RESUMEN
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.
Asunto(s)
Genoma Humano/genética , Mutación/genética , Neoplasias del Cuello Uterino/genética , Adenocarcinoma/genética , Adenocarcinoma/virología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/virología , Estudios de Casos y Controles , Proteínas de Ciclo Celular/genética , Subunidad beta del Factor de Unión al Sitio Principal/genética , Variaciones en el Número de Copia de ADN/genética , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Proteína p300 Asociada a E1A/genética , Exoma/genética , Proteínas F-Box/genética , Proteína 7 que Contiene Repeticiones F-Box-WD , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Genómica , Antígenos HLA-B/genética , Humanos , Proteína Quinasa 1 Activada por Mitógenos/genética , Factor 2 Relacionado con NF-E2/genética , Papillomaviridae/genética , Papillomaviridae/fisiología , Infecciones por Papillomavirus/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-ets , Receptor ErbB-2/genética , Factores de Transcripción/genética , Transcriptoma/genética , Proteína p53 Supresora de Tumor/genética , Ubiquitina-Proteína Ligasas/genética , Neoplasias del Cuello Uterino/virología , Integración Viral/genéticaRESUMEN
The pathophysiology of endometriosis remains unclear but involves a complex interaction between ectopic endometrium and host peritoneal tissues. We hypothesized that disruption of this interaction would suppress endometriotic lesion formation. We hoped to delineate the molecular and cellular dialogue between ectopic human endometrium and peritoneal tissues in nude mice as a first step toward testing this hypothesis. Human endometrium was xenografted into nude mice, and the resulting lesions were analyzed using microarrays. A novel technique was developed that unambiguously determined whether RNA transcripts identified via microarray analyses originated from human cells (endometrium) or mouse cells (mesothelium). Four key pathways (ubiquitin/proteasome, inflammation, tissue remodeling/repair, and ras-mediated oncogenesis) were revealed, demonstrating communication between host mesothelial cells and ectopic endometrium. Morphometric analysis of nude mouse lesions confirmed that necrosis, inflammation, healing and repair, and cell proliferation occurred during xenograft development. These processes were entirely consistent with the molecular networks revealed by the microarray data. The transcripts detected in the xenografts overlapped with differentially expressed transcripts in a comparison between paired eutopic and ectopic endometria from human endometriotic patients. For the first time, components of the interaction between ectopic endometrium and peritoneal stromal tissues are revealed. Targeted disruption of this dialogue is likely to inhibit endometriotic tissue formation and may prove to be an effective therapeutic strategy for endometriosis.