Increased acid exposure in patients with gastroesophageal reflux disease influences cyclooxygenase-2 gene expression in the squamous epithelium of the lower esophagus

Hypothesis: Although genetic changes associated with the progression to Barrett esophagus and adenocarcinoma have been identified, changes in gene expression associated with gastroesophageal reflux disease have not been reported. We examined expression levels of several genes important in carcinogenesis and compared expression levels with alterations in esophageal acid exposure. Patients, Design, and Setting: Prospective analysis of 61 patients initially seen with reflux symptoms at a private academic hospital. Interventions: Paired esophageal biopsy specimens of squamous epithelium 3 cm above the squamocolumnar junction. All patients had 24-hour pH monitoring performed. Main Outcome Measures: Cyclooxygenase (COX) 1, COX-2, thymidylate synthase, human telomerase reverse transcriptase (hTERT), Bcl-2 protein, survivin protein, secreted protein acidic and rich in cysteine (SPARC), tetraspan (TSPAN), and caudal-type homeobox transcription factor 2 (CDX2) messenger RNA expression analysis was performed on snap-frozen, microdissected tissue using a quantitative reverse transcriptase-polymerase chain reaction method. Linear regression and the Pearson product moment correlation were used to relate gene expression to parameters of the 24-hour pH record. Results: Expression levels of COX-2 correlated positively with the 24-hour pH score (r = 0.25, P = .05). There was no correlation between the expression of other tested genes and esophageal acid exposure. There was also no significant increase in COX-2 expression in patients with esophagitis or in those who used nonsteroidal anti-inflammatory drugs. Conclusions: To our knowledge, these data provide among the first reported correlation of genetic changes and increased esophageal acid exposure in patients with gastroesophageal reflux symptoms. The changes in gene expression occur before any metaplastic changes in the tissue are apparent, and may in the future be useful in predicting which patients will progress through a metaplasia-dysplasia carcinoma sequence.