Projektbeschreibung
Pathogene Rolle synonymer Mutationen bei Krebs wird nun erforscht
Bei genetischen Untersuchungen zu Krebs sind stille bzw. stumme Mutationen bislang meist übersehen worden. Neue Daten zeigen jedoch, dass synonyme Mutationen Proteinspiegel oder Proteinkonformation durch Modifizierung der regulierenden Spleißstellen, mRNA-Stabilität, miRNA-Bindungsstellen oder der Effizienz der Translation verändern können. Überdies wurde nachgewiesen, dass synonyme Mutationen über neuartige und bisher weitgehend ungeklärte Mechanismen der Genexpressionsdysregulation auf der Ebene der Transkription oder Translation Krebs fördern. Das EU-finanzierte Projekt SILENT zielt auf die Erforschung der pathogenen Rolle synonymer Mutationen bei Krebs ab, die weitgehend unterschätzt und kaum untersucht werden. Die Forschungsgruppe wird Bioinformatik anwenden, um relevante synonyme Mutationen in zuvor generierten Sequenzdaten aus 11 400 Tumorproben zu identifizieren. Mithilfe von In-silico-Methoden können die am stärksten krebsfördernden Mutationen ausgewählt werden, um diese im Nasslabor weiteren Versuchen zur Klärung ihrer Fähigkeit zur Veränderung der Genexpressionsebene und zur Begünstigung des Krebszellverhaltens zu unterziehen.
Ziel
Our genome contains 20 000 genes, which are transcribed into mRNAs. These mRNAs are then in turn translated into proteins that exert the cellular functions. In the past decade, researchers have analysed the genetic sequence of all protein coding genes in thousands of tumor samples, with the aim to identify gene defects (‘mutations’) that cause cancer. In most of these studies, only gene mutations that cause amino acid changes in the proteins for which they encode were analysed, and it was assumed that mutations that do not cause amino acid changes (=synonymous or silent mutations) are innocent and meaningless events in cancer pathogenesis.
Despite the fact that synonymous mutations have thus largely been ignored by cancer researchers, there are a couple of synonymous mutations that have been shown to promote cancer. This happens via highly novel and poorly understood mechanisms of gene expression dysregulation that occur at the level of gene transcription to mRNA or at the level of translation of the mRNA into protein. Since the role of synonymous mutations in cancer has not been systematically explored so far, and since there is thus evidence that these mutations are not as ‘silent’ and innocent as many people think, we hypothesized that the pathogenic role of synonymous mutations in cancer is largely underestimated. First, we will delineate the landscape of synonymous driver mutations in cancer. For this purpose, we will develop bioinformatics and statistics approaches to identify relevant synonymous mutations in previously generated sequence data from 11 400 tumor samples. Furthermore, we will apply in silico methods to rank identified mutations and filter out the mutations that are predicted to most efficiently promoting cancer. For 50 of the mutations that are predicted to be pathogenic, we will perform wet lab experimental testing of their capacity to alter gene expression level and to promote cancer cell behavior. Special attention will go to mutations that affect poorly characterized mechanisms to regulate the efficiency of protein translation of the mutated gene, because our lab has a strong expertise in this field. Results from this project may also be relevant for more classical non-synonymous mutations, because the novel modes of gene expression regulation we will discover might also be relevant for such mutations, and the project may thus have broad very implications in the cancer field.
Synonymous mutations are currently difficult to find for researchers. We will make these mutations visible via a public website and we will make the methodology we develop in this project available to the research community. This project will thus give silent synonymous mutations a voice through their first comprehensive characterization in cancer.
Wissenschaftliches Gebiet
Schlüsselbegriffe
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-COG - Consolidator GrantGastgebende Einrichtung
3000 Leuven
Belgien