A new research has found how cancer treatments, including chemotherapy and radiation therapy, give a growth advantage to cells with particular genetic changes in healthy tissue.
Researchers from the Wellcome Sanger Institute, University of Cambridge, University College, London, alongside other 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.
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.
The 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 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.
