Chemotherapy alters 'Darwinian battleground' in our bodies

by Wellcome Trust Sanger Institute

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Cancer treatments, including chemotherapy and radiation therapy, 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 mutations in normal esophageal tissue from esophageal cancer patients who had received either chemotherapy, chemotherapy and radiation therapy, or no treatment before surgery.

The results, published in Nature Genetics, show that different cancer treatments changed the landscape of mutations in normal tissue. In particular, combined chemotherapy and radiation therapy 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.

A tissue already shaped by mutations

Over time, all cells in the body acquire genetic changes, known as somatic mutations. While the majority of these do not affect how cells function, some make cells fitter, allowing them to outcompete their neighbors. Sometimes, combinations of these mutations cause uncontrollable growth, leading to cancer and the formation of tumors.

By middle age, the human esophagus has evolved into a patchwork of mutated cells. By ages 60 to 70, almost all cells in the esophagus will be mutated. While the majority of these mutations do not lead to cancer, tumors can be hard to treat if they form because symptoms often appear after the cancer has started to spread.

Around 9,500 people are diagnosed with esophageal cancer in the UK each year, with almost half of new cases in people ages 75 and older. It is treated with surgery, chemotherapy, radiation therapy, a combination of the two—known as chemoradiotherapy—and immunotherapy.

Comparing treated and untreated tissue

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 radiation therapy give some mutant cells an advantage.

The team used DNA sequencing to analyze normal cells from the lining of the esophagus—esophageal epithelium—that had been removed from patients after treatment for esophageal 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.

Different therapies favored different clones

In patients who received chemoradiotherapy, there were significantly more cells, or clones, with mutations in TP53—a vital tumor 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 telltale 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.

Clues to safer cancer treatment

Cancer treatments can cause severe side effects in normal tissues, which may result in reduced treatment doses. 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 minimize damage to normal tissues. The study might also help inform the development of targeted treatments that destroy cancer cells while leaving normal tissue unharmed.

Identifying the mutant cells in normal tissue that are selected for by cancer treatment may provide a catalog of potential genetic targets that modify how our cells respond to treatment and lead to further research into how tumors 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 treatment for skin, head and neck cancers. They are investigating whether, on a larger scale, there is further evidence of genetic mutations in normal cells that are being selected for by cancer treatment.

Dr. Joanna Fowler, first author at the Wellcome Sanger Institute, said, "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 esophagus from esophageal 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. Hayley Brown, research information manager at Cancer Research UK, said, "People with esophageal 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 tumor. 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. Phil Jones, co-senior author at the Wellcome Sanger Institute and University of Cambridge, said, "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 to make more effective treatments with fewer side effects in the future."

Publication details

Cancer treatment alters mutant selection in normal esophagus, Nature Genetics (2026). DOI: 10.1038/s41588-026-02738-0

Journal information: Nature Genetics

Key medical concepts

Chemoradiotherapytumor protein p53Sequence, DNA

Clinical categories

OncologyClinical pharmacology Provided by Wellcome Trust Sanger Institute Who's behind this story?

Gaby Clark

MA in English, copy editor since 2021 with experience in higher education and health content. Dedicated to trustworthy science news. Full profile →

Robert Egan

Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →

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