11 March 2024 Detection of specific DNA signature colon cancer improved Back to news Researchers can better detect a specific ‘signature’ in DNA thanks to new techniques. Certain strains of the E. coli bacteria cause a DNA signature that occurs in people with colon cancer. This group of abnormalities in the DNA is not enough by itself to cause colon cancer. But it is one of the steps in the development of the disease. Dr Ruben van Boxtel: ‘Because we can better demonstrate the DNA signature and link it to how it arises, it also becomes better possible to find a way to prevent it. The method used could potentially be used in the future for research into the origin of other types of cancer, including childhood cancer.’ Changes in DNA, also known as mutations, can cause an ordinary The development of cancer requires successive DNA changes over a long period of time along with abnormalities in specific genes, called driver genes. The presence of such a signature does not always mean that cancer is directly present. Colibactin Previous research showed a link between certain intestinal bacteria and DNA abnormalities that could potentially cause colon cancer. This involved a type of E. coli bacteria that damages DNA by secreting the substance colibactin. This study was led by Dr Ruben van Boxtel, research group leader at the Princess Máxima Centre and Oncode researcher, and Prof Hans Clevers, pioneer in the field of organoids, former research group leader at the Princess Máxima Centre and the Hubrecht Institute, and also Oncode researcher. In the follow-up study, published today in Cancer Cell, they expand on this research. Genetic signature The researchers looked at the link between individual E. coli bacterial strains and a genetic signature also found in the tumour cells of colon cancer patients. To do this, they exposed colon cancer mini-tumours, also called organoids, to the different bacterial strains. They then analysed the DNA of these organoids. The researchers saw that all four E. coli strains studied caused the colon cancer signature in the organoids. This happened to varying degrees. For this, the researchers compared the strains with the signature of strain EcC, detected in the earlier study. They saw that strain 2F8 caused the most similar abnormalities: 112%. For the least harmful strain, E. coli Nissle 1917, this was 32%. Artificial intelligence was also used to examine DNA in cells obtained from population screening and people with colon cancer. Dr Joske Ubels, postdoctoral researcher and bioinformatician in the Van Boxtel group: ‘We analysed a large amount of data from over 600 different people and linked this data to the genetic signature. For example, we saw that people with DNA damage caused by colibactin are on average younger when they are diagnosed with colon cancer, 63 versus 68 years. In addition, we saw that two in 25 people (8%) with the colibactin-induced DNA signature also had a specific change in the APC gene, one of the main driver genes in colon cancer. That is almost four times more common than in the no-harm group (2%). Only when changes also occur in other driver genes colon cancer can develop.’ This underlines the researchers’ earlier theory that damage by colibactin may contribute to the development of colon cancer. And that better recognition of the DNA signature provides important new insights into the factors involved in the development of cancer, such as the change in the APC driver gene. Probiotics The four bacteria studied included the colibactin-producing E. coli Nissle 1917 (EcN), which is used as a probiotic and prescribed as a treatment for the intestinal diseases Crohn’s and colitis. Van Boxtel: ‘In this study, we did not investigate the direct link between the specific bacteria and the development of colon cancer, so we did not demonstrate this. The results do indicate that colibactin can prepare a cell for transformation into a cancer cell. However, additional damage caused by other mutational processes are necessary for the development of cancer.’ The researchers thus highlight the importance of carefully assessing the potential long-term consequences in relation to the short-term clinical benefits. Future research The methods used for this study may also be applicable in future research into the development of (second) forms of cancer and thus also childhood cancer. Clevers who led the research together with Van Boxtel: ‘This new study offers possibilities for possible future research into links between specific substances and the emergence of recognisable genetic signatures. After all, if we can better recognise the cause of the emergence of mutations then that is also an immediate starting point for research into a way to prevent them.’ Publication Improved detection of colibactin-induced mutations by genotoxic E. coli in organoids and colorectal cancer. Axel Rosendahl Huber, Cayetano Pleguezuelos-Manzano, Jens Puschhof, Joske Ubels, Charelle Boot ,Aurelia Saftien, Mark Verheul, Laurianne T. Trabut, Niels Groenen, Markus van, Roosmalen, Kyanna S. Ouyang, Henry Wood, Phil Quirke, Gerrit Meijer, Edwin Cuppen, Hans Clevers, Ruben van Boxtel. Cancer Cell, 2024.
