Esophageal cells accumulate thousands of mutations over time!

By the time we reach middle age, more than half of the oesophagus in healthy people has been taken over by cells carrying mutations in cancer genes, scientists have uncovered. By studying normal oesophagus tissue, scientists uncovered a hidden world of mutations and evolution in our tissues as we age.

The results, published in Science show how mutant cells mutate and compete with each other throughout life, and only the fittest mutations survive.

Every person accumulates genetic changes, or mutations, throughout their lifetime. These mutations in normal tissue, called somatic mutations, are key to understanding the first steps to cancer and likely contribute towards ageing, but are unchartered territory due to technical limitations.

For the first time, scientists have uncovered that on average, healthy cells in the oesophagus carry at least several hundred mutations per cell in people in their twenties, rising to over 2,000 mutations per cell later in life. Only mutations in a dozen or so genes seem to matter however, as these give the cells a competitive advantage allowing them to take over the tissue and form a dense patchwork of mutations.

The lead author said: "Under the microscope, the oesophageal tissue looked completely normal - it came from healthy individuals who had no signs of cancer. After studying the genetics we were shocked to see that the healthy oesophagus was riddled with mutations. We discovered that by the time an individual reaches middle age, they probably have more mutant than normal cells."

The team used targeted and whole-genome sequencing to map groups of mutant cells in normal oesophageal tissue from nine individuals aged 20 to 75 years*. The individuals' oesophageal tissues were considered healthy as none of the donors had a known history of oesophageal cancer, nor were taking medication for problems relating to the oesophagus.

The study also casts new light on the mutations that are found in the squamous kind of oesophageal cancers. One mutated gene, TP53, which is found in almost all oesophageal cancers is already mutated in 5-10 per cent of normal cells, suggesting that cancer develops from this minority of cells.

In contrast, mutations in the NOTCH1 gene, known to control cell division, were found in nearly half of all cells of normal oesophagus by middle age, being several times more common in normal tissue than cancer. This observation suggests that researchers need to reconsider the role of some genes recurrently mutated in cancer in the light of mutations in normal tissue, and raises the possibility that the NOTCH1 mutation may even protect cells against cancer development.

The discovery that normal aged oesophagus is a dense patchwork of mutant cells carrying mutations previously linked with oesophageal cancer has important implications. It provides insights into key genes that control cell behaviour in normal tissues. It also gives a window into the first steps in the development of some oesophageal cancers, which are believed to arise from these mutant cells, and will be informative for current research efforts on early detection of cancer.

"This study shows that some genetic changes linked to cancer are present in surprisingly large numbers of normal cells. We still have a long way to go to fully understand the implications of these new findings, but we hope that studies like this will one day help us to develop targeted diagnostic tests. In particular, oesophageal cancer is very hard to treat so detecting signs of the disease at the earliest possible stage could make a huge difference for patients." The author said.

https://www.sanger.ac.uk/news/view/mutant-cells-colonise-our-tissues-over-our-lifetime