Frequent methylation of Eyes absent 4 gene in Barrett's esophagus and esophageal adenocarcinoma

Hongzhi Zou, Neal K. Osborn, Jonathan J. Harrington, Kristie K. Klatt, Julian R Molina, Lawrence J. Burgart, David A. Ahlquist

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Abstract

Most esophageal adenocarcinomas arise within Barrett's esophagus but the cause of this increasingly prevalent condition remains unknown. Early detection improves survival and discriminant screening markers for Barrett's esophagus and cancer are needed. This study was designed to explore the natural history of eyes absent 4 (EYA4) gene methylation in the neoplastic progression of Barrett's esophagus and to evaluate methylated EYA4 as a candidate marker. Aberrant promoter methylation of EYA4 was studied by methylation-specific PCR using bisulfite-treated DNA from esophageal adenocarcinomas, Barrett's esophagus, and normal epithelia, and then confirmed by sequencing. Eight cancer cell lines were treated with the demethylation agent 5-aza-2′-deoxycytidine, and EYA4 mRNA expression with and without treatment was quantified by real-time reverse-transcription PCR. EYA4 hypermethylation was detected in 83% (33 of 40) of esophageal adenocarcinomas and 77% (27 of 35) of Barrett's tissues, but only in 3% (2 of 58) of normal esophageal and gastric mucosa samples (P < 0.001). The unmethylated cancer cell lines had much higher EYA4 mRNA expression than the methylated cancer cell lines. Demethylation caused by 5-aza-2′- deoxycytidine increased the mRNA expression level by a median of 3.2-fold in methylated cells, but its effect on unmethylated cells was negligible. Results indicate that aberrant promoter methylation of EYA4 is very common during tumorigenesis in Barrett's esophagus, occurs in early metaplasia, seems to be an important mechanism of down-regulating EYA4 expression, and represents an intriguing candidate marker for Barrett's metaplasia and esophageal cancer.

Original languageEnglish (US)
Pages (from-to)830-834
Number of pages5
JournalCancer Epidemiology Biomarkers and Prevention
Volume14
Issue number4
DOIs
StatePublished - Apr 2005

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Barrett Esophagus
Methylation
Adenocarcinoma
decitabine
Genes
Esophageal Neoplasms
Cell Line
Messenger RNA
Neoplasms
Polymerase Chain Reaction
Metaplasia
Gastric Mucosa
Natural History
Reverse Transcription
Carcinogenesis
Epithelium
DNA

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

Frequent methylation of Eyes absent 4 gene in Barrett's esophagus and esophageal adenocarcinoma. / Zou, Hongzhi; Osborn, Neal K.; Harrington, Jonathan J.; Klatt, Kristie K.; Molina, Julian R; Burgart, Lawrence J.; Ahlquist, David A.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 14, No. 4, 04.2005, p. 830-834.

Research output: Contribution to journalArticle

Zou, Hongzhi ; Osborn, Neal K. ; Harrington, Jonathan J. ; Klatt, Kristie K. ; Molina, Julian R ; Burgart, Lawrence J. ; Ahlquist, David A. / Frequent methylation of Eyes absent 4 gene in Barrett's esophagus and esophageal adenocarcinoma. In: Cancer Epidemiology Biomarkers and Prevention. 2005 ; Vol. 14, No. 4. pp. 830-834.
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