Mechanisms of proliferation-independent mutation

Información del proyecto

CLOCK

Identificador del acuerdo de subvención: 101041308

DOI

10.3030/101041308

Fecha de la firma de la CE 8 Marzo 2022

Fecha de inicio 1 Mayo 2022

Fecha de finalización 30 Abril 2027

Financiado con arreglo a

• European Research Council (ERC)

Coste total

€ 1 500 000,00

Aportación de la UE

€ 1 500 000,00

Coordinado por

KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Netherlands

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

Período documentado: 2022-05-01 hasta 2024-10-31

Resumen del contexto y de los objetivos generales del proyecto

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.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

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.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

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.