Somatic mutant selection is altered by prior NOTCH1 mutation 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. Mutant NOTCH1 clones 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 mostly NOTCH1 wildtype, samples predominantly mutant for NOTCH1 showed weaker selection of mutant TP53 and increased selection of NOTCH2 mutants. In mouse esophagus lacking Notch1 we observed strong selection of mutant Notch2 , 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.