alterations in the pathogenesis of cervical carcinomas 8 , 9 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45/23 / 45/91 / 631/208/69 / 631/67/1517/1371 / Adenocarcinoma - genetics / Adenocarcinoma - virology / Cancer / Carcinoma, Squamous Cell - genetics / Carcinoma, Squamous Cell - virology / Case-Control Studies / Cell Cycle Proteins - genetics / Cervical cancer / 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 / Exome sequencing / F-Box Proteins - genetics / F-Box-WD Repeat-Containing Protein 7 / Female / Gene Expression Regulation, Neoplastic - genetics / Gene mutations / Genetic aspects / Genome, Human - genetics / Genomics / HLA-B Antigens - genetics / Human papillomavirus / Humanities and Social Sciences / Humans / letter / Mitogen-Activated Protein Kinase 1 - genetics / multidisciplinary / Mutation / Mutation - genetics / NF-E2-Related Factor 2 - genetics / Oncology, Experimental / Papillomaviridae - genetics / Papillomaviridae - physiology / Papillomavirus Infections - genetics / Prevention / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins c-ets / Receptor, ErbB-2 - genetics / Science / 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