Descrizione del progetto
Studiare il ruolo patogeno delle mutazioni sinonime nel cancro
Le mutazioni silenti, o sinonime, sono state per lo più trascurate nella genetica del cancro. Tuttavia, i nuovi dati dimostrano che le mutazioni sinonime possono modificare i livelli proteici o la conformazione delle proteine alterando i siti di regolamentazione dello splicing, la stabilità dell’mRNA, i siti di legame miRNA o l’efficienza della traslazione. Inoltre, è stato dimostrato che le mutazioni sinonime promuovono il cancro attraverso meccanismi nuovi e poco conosciuti di disregolazione dell’espressione genica a livello di trascrizione o traslazione. Il progetto SILENT, finanziato dall’UE, è volto a studiare il ruolo patogeno delle mutazioni sinonime nel cancro, che è stato ampiamente sottovalutato e poco studiato. I ricercatori svilupperanno la bioinformatica per identificare le mutazioni sinonime rilevanti nei dati di sequenza generati in precedenza da 11 400 campioni tumorali. L’applicazione di metodi in silico consentirà di selezionare le mutazioni più efficaci nel promuovere il cancro per ulteriori test sperimentali analizzando i campioni per verificarne la capacità di alterare il livello di espressione genica e promuovere il comportamento delle cellule tumorali.
Obiettivo
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.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
3000 Leuven
Belgio