Early

Background: Somatic mutations commonly accumulate in histologically normal tissues and contribute to cancer development. However, many somatic variants found at high frequencies in normal tissues are also found at high frequencies in cancers arising from the same tissue types. Consequently, the roles of these variants in cancer development remain poorly understood. To address this, we assessed the selective pressures across steps of tumorigenesis, as well as epistasis between driver mutations. Methods: We employed evolutionary modeling to quantify the strength of selection on somatic variants across two key steps of esophageal development: from organogenesis to clonal histologically normal epithelium, and from there to esophageal squamous-cell carcinoma. Analyzing sequence data from 2171 samples, our first-of-its kind model revealed the stepwise contributions of somatic mutations to increased cellular division and survival and their pairwise epistatic effects on driver mutation selection. Results: Conclusions: Our findings demonstrate that early positively selected mutations in