As a motivating example, the mutational burden of the cancer driver TP53 in normal oesophagus falls far below that observed in oesophageal cancer, while the mutational burden of NOTCH1 is much higher in normal tissue, with the latter representing an extreme example of cancer-protective behaviour (Martincorena et al, 2018; Abby et al, 2023). This evidence concerns the gene NOTCH1 and carcinoma of esophagus.