The overall goal of this project is to understand the role of genetics in the etiology and prevention of upper gastrointestinal cancers, including esophageal cancer and gastric cancer. The objectives of current studies are: (1) to identify susceptibility genes as potential early detection markers for esophageal cancer and gastric cancer, beginning with esophageal cancer; and (2) to identify practice blood-based biomarkers that can be used as a screening test to determine who has Barrett's esophagus, a precursor to esophageal adenocarcinoma. BACKGROUND: Esophageal cancer is the 6th most common cause of cancer death worldwide, and gastric cancer is the 2nd most common cause of cancer death worldwide. Several lines of evidence (family history, familial aggregation, segregation, cytogenetics) suggest that genetic factors may play an important role in the etiology of esophageal cancer. Molecular approaches to identify susceptibility genes (and their protein products) may allow screening of populations to identify persons at particularly high risk who could then be targeted for prevention strategies (e.g., chemoprevention or early detection). METHODS: CHINA STUDIES - Several studies have been completed or are in progress to study these cancers in persons from Shanxi Province, China, where rates are among the highest in the world, including (1) a tumor/nontumor study of over 700 cases of esophageal cancer and gastric cancer (including both cardia and body cancers), (2) a high-risk/low-risk population study of 300+ healthy subjects, (3) a case-control study of 1,500 esophageal cancer and gastric cancer cases and 1,500 controls, (4) a linkage study in 150 families with multiple cases of esophageal cancer and/or gastric cancer, and (5) an endoscopic study of persons with esophageal cancer pre-malignant lesions. U.S. STUDIES - In the U.S., where esophageal adenocarcinoma has now become the most common form of esophageal cancer, a new project to evaluate esophageal adenocarcinoma and its precursor, Barrett's esophagus, has been initiated, and will emphasize serum and tissue proteomics to distinguish Barrett's esophagus from non-Barrett's esophagus patients. PROGRESS: CHINA STUDIES - (1) The tumor/nontumor study reached its original goal and has been extended; the high-/low-risk population study is completed; the initial field work for the esophageal cancer and gastric cancer case-control studies was recently completed, but has also been extended to collect an additional 300 gastric cancer cases and controls; and the family study has identified and recruited approximately two-thirds of its targeted number of families. A new endoscopy study was initiated in 2005 to collect samples from patients with esophageal cancer pre-malignant lesions and early invasive malignancies. (2) Laboratory work has focused on the molecular and genomic analyses, including: (i) DNA analyses (genome-wide microsatellite scanning for allelic loss as well as SNP scanning of tumors with the 10K Affymetrix GeneChip mapping array for LOH, fine mapping, and candidate gene mutational testing in tumors; case-control comparisons of SNP profiles using the Affymetrix 10K, 100K, and 500K GeneChip mapping arrays in germ-line DNA) and subsequent validation studies of highlighted SNPs; (ii) RNA analyses (analysis of tumor vs nontumor expression using Affymetrix Hu133 chips for esophageal cancer and gastric cancers (both cardia and body cancers); validation studies of dysregulated candidate genes from expression array analyses using real time RT-PCR); and (iii) protein analyses (2D gel/MS analyses, immunohistochemical analyses of tissue microarrays of esophageal cancers and gastric cancers). U.S. STUDIES - Recruitment for the Barrett's esophagus study started in July 2006. In the first year, approximately 50 Barrett's esophagus and 100 non-Barrett's esophagus patients were enrolled.
