DNA damage that evades repair could increase risk of cancer

Unrepaired DNA damage lingers longer within cells than previously thought, potentially increasing cancer risk.

DNA repair is an efficient mechanism that works to fix DNA damage, meaning most damage has a half-life of minutes to hours. However, scientists have analysed cellular family trees from 89 people and found certain forms of DNA damage escape a cell's internal repair mechanisms. The damage can persist for years, increasing the chance of somatic mutations that could lead to cancer.

'It's these large-scale, novel datasets that have led us to this unexpected finding that some forms of DNA damage can last for a long time without being repaired,' said Dr Michael Spencer Chapman, from the Wellcome Sanger Institute, near Cambridge, and Barts Cancer Institute at Queen Mary University of London.

The research team used whole genome sequencing to analyse family trees of single cells from hundreds of people, highlighting shared patterns of ancestry. By analysing the mutation patterns shared across the genomes between cells, the scientists assembled family trees, known as somatic phylogenies, helping to understand the ancestry of the cells. From the data, they collated seven published sets of somatic phylogenies.

'With these family trees, we can link the relationships of hundreds of cells from one person right back to conception, meaning we can track back through the divisions each cell has gone through' added Dr Chapman, first author of the paper published in Nature.

While analysing the family trees, the scientists unveiled an unexpected pattern of mutations. Some DNA damage would persist across multiple cell cycles in blood stem cells, liver cells and bronchial epithelial cells. Particularly in blood stem cells, 15 to 20 percent of mutations would last up to three years. DNA damage remaining unrepaired during cell division would mean damaged DNA is copied and potentially misinterpreted. Errors in the code could lead to the generation of different mutations in each round of replication, creating opportunities for cancer-causing mutations.

'...It is unclear why this process is only found in blood stem cells and not other healthy tissues. Knowing that the DNA damage is long-lasting gives new routes to investigate what the damage actually is. As we continue to better understand the causes of mutations, we may one day be able to intervene and remove them,' said PhD student Emily Mitchell from the Wellcome Sanger Institute.

If mutations from replicating damaged DNA can remain unrepaired for years, the findings from the study reframe how we understand mutations and their role in cancer.

'These findings don't fit with what scientists have previously thought... This paradigm shift brings a new dimension to the way we think about mutations,' said lead author, Dr Peter Campbell, former head of cancer, ageing and somatic mutation at the Wellcome Sanger Institute.

The research team suggests that, even though this type of DNA damage occurs infrequently, further understanding why damaged DNA escapes a cell's internal repair mechanisms could also have implications for understanding the development of cancer.