Mechanisms of proliferation-independent mutation

Project Information

CLOCK

Grant agreement ID: 101041308

DOI

10.3030/101041308

EC signature date 8 March 2022

Start date 1 May 2022

End date 30 April 2027

Funded under

• European Research Council (ERC)

Total cost

€ 1 500 000,00

EU contribution

€ 1 500 000,00

Coordinated by

KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Netherlands

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

Reporting period: 2022-05-01 to 2024-10-31

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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.