Barretts esophagus is a metaplastic condition that occurs in 10-20% of persons with chronic gastroesophageal reflux. Persons with this condition are at high risk, estimated at 1-2% per year, of developing esophageal adenocarcinoma, a cancer that is increasing rapidly in incidence. This proposal builds upon an ongoing cohort study of persons with Barrett's metaplasia that is designed to identify cell cycle and genetic abnormalities that predict risk of developing high grade dysplasia or adenocarcinoma, and to use these biomarkers as intermediate endpoints in epidemiologic studies. The overall goal of the proposed study is to determine whether chromosomal instability, as measured in vitro in cultured lymphocytes by the bleomycin sensitivity assay, or in vivo as allelic losses on specific chromosomes, predicts neoplastic progression among patients (N=335) with Barrett s esophagus.
Specific aims are to test the hypothesis that 1) bleomycin-sensitive persons are at increased risk of histologic progression to high grade dysplasia or cancer, or of developing validated intermediate endpoints including aneuploidy or elevated G2 fractions; and 2) patients in whom allelic losses are observed on chromosomes 1p, 5q, 9p, 13q, or 18q in esophageal biopsies are at increased risk of neoplastic progression as defined above. In the third aim, cross-sectional analyses of baseline blood samples and biopsy tissue will test the hypothesis that sensitivity to bleomycin-induced chromosomal damage in vitro predicts chromosomal instability in vivo as evidenced by allelic losses. The ongoing study will provide biopsies and blood samples, along with data on major risk factors for esophageal adenocarcinoma for assessment of confounding and effect modification. Allelic losses in biopsy tissue will be identified by whole genome amplification and PCR using multiple polymorphic markers. This study will validate a proposed marker of cancer susceptibility in a prospective study of high risk persons; test a mechanism by which mutagen sensitivity may affect cancer risk; and further understanding of the genetic events leading to the development of esophageal adenocarcinoma, which serves as a model system for other human cancers.
