Somatic mutant selection is altered by prior NOTCH1 mutation in aging esophageal epithelium

The ageing mid esophagus is progressively colonized by somatic mutations, including oncogenic TP53 and antioncogenic NOTCH1 mutants. Most esophageal squamous carcinomas are TP53 mutant, NOTCH1 wild type. By middle age, much of the esophagus is NOTCH1 mutant. We hypothesised that prior NOTCH1 mutation may alter subsequent mutant selection. Here we show that selection of mutant NOTCH2 was increased and mutant TP53 decreased within NOTCH1 mutant epithelium. Potential mechanisms include spatial competition between adjacent clones and/or epistasis altering the fitness NOTCH1 double mutants. We investigated these possibilities in transgenic mice. Spontaneous Notch2 mutant clones emerged in aged Notch1 null, but not wild type, esophagus, consistent with epistasis increasing Notch1/Notch2 double mutant fitness. However, there was no evidence of epistasis between Notch1 and Trp53, as Notch1 mutation alone increased fitness. In consequence, over time, Trp53 mutant Notch1 wild type clones were outcompeted by expanding Notch1 and Trp53/Notch1 mutants. NOTCH1 mutant takeover of the aging esophagus alters the trajectory of somatic evolution, decreasing selection of TP53 mutants and potentially reducing cancer risk.