Somatic mutant selection is altered by priorNOTCH1mutation in aging esophageal epithelium

In cancer evolution, genome alterations often occur in a specific order, implying selection depends on the prior clonal genotype^1-3. It is unknown if similar constraints operate in normal epithelia. Here, we mapped mutations in normal mid-esophagus of aged UK subjects. MutantNOTCH1clones colonized most of the epithelium by age 60 and the tissue became saturated with mutants under strong competitive selection by age 70. Compared to samples that were mostlyNOTCH1wildtype, samples predominantly mutant forNOTCH1showed weaker selection of mutantTP53and increased selection ofNOTCH2mutants. In mouse esophagus lackingNotch1we observed strong selection of mutantNotch2, not seen in wild type epithelium. In aging esophagus, the first driver mutation may change the trajectory of subsequent somatic evolution by altering mutational selection and by restricting space available for the expansion of other mutant clones.