The overall goal of this project is to understand the role of genetics in the etiology and prevention of esophageal cancer and gastric cancer. Five different but complementary approaches have been used to identify esophageal cancer susceptibility genes. First, a tumor/nontumor study has been conducted in which a biological specimen bank consisting of samples (tumor, nontumor, venous blood, finger stick blood, and buccal cells) from several hundred cases of esophageal cancer and gastric cancer (both cardia and body) was developed in Taiyuan for the identification of esophageal cancer and gastric cancer susceptibility genes and potential early genetic markers of these cancers. High-density genome-wide scans with microsatellite markers have been conducted to identify potential hot spots, and further testing of these hot spots and other candidate markers in additional tumor/nontumor samples is in progress. Premalignant morphologic lesions will also be examined. Second, blood samples for DNA have been collected from several hundred healthy individuals from high-risk (Yangcheng County) and low-risk (Beijing) areas to examine potential population differences in polymorphisms for selected genomic markers. Third, a large case-control study with cases of esophageal cancer and gastric cancer (both cardia and body) has been conducted and is being used to evaluate polymorphisms in the candidate markers identified in other components of this project, and to evaluate gene-environment interactions. Fourth, a family study is in progress which will permit linkage of candidate markers with cancer in families having 2 or more cases with esophageal cancer or gastric cancer. Finally, an endoscopic study is being conducted to obtain specimens from a morphologic spectrum of disease ranging from normal to early invasive esophageal cancer in order to characterize molecular progression. Recent studies have emphasized UGI cancer GWAS and post-GWAS analyses, exome sequencing of subjects in the family study, profiling of UGI cancer tumors, and studies of the microbiome of UGI cancers.