Clonal expansion in aged normal tissues has been implicated in the development of cancer. However, the chronology and risk dependence of the expansion are poorly understood. Here we intensively sequence 682 micro-scale esophageal samples and show, in physiologically normal esophageal epithelia, the progressive age-related expansion of clones that carry mutations in driver genes (predominantly NOTCH1), which is substantially accelerated by alcohol consumption and by smoking. Driver-mutated clones emerge multifocally from early childhood and increase their number and size with ageing, and ultimately replace almost the entire esophageal epithelium in the extremely elderly. Compared with mutations in esophageal cancer, there is a marked overrepresentation of NOTCH1 and PPM1D mutations in physiologically normal esophageal epithelia; these mutations can be acquired before late adolescence (as early as early infancy) and significantly increase in number with heavy smoking and drinking. The remodeling of the esophageal epithelium by driver-mutated clones is an inevitable consequence of normal ageing, which – depending on lifestyle risks – may affect cancer development.
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