PROJECT SUMMARY Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) are complex diseases with undiscovered genetic factors. We successfully discovered a deleterious variant in VSIG10L segregating in a large family. This is the first such reported gene for susceptibility to BE and EAC. VSIG10L appears to function in adhesion and differentiation/maturation of stratified squamous epithelium. Further clues for a genetic basis comes from our admixture mapping study, which has identified two specific chromosomal regions associated with excess European ancestry in African Americans. The BETRNet focus of Project 1 is thus to identify the genetic basis of racial disparity in the prevalence of BE and EAC. A second BETRNet focus of Project 1 is to create a genetically engineered mouse model based on VSIG10L to understand the transformation from squamous epithelium to metaplastic Barrett's epithelium. This project will now build on these discoveries by: 1) Using dense SNP genotyping, NextGen sequencing, and ATAC-seq to identify racially disparate genetic variants that explain racial differences in prevalence of BE and EAC; 2) Using genetically engineered VSIG10L knockout and VSIG10L S631G variant carrying mice to understand how VSIG10L contributes to the normal squamous epithelium esophagitis BE metaplasia dysplasia cancer progression; The significance of Project 1 is first to translate the clinical observation of racial disparity in BE and EAC into the laboratory to identify a causative genetic basis. Furthermore, the project will build on our successful discovery of the first familial susceptibility genetic variant by understanding how this gene functions in metaplastic transformation of Barrett's epithelium.