Blog

Our lab has produced the first exome-based diagnosis of a cancer hereditary syndrome in an agnostic setting (without a previous presuntive disease) in Mexico.

Links to some of the coverage news (some are clearly wrong…)

La crónica – http://www.cronica.com.mx/notas/2016/990358.html

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.

Introduction

Este es el proyecto global en el que participa el INMEGEN. El ICGC es uno de los dos proyectos más grandes a nivel mundial (el oro es el TCGA). México es el único país latinoamericano en participar. En él están 13 países y 390 grupos de investigación.

ICGC Goal: To obtain a comprehensive description of genomic, transcriptomic and epigenomic changes in 50 different tumor types and/or subtypes which are of clinical and societal importance across the globe.

!Al final esperamos tener 18000 tumores secuenciados!

Pueden echarle un vistazo en icgc.org

Entrevista

Aunque el mapa de como estamos en producción científica es poco halagador, lo interesante es que hemos crecido, sobre todo comparando a otros países (incluído EU). Compare la primera foto con la segunda. Este tipo de gráficas se parecen al homúnculo de Penfield (http://es.wikipedia.org/wiki/Homúnculo) 🙂

PRODUCCION CIENTIFICA

CRECIMIENTO PRODUCCION CIENTIFICA

fuente http://www.worldmapper.org

Cancer biology: BET-ting on chromatin

Tumor development often involves genomic changes that affect protein expression, so chromatin alterations have received a lot of attention as possible therapeutic targets. A handful of recent studies support this idea by identifying a role for the bromodomain and extraterminal (BET) family of transcriptional regulators, which bind and recognize histone acetylation, in several human hematological malignancies.

Four independent groups—from Boston’s Dana-Farber Cancer Institute, New York state’s Cold Spring Harbor Laboratory, the UK’s Cambridge University and Massachusetts’s Constellation Pharmaceuticals—started from different points and used different models, but they all converged on the finding that interfering with the function of BET proteins reduces the transcription of key oncogenes such as Myc, arrests cell-cycle progression and leads to apoptosis (Cell 146, 904–917, 2011; Nature 478, 524–528 & 529–533, 2011; Proc. Natl. Acad. Sci. USA 108, 16669–16674, 2011).

Crucially, the four studies highlighted the clinical implications of this finding by showing that small-molecule inhibitors of BET family members had therapeutic effects in mouse models of leukemia, lymphoma and myeloma, as well as in primary cells isolated from people with cancer. —JCL

Nature 464, 993-998 (15 April 2010) doi:10.1038/nature08987

International Cancer Genome Consortium
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The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.