Abstract
Esophageal squamous cell carcinoma (ESCC) remains one of the most lethal malignancies worldwide, with pronounced geographic and ethnic disparities in incidence and outcomes. Rapid advances in genome-wide and sequencing technologies have revealed population-specific mutation spectra and risk loci, highlighting the interplay between inherited susceptibility and environmental exposures. The recent Han-Kazakh whole-exome study provided compelling evidence that ethnic background can shape the mutational landscape of Chinese ESCC, identifying population-restricted alterations such as GIGYF1 and distinct mutational signatures related to apolipoprotein B mRNA-editing enzyme catalytic polypeptide activity. These findings underscore the biological consequences of ethnic heterogeneity but also expose critical gaps: Most available data derive from limited Asian cohorts, cross-sectional designs, and coding-region analyses, leaving African, Central Asian, and multi-ancestry populations underrepresented and the functional relevance of non-coding and epigenetic changes unresolved. Building on this foundation, the present review synthesizes current genomic, transcriptomic, and epigenomic evidence across diverse ethnic groups to delineate shared and population-specific drivers of ESCC carcinogenesis. We emphasize how polymorphisms in alcohol-metabolizing enzymes (ADH1B, ALDH2), DNA-repair and oxidative-stress pathways, and immune-related networks interact with lifestyle and environmental factors to influence tumor initiation and progression. By integrating multi-ethnic multi-omics data, we highlight emerging biomarkers and therapeutic targets that may inform ancestry-aware screening, risk stratification, and individualized treatment strategies. Bridging these ethnic and molecular divides is essential for translating genomic discoveries into equitable precision oncology for ESCC.