Objective To integrate the latest evidence regarding inherited genetic risk factors for esophageal cancer while emphasizing contrasting susceptibility profiles between esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC)/Barrett’s esophagus as this integration also allows assessment of how genome-wide association studies (GWAS) together with new trans-ancestry genomic methods have advanced the discovery of risk loci and their potential clinical application.


Results More than 30 reliable risk loci are now recognized for ESCC mostly identified in East Asian populations with major signals located in PLCE1 alcohol/aldehyde metabolism genes ADH/ALDH2 (showing strong interaction with alcohol consumption) CHEK2 and HLA-region immune pathways whereas recent trans-ancestry studies have validated shared loci such as PLCE1 while uncovering novel African-enriched variants that highlight population-specific genetic architecture. By comparison EAC and Barrett’s esophagus present a separate genetic profile shaped largely by European-ancestry consortia featuring risk loci near BARX1 FOXP1 CRTC1 (involved in mucosal development) as well as CFTR MSRA BLK (linked to barrier function and oxidative stress) and although fewer loci have been found overall EAC exhibits considerable shared heritability with Barrett’s esophagus which supports the value of genetically guided surveillance.


Conclusion ESCC and EAC display strikingly different inherited risk patterns that closely reflect their distinct environmental risk factors as this difference now permits the construction of polygenic risk scores that incorporate subtype-specific GWAS findings together with emerging rare-variant and functional genomic information thereby enabling personalized risk assessment and more targeted screening in high-risk families and populations.