Reprimo methylation is a potential biomarkerof Barrett's-associated esophageal neoplastic progression

James Hamilton, Fumiaki Sato, Zhe Jin, Bruce D. Greenwald, Tetsuo Ito, Yuriko Mori, Bogdan C. Paun, Takatsugu Kan, Yulan Cheng, Suna Wang, Jian Yang, John M. Abraham, Stephen Meltzer

Research output: Contribution to journalArticle

Abstract

Purpose: 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 neoptastic 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). Experimental Design: 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. Results: 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. 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, cell-specific early event with potential as a biomarker for the early detection of esophageal neoplasia.

Original languageEnglish (US)
Pages (from-to)6637-6642
Number of pages6
JournalClinical Cancer Research
Volume12
Issue number22
DOIs
StatePublished - Nov 15 2006

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Methylation
Esophagus
Deoxycytidine
Tumor Suppressor Genes
Polymerase Chain Reaction
Barrett Esophagus
G2 Phase
Esophageal Neoplasms
Cell Cycle Checkpoints
Epigenomics
Reverse Transcription
Adenocarcinoma
Research Design
Biomarkers
Epithelial Cells
Confidence Intervals
Carcinoma
Biopsy
Esophageal Squamous Cell Carcinoma
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Reprimo methylation is a potential biomarkerof Barrett's-associated esophageal neoplastic progression. / Hamilton, James; Sato, Fumiaki; Jin, Zhe; Greenwald, Bruce D.; Ito, Tetsuo; Mori, Yuriko; Paun, Bogdan C.; Kan, Takatsugu; Cheng, Yulan; Wang, Suna; Yang, Jian; Abraham, John M.; Meltzer, Stephen.

In: Clinical Cancer Research, Vol. 12, No. 22, 15.11.2006, p. 6637-6642.

Research output: Contribution to journalArticle

Hamilton, J, Sato, F, Jin, Z, Greenwald, BD, Ito, T, Mori, Y, Paun, BC, Kan, T, Cheng, Y, Wang, S, Yang, J, Abraham, JM & Meltzer, S 2006, 'Reprimo methylation is a potential biomarkerof Barrett's-associated esophageal neoplastic progression', Clinical Cancer Research, vol. 12, no. 22, pp. 6637-6642. https://doi.org/10.1158/1078-0432.CCR-06-1781
Hamilton, James ; Sato, Fumiaki ; Jin, Zhe ; Greenwald, Bruce D. ; Ito, Tetsuo ; Mori, Yuriko ; Paun, Bogdan C. ; Kan, Takatsugu ; Cheng, Yulan ; Wang, Suna ; Yang, Jian ; Abraham, John M. ; Meltzer, Stephen. / Reprimo methylation is a potential biomarkerof Barrett's-associated esophageal neoplastic progression. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 22. pp. 6637-6642.
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abstract = "Purpose: 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 neoptastic 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). Experimental Design: 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. Results: 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. 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, cell-specific early event with potential as a biomarker for the early detection of esophageal neoplasia.",
author = "James Hamilton and Fumiaki Sato and Zhe Jin and Greenwald, {Bruce D.} and Tetsuo Ito and Yuriko Mori and Paun, {Bogdan C.} and Takatsugu Kan and Yulan Cheng and Suna Wang and Jian Yang and Abraham, {John M.} and Stephen Meltzer",
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T1 - Reprimo methylation is a potential biomarkerof Barrett's-associated esophageal neoplastic progression

AU - Hamilton, James

AU - Sato, Fumiaki

AU - Jin, Zhe

AU - Greenwald, Bruce D.

AU - Ito, Tetsuo

AU - Mori, Yuriko

AU - Paun, Bogdan C.

AU - Kan, Takatsugu

AU - Cheng, Yulan

AU - Wang, Suna

AU - Yang, Jian

AU - Abraham, John M.

AU - Meltzer, Stephen

PY - 2006/11/15

Y1 - 2006/11/15

N2 - Purpose: 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 neoptastic 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). Experimental Design: 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. Results: 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. 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, cell-specific early event with potential as a biomarker for the early detection of esophageal neoplasia.

AB - Purpose: 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 neoptastic 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). Experimental Design: 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. Results: 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. 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, cell-specific early event with potential as a biomarker for the early detection of esophageal neoplasia.

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