HYPER-INSIGHT SIGNED
Hypermutated tumors: insight into genome maintenance and cancer vulnerabilities provided by an extreme burden of somatic mutations
Total Cost €
0EC-Contrib. €
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Project "HYPER-INSIGHT" data sheet
The following table provides information about the project.
| Coordinator |
FUNDACIO INSTITUT DE RECERCA BIOMEDICA (IRB BARCELONA)
Organization address contact info |
| Coordinator Country | Spain [ES] |
| Total cost | 1˙499˙812 € |
| EC max contribution | 1˙499˙812 € (100%) |
| Programme |
1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC)) |
| Code Call | ERC-2017-STG |
| Funding Scheme | ERC-STG |
| Starting year | 2018 |
| Duration (year-month-day) | from 2018-02-01 to 2023-01-31 |
Partnership
Take a look of project's partnership.
| # | ||||
|---|---|---|---|---|
| 1 | FUNDACIO INSTITUT DE RECERCA BIOMEDICA (IRB BARCELONA) | ES (BARCELONA) | coordinator | 1˙499˙812.00 |
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Project objective
Mutations are the fuel of any evolutionary process, and this also applies to carcinogenesis. The advent of affordable DNA sequencing has enabled mutagenic processes in the human soma to be quantified genome-wide, revealing a striking occurrence of hypermutated tumors. They exhibit an extreme load of somatic changes, often harbouring hundreds of single-nucleotide variants and/or indels per megabase. The HYPER-INSIGHT project is organized into three objectives, which aim to take advantage of the unique opportunity provided by genome sequences of hypermutated and ultramutated tumors. In particular, this work planned in this project aims to further our knowledge on (i) the regional organization of the DNA replication and repair program in human cells, and the determinants thereof, (ii) the extent of selection which acts on somatic variants in various pathways or complexes and (iii) opportunities for selectively targeting DNA repair deficiencies that manifest as hypermutation. Methodologically, our work will employ a three-pronged approach. First, we will perform a multitude of rigorous statistical analyses that draw on the rich and still-expanding resources provided by cancer genomics consortia. Second, we will perform exome and genome sequencing, focusing on ultramutated tumors caused by specific defects in the DNA maintenance machinery. Third, the project involves conditional essentiality screens on cancer cell lines with hypermutant backgrounds. Their goal is to discover synthetic lethality relationships, useful for targeting hypermutating cells, while sparing healthy ones. In summary, one of the promises of cancer genome sequencing projects was to elucidate the mechanisms underlying mutational processes in the human soma, advancing our understanding of this important facet of cancer biology. We will work towards realizing this promise, thereby strengthening the EU’s position in the global scientific endeavour.
Publications
| year | authors and title | journal | last update |
|---|---|---|---|
| 2019 |
Fran Supek, Ben Lehner Scales and mechanisms of somatic mutation rate variation across the human genome published pages: 102647, ISSN: 1568-7864, DOI: 10.1016/j.dnarep.2019.102647 |
DNA Repair 81 | 2019-10-29 |
| 2019 |
Rik Lindeboom, Michiel Vermeulen, Ben Lehner, Fran Supek The impact of nonsense-mediated mRNA decay on genetic disease, gene editing and cancer immunotherapy published pages: , ISSN: 1061-4036, DOI: 10.1038/s41588-019-0517-5 |
Nature Genetics in press | 2019-10-29 |
| 2019 |
Marina Salvadores, David Mas-Ponte, Fran Supek Passenger mutations accurately classify human tumors published pages: e1006953, ISSN: 1553-7358, DOI: 10.1371/journal.pcbi.1006953 |
PLOS Computational Biology 15/4 | 2019-10-29 |
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