Whole-Exome Sequencing in Cancer Chemoprevention: Tracking Mutational Trajectories in High-Risk Populations

Abstract

Whole-exome sequencing (WES) has revolutionized understanding of cancer chemoprevention by enabling comprehensive characterization of mutational landscapes in high-risk populations and monitoring of clonal evolution during prevention interventions. This review synthesizes current knowledge on WES applications in cancer prevention, emphasizing tracking of mutational trajectories from normal epithelium through dysplasia to invasive carcinoma. We examine discovery of driver mutations and mutational burden as chemoprevention biomarkers, computational approaches for inferring genetic progression (PhylogicNDT), and longitudinal monitoring of clonal evolution using circulating cell-free DNA in prevention trials. Particular emphasis is placed on oral squamous cell carcinoma (OSCC) and oral epithelial dysplasia (OED) as model systems where WES has identified key early driver mutations (TP53, NOTCH1, PIK3CA, CDKN2A) enabling molecular stratification of malignant transformation risk and personalization of prevention strategies. The review discusses universal cancer screening with WES identifying occult cancer predisposition syndromes, prospectively validated genetic progression models (gMART) predicting dysplasia-to-carcinoma risk, and emerging single-cell sequencing approaches revealing subclonal heterogeneity driving prevention failures. Integration of WES with spatial transcriptomics and single-cell RNA-seq provides unprecedented mechanistic insight into how dysplastic lesions acquire transformative mutations, enabling identification of optimal intervention windows during clonal evolution. Clinical applications including window-of-opportunity trials, real-time ctDNA monitoring of chemopreventive efficacy, and evolution-informed adaptive treatment strategies are discussed. We address critical challenges including tumor heterogeneity interpretation, distinguishing driver from passenger mutations in premalignant lesions, clinical translation of discovery findings, and cost-effectiveness of universal WES screening in prevention cohorts.