Month: January 2014

Nuestro nuevo artículo de Genómica del Cáncer Cérvicouterino acaba de ser publicado

http://www.nature.com/nature/journal/vaop/ncurrent/full/nature12881.html

Básicamente logramos encontrar varias nuevas mutaciones. Tres o cuatro de ellas muy interesantes, como HLA, MAPK1 y (para nosotros) CBFB yERBB2. La primera es importante dado a que podría ser el primer ejemplo de drivers inmunológicos, la segunda dado a que es una cinasa (potencialmente “drogable”) y la tercera se comparte con cáncer de mama. Asimismo hay alguna evidencia inicial de que la inserción del HPV puede ser también importante en la patogénesis, dado a que se inserta en algunos genes importantes.  A partir de aquí nos falta todavía validar los genes más importantes en un número grande de pacientes, realizar algo similar con RNA y con esto, considerar la validez de usar algunos de los genes para diagnóstico/pronóstico y terapia.

http://eleconomista.com.mx/entretenimiento/2014/01/27/hallan-nuevos-genes-cancer-cervicouterino

http://www.jornada.unam.mx/ultimas/2014/01/28/hallan-dos-mutaciones-geneticas-relacionadas-con-el-cancer-1512.html

Landscape of genomic alterations in cervical carcinomas.

Ojesina AI1, et al. Nature. 2013 Dec 25. doi: 10.1038/nature12881

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.

Interesante artículo. ¿Cual será el mecanismo para producir estos fragmentos extracromosomales? La creación  de cromosomas doble minuta y selección? Sin embargo habría que explicar como a partir de una célula se puede reproducir la población (debería ser un mecanismo rápido y lo suficientemente importante para seleccionarse).

Targeted Therapy Resistance Mediated by Dynamic Regulation of Extrachromosomal Mutant EGFR DNA Science 3 January 2014: Vol. 343 no. 6166 pp. 72-76

Intratumoral heterogeneity contributes to cancer drug resistance, but the underlying mechanisms are not understood. Single-cell analyses of patient-derived models and clinical samples from glioblastoma patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) demonstrate that tumor cells reversibly up-regulate or suppress mutant EGFR expression, conferring distinct cellular phenotypes to reach an optimal equilibrium for growth. Resistance to EGFR TKIs is shown to occur by elimination of mutant EGFR from extrachromosomal DNA. After drug withdrawal, reemergence of clonal EGFR mutations on extrachromosomal DNA follows. These results indicate a highly specific, dynamic, and adaptive route by which cancers can evade therapies that target oncogenes maintained on extrachromosomal DNA.