Ectopic activation of germline and placental genes identifies aggressive metastasis-prone lung cancers

Activation of normally silent tissue-specific genes and the resulting cell "identity crisis" are the unexplored consequences of malignant epigenetic reprogramming. We designed a strategy for investigating this reprogramming, which consisted of identifying a large number of tissue-restricte...

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Vydáno v:Science translational medicine Ročník 5; číslo 186; s. 186ra66
Hlavní autoři: Rousseaux, Sophie, Debernardi, Alexandra, Jacquiau, Baptiste, Vitte, Anne-Laure, Vesin, Aurélien, Nagy-Mignotte, Hélène, Moro-Sibilot, Denis, Brichon, Pierre-Yves, Lantuejoul, Sylvie, Hainaut, Pierre, Laffaire, Julien, de Reyniès, Aurélien, Beer, David G, Timsit, Jean-François, Brambilla, Christian, Brambilla, Elisabeth, Khochbin, Saadi
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 22.05.2013
Témata:
Animals
Cell Line, Tumor
DNA Methylation - genetics
Epigenesis, Genetic
Female
Gene Expression Regulation, Neoplastic
Germ Cells - metabolism
Humans
Lung Neoplasms - drug therapy
Lung Neoplasms - genetics
Lung Neoplasms - pathology
Neoplasm Invasiveness
Neoplasm Metastasis - genetics
Neoplasm Staging
Organ Specificity
Placenta - metabolism
Pregnancy
Prognosis
Promoter Regions, Genetic - genetics
Reproducibility of Results
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ISSN:1946-6242, 1946-6242
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Shrnutí:Activation of normally silent tissue-specific genes and the resulting cell "identity crisis" are the unexplored consequences of malignant epigenetic reprogramming. We designed a strategy for investigating this reprogramming, which consisted of identifying a large number of tissue-restricted genes that are epigenetically silenced in normal somatic cells and then detecting their expression in cancer. This approach led to the demonstration that large-scale "off-context" gene activations systematically occur in a variety of cancer types. In our series of 293 lung tumors, we identified an ectopic gene expression signature associated with a subset of highly aggressive tumors, which predicted poor prognosis independently of the TNM (tumor size, node positivity, and metastasis) stage or histological subtype. The ability to isolate these tumors allowed us to reveal their common molecular features characterized by the acquisition of embryonic stem cell/germ cell gene expression profiles and the down-regulation of immune response genes. The methodical recognition of ectopic gene activations in cancer cells could serve as a basis for gene signature-guided tumor stratification, as well as for the discovery of oncogenic mechanisms, and expand the understanding of the biology of very aggressive tumors.
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ISSN:1946-6242
1946-6242
DOI:10.1126/scitranslmed.3005723