Chemotherapy alters 'Darwinian battleground' in our bodies
Cancer treatments, including chemotherapy and radiotherapy, give a growth advantage to cells with particular genetic changes in healthy tissue, new research finds.
Researchers from the Wellcome Sanger Institute, University of Cambridge, University College London and their collaborators used DNA sequencing to map the mutations in normal oesophagus tissue from oesophageal cancer patients who had received either chemotherapy, chemotherapy and radiotherapy, or no treatment before surgery.
The results, published today (11 September) in Nature Genetics, show that different cancer treatments changed the landscape of mutations in normal tissue. In particular, combined treatment of chemotherapy and radiotherapy led to significantly more normal cells with cancer-related mutations in these patients.
The team suggests that sequencing normal tissue from cancer patients receiving treatment could show how our genes regulate our tissue’s response to drugs, including side effects.
Over time, all cells in the body acquire genetic changes, known as somatic mutations1. While the majority of these do not affect how the cell functions, some make cells fitter, so they outcompete their neighbours. Sometimes, combinations of these mutations cause uncontrollable growth leading to cancer and the formation of tumours.
By middle age, the human oesophagus has evolved into a patchwork of mutated cells. By age 60 to 70, almost all of the cells in the oesophagus will be mutated2. While the majority of these mutations do not lead to cancer, if tumours do form they can be hard to treat, as often symptoms appear when the cancer has started to spread.
Around 9,500 people are diagnosed with oesophageal cancer in the UK each year, with almost half of new cases in people aged 75 and over3. It is treated with surgery, chemotherapy, radiotherapy, a combination of the two – known as chemoradiotherapy, and immunotherapy4.
In a new study, Sanger Institute researchers and their collaborators set out to understand the effects of cancer treatments on normal cells, and whether chemotherapy and radiotherapy treatments give some mutant cells an advantage.
The team used DNA sequencing to analyse normal cells from the lining of the oesophagus – oesophageal epithelium – that had been removed from patients after treatment for oesophageal cancer. Patients had either received combination chemotherapy, chemoradiotherapy, or no treatment before surgery.
Researchers found significant differences in the genetic mutations seen in patients, depending on the treatment they received.
In patients who received chemoradiotherapy, there were significantly more cells, or clones, with mutations in TP53 – a vital tumour suppressor gene known as the ‘guardian of the genome’ – and PPM1D – a gene that makes an enzyme that manages cell stress and TP53 function.
In patients who had received combination chemotherapy, there was an increase in normal cells carrying mutations associated with resistance to the chemotherapy drug 5-fluorouracil (5-FU). The increased resilience to 5-FU in a patient’s healthy cells during cancer treatment leads to protection from life-threatening toxicities.
Chemotherapy drugs usually leave tell-tale patterns of mutations, known as mutational signatures, in the genomes of normal tissues. Despite seeing changes in mutant cell fitness following treatments, the team found no mutational signatures associated with the chemotherapies.
Cancer treatments can cause severe side effects in normal tissues, which may result in reducing the doses of the treatment. The researchers suggest that these findings begin to uncover the genes and protein domains that make normal cells sensitive or resistant to treatment and could help shape cancer treatment in the future to minimise damage to normal tissues. The study might also help inform the development of targeted treatments that destroy cancer cells while leaving normal tissue unharmed.
By identifying the mutant cells in normal tissue that are selected for by cancer treatment, it may provide a catalogue of potential genetic targets that modify how our cells respond to treatment, and lead to further research into how tumours become drug resistant.
In next steps, the team is conducting a pilot study to investigate these effects in other tissues. The researchers are taking cheek swabs, blood and urine samples from patients before and after having treatment for skin, head and neck cancers. They are investigating on a larger scale, whether there is further evidence of genetic mutations in normal cells that are being selected for by cancer treatment.
“Cancer treatments not only kill cancer cells but also affect normal tissues. To investigate this, we used genome sequencing to study the normal lining of the oesophagus from oesophageal cancer patients before and after treatment. In particular, in patients who received chemoradiotherapy, we found there were significantly more cells with TP53 mutations – a well-known cancer mutation. By understanding the genetic changes across these tissues we will help unlock a more detailed understanding of how treatments can be better tailored to patients.”
Dr Joanna Fowler, first author at the Wellcome Sanger Institute
“People with oesophageal cancer often need intensive treatment, but we still have much to learn about how these therapies affect the rest of the body.
“Cancer treatments can be incredibly effective, but they can also affect healthy tissues. This study gives us an unusual opportunity to see how healthy cells change during treatment, helping us understand what happens elsewhere in the body, not just in the tumour. The more we learn about these changes, the better chance researchers have of finding ways to reduce the impact of treatment on patients without making it less effective against cancer.”
Dr Hayley Brown, Research Information Manager at Cancer Research UK
“Our bodies are a Darwinian battleground, where cells are constantly evolving, expanding and fighting for space in our normal tissues. If you change the rules of this competition by introducing a drug, different genetic mutations are going to enable cells to win or lose. We were surprised to find that only a few weeks of cancer treatment can drastically change decades of evolution in our cells. By looking at normal tissues, we can begin to uncover how drugs work in the body, in order to make more effective treatments with fewer side effects in the future.”
Dr Phil Jones, co-senior author at the Wellcome Sanger Institute and University of Cambridge
More information
Notes:
The limitations of this study include the number of patients studied (70, split over five groups), the use of targeted sequencing for 324 cancer associated genes, and that sequencing was only performed after treatment. Further mutations may be detected with whole exome sequencing of paired samples collected before and after treatment.
1. To find out more about somatic mutations, visit the Sanger Institute blog: https://sangerinstitute.blog/2026/01/15/what-are-somatic-mutations/ [74n5c4m7.r.eu-west-1.awstrack.me]
2. Inigo Martincorena et al. (2018) ‘Somatic mutant clones colonize the human esophagus with age’. Science. DOI: 10.1126/science.aau3879 [74n5c4m7.r.eu-west-1.awstrack.me]
3. ‘Oesophageal cancer’. Cancer Research UK website: https://www.cancerresearchuk.org/about-cancer/oesophageal-cancer [74n5c4m7.r.eu-west-1.awstrack.me] [Accessed August 2026]
4. ‘Treatment options for oesophageal cancer’. Cancer Research UK website: https://www.cancerresearchuk.org/about-cancer/oesophageal-cancer/treatment/decisions-about-your-treatment [74n5c4m7.r.eu-west-1.awstrack.me] [Accessed September 2026]
Publication:
Joanna Fowler et al. (2026) ‘Cancer treatment alters mutant selection in normal esophagus’. Nature Genetics. DOI: 10.1038/s41588-026-02738-0
Funding:
This research was supported by Wellcome, Cancer Research UK and others. For full details please see the publication.
