The incidence of esophageal adenocarcinoma (EAC) in the United States is increasing markedly. Five-year survival remains a disappointing 15%. Better methods are urgently needed to detect patients at high risk of EAC and to interrupt disease progression. Intestinal metaplasia, a condition commonly referred to as Barrett's esophagus, is associated with increased risk of EAC. A histopathological diagnosis of dysplasia in Barrett's indicates further risk but shows poor agreement among pathologists. Improved markers are needed to accurately guide clinical decisions and to serve as effective surrogate endpoints in studies of interventions to prevent development of EAC. Progression in Barrett's is associated with genomic instability, such as changes in changes in DNA copy number, that reflect the occurrence of DNA damage. Furthermore, the two principal, mechanistically important oncogenic events in Barrett's progression that have been identified to date inactivate cell cycle inhibitors that can be induced by the DNA damage checkpoint response. Activation of this response can be detected in intestinal neoplasia but has not been well studied in Barrett's. We propose a model in which disease progression in Barrett's is driven by DNA damage, countermanded by the DNA damage checkpoint response, and accelerated when the checkpoint fails. We have obtained preliminary evidence to support this model in immunohistochemical studies of Barrett's surgical resection specimens. We propose to extend these studies to endoscopic biopsy and brushing samples, with the goal of identifying clinically useful markers for progression to EAC. Biopsies from existing tissue banks will be stained for cyclin A, phosphorylated histone H3, and ?H2AX, to assess their correlation with histopathological diagnosis and with progression to high-grade dysplasia and EAC. Biopsies and endoscopic brushings will be prospectively collected. Cell cycle and checkpoint markers will be assayed in these samples to assess their ability to predict disease progression.
Esophageal adenocarcinoma is the only major human tumor type in the United States to be increasing in incidence. Better methods are urgently needed to identify patients at high risk for this cancer, who are most likely to benefit from intensive surveillance and interventions. This goal of this application is to develop clinically useful predictors of risk by assaying tissue samples from a precursor lesion, Barrett's esophagus, for markers that reflect the cellular response to DNA damage.
