Trial Information

Methylation in Cancer Progression of Barrett's Esophagus

Patients with Barrett's esophagus (BE) have an increased risk of esophageal adenocarcinoma
which is 40-125 fold higher than in the general population. However, the current techniques
of detecting dysplasia and observing abnormal p53 immunohistochemical staining are not
accurate or reliable methods for determining which BE patients will progress to cancer. DNA
hypermethylation is an epigenetic process that occurs in the promoter region of certain
genes, resulting in suppression of gene expression. Inactivation of specific genes via
hypermethylation has been highly associated with cancer.

The primary objective of this research is to determine whether DNA hypermethylation is a
biomarker that will predict which patients with BE are likely to progress to adenocarcinoma.
Patients with BE and/or esophageal adenocarcinoma who undergo endoscopy at the Johns
Hopkins Hospital will comprise the cohort of subjects. Gene hypermethylation will be
assessed by performing methylation-specific PCR on a panel of 8 cancer-related genes.

Specific Aim 1: To compare the prevalence of gene hypermethylation in BE patients with
different grades of dysplasia and/or adenocarcinoma, using archived specimens.

Specific Aim 2: To determine whether the presence of gene hypermethylation in initial
biopsies of BE patients is associated with progression to adenocarcinoma, using archived
specimens. To compare gene hypermethylation with currently available markers for neoplastic
progression.

Specific Aim 3: To determine whether methylated DNA from BE and/or adenocarcinoma can be
detected in the peripheral blood of patients, by comparing methylation profiles of
esophageal biopsy specimens with peripheral blood samples taken at the same time in
prospectively enrolled patients.

If hypermethylation of one or more genes is detected at an early stage in BE patients who
later progress to adenocarcinoma, hypermethylation could be used as an early predictor for
adenocarcinoma even before pathologic changes are evident. Furthermore, this research will
help determine the specific genetic events that occur in the neoplastic transformation from
BE to adenocarcinoma.

The long-term goal of this project is to determine whether hypermethylation can identify BE
patients who are at high risk for neoplastic progression, thus allowing for early
intervention in the form of more frequent endoscopic surveillance, chemoprevention, ablative
therapy, or surgery.