Many of the normal changes to the esophageal epithelium that occur with age due to driver mutation clones can be accelerated with unhealthy lifestyle habits, such as heavy smoking and drinking, according to a recent study.1

“Clones emerge multifocally in virtually all individuals as early as in early infancy. These clones increase their number and size over the years, and eventually remodel almost the entire esophageal epithelium with thousands of sizable driver-mutated clones (about 9000−15,000 clones per esophagus),” the researchers wrote. “This can proceed even in the absence of heavy alcohol drinking and smoking, but—when present— these lifestyle risks substantially accelerate this remodelling process.”

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Study researchers looked at 682 samples of both healthy and cancerous esophageal tissue taken from 139 patients. All patients had differing age and risk for developing esophageal cancer. They sequenced the samples and found that in normal esophageal cells, age-related expansion of clones that carry driver mutations were substantially accelerated by alcohol consumption and smoking.

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There were 24 genes found that were most frequently mutated in the healthy and cancerous samples. Six were altered in both, the most common of which were TP53 and NOTCH1. TP53 was mutated in 79.8% of cancer samples and 91.7% of dysplasia, but only 30.6% of normal epithelium. In contrast, NOTCH1 was mutated in only 15.0% of cancer samples, but 66.2% of healthy tissue samples.

An editorial published with the study said the results “offer insights into the evolution of healthy tissues as people age, and prompt speculation about how this might relate to cancer.”2 The authors of that editorial pointed out that the gene PAX9, which encodes a transcription factor, is commonly mutated in normal esophageal tissue, but that this gene had not previously been linked to esophageal cancer. “This suggests that a less ‘cancer-centric’ analysis might reveal other genes that can drive the expansion of clones in normal tissue,” the authors of the associated editorial wrote.


  1. Yokoyama A, Kakiuchi N, Yoshizato T, et al. Age-related remodeling of oseophageal epithelia by mutated cancer drivers [published online January 2, 2019]. Nature. doi: 10.1038/s41586-018-0811-x
  2. Ciccarelli FD. Mutations differ in normal and cancer cells of the oesophagus. Nature. 2019;doi:10.1038/d41586-018-07737-8.