Endoglin promoter hypermethylation identifies a field defect in human primary esophageal cancer

Authors

  • Zhe Jin MD, PhD,

    Corresponding author
    1. Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
    2. Shenzhen Key Laboratory of Micromolecule Innovative Drugs, Shenzhen, Guangdong, People's Republic of China
    3. Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, People's Republic of China
    • Corresponding author: Zhe Jin, MD, Department of Pathology, The Shenzhen University School of Medicine, 3688 Nanhai Ave, Rm 703, Nanshan, Shenzhen, Guangdong, People's Republic of China 518060; Fax: (086) 0755-86671906; zhejin1995@yahoo.com or Stephen J. Meltzer, Division of Gastroenterology, Department of Medicine, Johns Hopkins University School of Medicine. 1503 E. Jefferson St, Rm 112, Baltimore, MD 21231; Fax: (410) 502-1329; smeltzer@jhmi.edu

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    • The first 2 authors contributed equally to this work.

  • Zhenfu Zhao MD, PhD,

    1. Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
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    • The first 2 authors contributed equally to this work.

  • Yulan Cheng MD,

    1. Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
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  • Ming Dong MD, PhD,

    1. Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
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  • Xiaojing Zhang MD, PhD,

    1. Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
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  • Liang Wang PhD,

    1. Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
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  • Xinmin Fan MD, PhD,

    1. Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
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  • Xianling Feng MD,

    1. Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China
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  • Yuriko Mori MD, PhD,

    1. Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
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  • Stephen J. Meltzer MD

    Corresponding author
    1. Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
    • Corresponding author: Zhe Jin, MD, Department of Pathology, The Shenzhen University School of Medicine, 3688 Nanhai Ave, Rm 703, Nanshan, Shenzhen, Guangdong, People's Republic of China 518060; Fax: (086) 0755-86671906; zhejin1995@yahoo.com or Stephen J. Meltzer, Division of Gastroenterology, Department of Medicine, Johns Hopkins University School of Medicine. 1503 E. Jefferson St, Rm 112, Baltimore, MD 21231; Fax: (410) 502-1329; smeltzer@jhmi.edu

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Abstract

BACKGROUND

Endoglin (ENG) is a 180-kilodalton transmembrane glycoprotein that functions as a component of the transforming growth factor-β receptor complex. Recently, ENG promoter hypermethylation was reported in several human cancers.

METHODS

The authors examined ENG promoter hypermethylation using real-time, quantitative, methylation-specific polymerase chain reaction in 260 human esophageal tissues.

RESULTS

ENG hypermethylation demonstrated highly discriminative receiver operating characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) from normal esophagus (P < .01). It is interesting to note that ENG normalized methylation values were significantly higher in ESCC compared with normal tissue (P < .01) or EAC (P < .01). The ENG hypermethylation frequency was 46.2% in ESCC and 11.9% in normal esophageal tissue, but increased early and sequentially during EAC-associated neoplastic progression to 13.3% in Barrett metaplasia (BE), 25% in dysplastic BE, and 26.9% in frank EAC. ENG hypermethylation was significantly higher in normal esophageal tissue from patients with ESCC (mean, 0.0186) than in normal tissue from patients with EAC (mean, 0.0117; P < .05). Treatment of KYSE220 ESCC cells with the demethylating agent 5-aza-2′-deoxycytidine was found to reverse ENG methylation and reactivate ENG mRNA expression.

CONCLUSIONS

Promoter hypermethylation of ENG appears to be a frequent, tissue-specific event in human ESCC and exhibits a field defect with promising biomarker potential for the early detection of ESCC. In addition, ENG hypermethylation occurs in a subset of human EAC, and early during BE-associated esophageal neoplastic progression. Cancer 2013;119:3604–3609. © 2013 American Cancer Society.

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