Mechanisms of proliferation-independent mutation

Informazioni relative al progetto

CLOCK

ID dell’accordo di sovvenzione: 101041308

DOI

10.3030/101041308

Data della firma CE 8 Marzo 2022

Data di avvio 1 Maggio 2022

Data di completamento 30 Aprile 2027

Finanziato da

• European Research Council (ERC)

Costo totale

€ 1 500 000,00

Contributo UE

€ 1 500 000,00

Coordinato da

KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Netherlands

Periodic Reporting for period 1 - CLOCK (Mechanisms of proliferation-independent mutation)

Periodo di rendicontazione: 2022-05-01 al 2024-10-31

Sintesi del contesto e degli obiettivi generali del progetto

Cancer is caused by the accumulation of changes on DNA. These alterations, known as mutations, are the consequence of mis-repaired DNA damage. Carcinogens like UV light or cigarette smoke lead to cancer by damaging DNA and inducing mutations. However, the recent explosion in genome sequencing has revealed a much greater diversity of mutation patterns than expected. These patterns are an ‘archaeological record’, shedding light on the history of all mutagenic processes at play during the evolution of a tumour. While some of them are caused by known carcinogens (e.g. smoking); many others have unknown origins, indicating that there are sources of mutation still to be uncovered.
One of these ‘mutational patterns’ is particularly interesting for several reasons: 1) it is responsible for the vast majority of mutation in human tissues, 50-90% depending on the tissue; 2) it is caused by an endogenous process (in other words, our own body), unlike carcinogens like smoking; 3) mutations accumulate constantly over time and receive the name of ‘clock mutations’; 4) finally, unlike other types of mutation, they accumulate without cell division, with an unknown mechanism. Therefore, the objective of our project is to understand the origin of ‘clock mutation’, the most common mutational process in humans.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

For the first half of the project, we have been focusing on establishing tools for the project. The innovative aspect of this proposal is our unique strategy to detect mutation in single cells with high confidence. This strategy overcomes major technical barriers of single cell sequencing and allows us to 1) uncouple the study of mutation from cell division in mammalian cells for the first time and 2) interrogate the genome of specialised cell types in mammalian tissues with unprecedented detail: we can ask how very specific cell types mutate over time. We have compared our single-cell technique with the recently developed Nanoseq, and are now applying this to genetically manipulated mouse tissues.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

We have known for some time that cancer is caused by mutations in our DNA. But what causes these mutations in the first place? For a long time, it was thought that external insults (like cigarette smoke or sunlight) were the main culprits, but recent studies have revealed that there are many more types of mutation, and we do not know what is causing the majority of them. Recent epidemiological and mathematical models have also estimated that a significant proportion of cancer risk is attributed to intrinsic risk factors (rather than environmental or hereditary).
Understading ‘clock mutations’ will shed light on the most common source of mutation in tissues. If we were able to identify the internal agents that mutate DNA, some of this damage might be averted, for example though changes in our diet (much like sunscreen protects us from skin cancer). Also, if we could better understand how cells deal with damaged DNA, this knowledge might allow us to design new cancer treatments.