A research consortium featuring scientists from the University of Dundee have detailed how the genetic mutations that give rise to cancer are caused by a combination of DNA damage and inaccurate repair.
Researchers at Dundee’s School of Life Sciences, EMBL’s European Bioinformatics Institute (EMBL-EBI), and the Wellcome Sanger Institute analysed over 2700 genomes from C. elegans worms in order to better understand the causes of mutations. Their findings characterise how DNA mutations result from the combined action of DNA damage and inaccurate DNA repair mechanisms.
A cell’s DNA is constantly exposed to physical and chemical stresses – or genotoxins – that can damage it and cause mutations. However, cells have a myriad of repair mechanisms to fix DNA lesions soon after they arise. Occasionally, the restorative repair process fails, either by making extra errors, or by failing to detect the DNA lesions altogether. This leads to mutations, which are the root cause of cancer.
This study combined whole genome sequencing with an experimental screen to better understand the causes of mutational signatures. The results have potential implications for cancer research, diagnosis and treatment.
Many genotoxins, like those found in tobacco smoke, were thought to cause a unique suite of mutations in the genome, recognisable as a mutational signature. However, many mutational signatures observed in cancer genomes do not seem to relate to any single genotoxin and others appear to result from a combination of factors.
To understand the origin of these signatures, the research team tested the effects of more than 150 combinations of twelve genotoxins on C. elegans worms whose DNA repair mechanisms were either unaltered or faulty. The scientists experimentally demonstrated that mutational signatures result from a combined action of DNA damage and specific repair mechanisms and that these signatures are more variable than previously thought.
“Understanding the interplay between DNA damage and repair helps to better gauge the risk of cancer predisposition, and to understand the response to cancer treatment,” explained Dr Bettina Meier, Senior Research Associate at Dundee.
“It took years to generate all these repair-defective C. elegans, to systematically expose them to a panel of genotoxins, and to prepare, sequence and analyse their DNA,” said Anton Gartner, Professor of Genetics at Dundee, recently appointed as Associate Director of the IBS Center for Genomic Integrity at UNIST Ulsan, South Korea. “It is great to see that experimental work on C. elegans is directly relevant for interpreting cancer genomes.”
The researchers found that different types of DNA alterations induced by the same genotoxin are often fixed by different DNA repair pathways, some error-free, others error-prone. As a result, a single genotoxin may leave a variety of mutational signatures at various rates, depending on the repair process. While many of these minor mutations may be harmless, in humans they can increase the probability of developing a tumour.
While the molecular mechanisms of DNA repair are very well-established, the exact types and frequency of mutations they can generate remained unclear until the development of high-throughput sequencing.
Mutational signatures have become a pillar of cancer genome analysis because they may shed light on the carcinogens cancer cells have been exposed to, and the repair mechanisms that were perturbed.
However, not all observed mutational signatures and their individual facets are fully understood. An experimental approach ensures that the observed patterns are the direct consequences of the conditions set by the scientists. It also helps understand how multiple DNA repair processes jointly shape mutational signatures.
The research is published in the latest edition of Nature Communications.