Project description
Studying the pathogenic role of synonymous mutations in cancer
Silent, or synonymous, mutations have been mostly overlooked in cancer genetics. However, new data show that synonymous mutations can change protein levels or protein conformation by altering splicing regulatory sites, mRNA stability, miRNA binding sites or translation efficiency. Moreover, synonymous mutations have been shown to promote cancer via novel and poorly understood mechanisms of gene expression dysregulation at the level of transcription or translation. The EU-funded SILENT project aims to study the pathogenic role of synonymous mutations in cancer, which is largely underestimated and barely studied. The researchers will develop bioinformatics to identify relevant synonymous mutations in previously generated sequence data from 11 400 tumour samples. Application of in silico methods will allow to select the mutations that are most efficient in promoting cancer for further wet lab experimental testing of their capacity to alter gene expression level and promote cancer cell behaviour.
Objective
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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences biological sciences genetics mutation
- medical and health sciences clinical medicine oncology
- natural sciences biological sciences genetics genomes
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)
MAIN PROGRAMME
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Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
ERC-COG - Consolidator Grant
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2019-COG
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
3000 LEUVEN
Belgium
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.