Project 4: Identification of Esophageal Adenocarcinoma Susceptibility Genes
The goals of the project are to find genes that when mutated confer a susceptibility to develop Barrett’s esophagus and esophageal cancer. The discovery of these genetic mutations will provide an understanding of how esophageal cancer develops and enable the future development of drugs that prevent the development of cancer and drugs that effectively treat cancer. Barrett’s esophagus is the precursor of most esophageal adenocarcinomas and a large proportion of esophagogastric junctional adenocarcinomas. These diseases are closely associated with gastroesophageal reflux. Screening endoscopy is therefore recommended for the evaluation of chronic gastroesophageal reflux symptoms. Endoscopic surveillance, performed in those identified with Barrett’s esophagus, detects cancer at an early stage. However, the large majority of these cancers occur in previously undiagnosed Barrett’s esophagus and nearly half of these persons have no history of gastroesophageal reflux symptoms. Our research has characterized familial aggregation of Barrett’s esophagus and its associated cancers, which we term Familial Barrett’s Esophagus (FBE). We have developed a network of investigators who are actively identifying and accruing FBE families and biobanking lymphoblastoid cell lines in a centralized biorepository. Furthermore, our segregation analysis of pedigrees accrued to date indicates that FBE is the manifestation of autosomal dominant susceptibility alleles. Our central hypothesis: "FBE has a genetic basis" will now be tested in translational experiments designed to result in gene discovery.
Aim 1: To identify genomic loci linked to the FBE trait in multiplex multi-generational families
Aim 2: To narrow identified linkage regions in the larger cohort of all FBE families by performing a case control association study
Aim 3: To sequence candidate genes of interest in linkage regions to discover FBE susceptibility genes.
Using the multidisciplinary approach of our collaborative team of investigators, these studies will result in novel information that explains the biological basis of FBE. Identification of genetic risk factors would lead to more effective screening programs and improved understanding of the molecular pathogenesis of cancer. Furthermore, we will discover novel pathways, which will provide molecular targets for preventing and treating esophageal cancer.