Abstract
Reprimo, a candidate tumor-suppressor gene, regulates p53-mediated cell cycle arrest at G2 phase, and tumor-suppressor gene methylation is involved in the pathogenesis and progression of esophageal cancer. Our aim was to determine whether and at what phase of neoplastic progression Reprimo methylation occurs in Barrett's adenocarcinogenesis, as well as its columnar or squamous cell-type specificity. We also sought to determine whether Reprimo expression could be restored in vitro by the demethylating agent 5-aza-deoxycytidine (5AzaC). Quantitative methylation-specific PCR for Reprimo was done using an ABI7700 (Taqman) apparatus on 175 endoscopic biopsy specimens. In addition, reverse transcription-PCR and quantitative methylation-specific PCR were done on esophageal carcinoma cells before and after treatment with 5AzaC. In Barrett's esophagus (BE; P=0.001), high-grade dysplasia (HGD; P=0.001), and esophageal adenocarcinoma (EAC; P=0.00003), the level and frequency of Reprimo methylation were significantly higher than in normal esophagus (NE). There was no statistically significant difference between BE and EAC, HGD and EAC, or NE and esophageal squamous cell carcinoma (ESCC). Reprimo methylation occurred in 0 of 19 NE samples, 6 (13%) of 45 ESCC, 9 (36%) of 25 BE, 7 (64%) of 11 HGD, and 47 (63%) of 75 EAC. Analysis of Reprimo methylation in EAC versus NE revealed an area under the receiver-operator characteristic curve of 0.812 (P<0.00001; 95% confidence interval, 0.73-0.90). In vitro 5AzaC treatment of OE33 EAC cells reduced Reprimo methylation and increased Reprimo expression. Reprimo methylation occurs significantly more frequently in BE, HGD, and EAC than in NE or ESCC, suggesting that this epigenetic alteration is a specialized columnar, cell-specific early event with potential as a biomarker for the early detection of esophageal neoplasia.
Highlights
Reprimo, a candidate tumor-suppressor gene, regulates p53-mediated cell cycle arrest at G2 phase, and tumor-suppressor gene methylation is involved in the pathogenesis and progression of esophageal cancer
The samples consisted of 75 esophageal adenocarcinoma (EAC), 45 esophageal squamous cell carcinoma (ESCC), 25 Barrett’s esophagus (BE), 11 high-grade dysplasia (HGD), and 19 normal esophagus (NE)
All patients were of similar age (Student’s t test, NE versus BE, P = 0.74; NE versus HGD, P = 0.06; NE versus EAC, P = 0.76; NE versus ESCC, P = 0.96)
Summary
A candidate tumor-suppressor gene, regulates p53-mediated cell cycle arrest at G2 phase, and tumor-suppressor gene methylation is involved in the pathogenesis and progression of esophageal cancer. Our aim was to determine whether and at what phase of neoplastic progression Reprimo methylation occurs in Barrett’s adenocarcinogenesis, as well as its columnar or squamous cell-type specificity. Conclusions: Reprimo methylation occurs significantly more frequently in BE, HGD, and EAC than in NE or ESCC, suggesting that this epigenetic alteration is a specialized columnar, cellspecific early event with potential as a biomarker for the early detection of esophageal neoplasia. Reprimo was frequently methylated in multiple human malignancies, including esophageal cancer (9 – 12). Our goal was to determine the methylation status of Reprimo in esophageal cancer, premalignant lesions [ called Barrett’s esophagus (BE) or BE with high-grade dysplasia (HGD), normal esophageal epithelium (NE), and esophageal squamous cell carcinoma (ESCC)]. We sought to examine the methylation of Reprimo in tissue that has been associated with neoplastic progression, i.e., BE segment length and the presence of HGD within a field of BE
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