The overall goal of this project is to understand the role of genetics in the etiology and prevention of upper gastrointestinal cancers (esophagus, gastric cardia, gastric body). The objectives of current studies are: (1) to identify susceptibility genes as potential early detection markers for these cancers, beginning with cancer of the esophagus; 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. Several lines of evidence (family history, familial aggregation, segregation, cytogenetics) suggest that genetic factors may play an important role in the etiology of this malignancy. 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, (2) a high-risk/low-risk population study of 300+ subjects, (3) a case-control study of 1,500 cases and 1,500 controls, (4) a linkage study in 150 families with multiple cases, and (5) an endoscopic study of persons with pre-malignant lesions of the upper GI tract. U.S. STUDIES - In the U.S., where adenocarcinoma of the esophagus 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 from non-Barrett's 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 field work for the case-control study was just recently completed; and the family study has identified and recruited approximately two-thirds of its targeted number of families. A new endoscopy study was initiated this year to begin collection of samples from patients with pre-malignant and early invasive cancer of the esophagus. (2) Laboratory work has focused on the analysis of: (i) DNA (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); (ii) RNA (analysis of tumor vs nontumor expression using Affymetrix Hu133 chips for cancers of the esophagus, gastric cardia, and gastric body; validation studies of dysregulated candidate genes from expression array analyses using real time RT-PCR); and (iii) protein (2D gel/MS analyses, immunohistochemical analyses of tissue microarrays). U.S. STUDIES - Recruitment for the Barrett's esophagus study is expected to begin in the Fall of 2005.
