Nature. 2013 Dec 25. doi: 10.1038/nature12881. [Epub ahead of print]
Landscape of genomic alterations in cervical carcinomas.
Ojesina AI1, Lichtenstein L2, Freeman SS3, Pedamallu CS4, Imaz-Rosshandler I5, Pugh TJ4, Cherniack AD3, Ambrogio L3, Cibulskis K3, Bertelsen B6,Romero-Cordoba S5, Treviño V7, Vazquez-Santillan K5, Guadarrama AS5, Wright AA8, Rosenberg MW3, Duke F9, Kaplan B4, Wang R10, Nickerson E3, Walline HM11, Lawrence MS3, Stewart C3, Carter SL3, McKenna A3, Rodriguez-Sanchez IP12, Espinosa-Castilla M5, Woie K13, Bjorge L14, Wik E14, Halle MK14, Hoivik EA14, Krakstad C14, Gabiño NB5, Gómez-Macías GS12, Valdez-Chapa LD12, Garza-Rodríguez ML12, Maytorena G15, Vazquez J15, Rodea C15, Cravioto A15,Cortes ML3, Greulich H16, Crum CP17, Neuberg DS18, Hidalgo-Miranda A5, Escareno CR19, Akslen LA20, Carey TE21, Vintermyr OK20, Gabriel SB3, Barrera-Saldaña HA12, Melendez-Zajgla J5, Getz G22, Salvesen HB23, Meyerson M24.
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.
- [PubMed - as supplied by publisher]