Abstract A035: Mutation of NOTCH1 is selected within normal esophageal tissues, yet leads to selective epistasis suppressive of further evolution into cancer

Abstract

Abstract Sequencing of tissues from histologically normal esophagus, among other organs, has revealed that normal tissues acquire somatic variants that are also found in cancers arising from the same tissue types. Our understanding of how somatic mutations that are 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 sequencing data 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 at high prevalence in normal tissue, and scaled selection coefficients indicate that NOTCH1 mutations are highly selected in normal esophageal tissue. In contrast, there is little to no positive selection for NOTCH1 mutations in ESCC, suggesting that NOTCH1 substitutions do not drive tumorigenesis. Indeed, NOTCH1 mutations have recently been shown to favor clonal expansion in normal esophageal tissue. Furthermore, we calculate that mutations in NOTCH1 exhibit antagonistic epistasis with well-known cancer drivers, including TP53, reducing selection for progressive mutations in tumorigenesis. This antagonistic epistasis likely underlies the low likelihood of tumor progression in the presence of NOTCH1 mutations in the esophagus. Citation Format: Kira A. Glasmacher, Vincent L. Cannataro, Jeffrey D. Mandell, Mia Jackson, J. Nic Fisk, Jeffrey P. Townsend. Mutation of NOTCH1 is selected within normal esophageal tissues, yet leads to selective epistasis suppressive of further evolution into cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A035.