Mutation of NOTCH1 is selected within normal esophageal tissues, yet leads to selective epistasis suppressive of further evolution into cancer

Sequencing of tissues from histologically normal esophagus, among other organs, has revealed that normal tissues harbor somatic variants that are also found in cancers arising from the same tissue types. Our understanding of how somatic mutations commonly found in normal tissue can contribute to tumorigenesis is limited: common somatic mutations may or may not confer phenotypes compatible with oncogenesis. However, the strength of selection for somatic variants that appear in both normal and cancer tissues can be quantified in each context using evolutionary modeling approaches. We studied the evolutionary trajectory from normal esophageal tissue to esophageal squamous-cell carcinoma (ESCC) by analysis of 2171 sequenced samples from previous studies on normal esophageal epithelium and ESCC to reveal the stepwise contributions of somatic mutations to increased cellular division and survival. We also analyzed pairwise selective epistasis between somatically mutated genes that may lead to stepwise substitution patterns. We found that NOTCH1 substitutions are highly selected along the trajectory from embryogenesis to adult normal esophageal tissue, explaining their high prevalence in the tissue. In contrast, there is little to no positive selection for NOTCH1 mutations along the trajectory from adult normal tissue to ESCC, suggesting that NOTCH1 substitutions do not drive tumorigenesis. Furthermore, mutations in NOTCH1 exhibit antagonistic epistasis with well-known cancer drivers including TP53, reducing selection for progressive mutations in tumorigenesis. This antagonistic epistasis likely corresponds with a low likelihood of tumor progression in the presence of NOTCH1 mutations in the esophagus. ### Competing Interest Statement The authors have declared no competing interest.