Mutation Signatures and Genome Protection: Applications of WES in Chemoprevention Trials

Abstract

Whole-exome sequencing (WES) has emerged as a transformative technology for understanding cancer initiation and progression through the lens of mutational signatures characteristic patterns of somatic mutations imprinted on cancer genomes by underlying mutagenic processes. This review synthesizes current knowledge on the application of WES-derived mutation signatures as biomarkers and endpoints in cancer chemoprevention trials, with emphasis on genomic approaches to preventing malignant transformation. We examine mechanistic underpinnings of major carcinogen-specific signatures (tobacco, ultraviolet, alcohol, aging), discuss technical considerations for implementing WES as a clinical platform, and outline strategies for integrating mutation signature analysis into adaptive trial designs. Particular focus is given to oral squamous cell carcinoma (OSCC) prevention, where loss of heterozygosity (LOH) profiling and emerging somatic mutation burden metrics offer unprecedented opportunities for patient enrichment and molecular monitoring. We review the paradigm shift from histologic endpoints (intraepithelial neoplasia) to genomic endpoints (tumor mutational burden, signature composition, clonal evolution), and discuss how mutation signatures can guide personalized chemoprevention through synthetic lethal approaches targeting DNA damage response deficiencies. The integration of multi-omic biomarkers, liquid biopsy, and adaptive trial designs promises to accelerate the clinical translation of genome protection strategies, ultimately improving cancer prevention outcomes in high-risk populations.