Epigenetic and genetic silencing of CHFR in esophageal adenocarcinomas

Authors

  • Mohammed Soutto PhD,

    1. Department of Surgery, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
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  • DunFa Peng MD, PhD,

    1. Department of Surgery, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
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  • Mohammad Razvi MD,

    1. Department of Surgery, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
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  • Petra Ruemmele MD,

    1. Department of Pathology, University of Regensburg, Germany
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  • Arndt Hartmann MD,

    1. Department of Pathology, University of Regensburg, Germany
    2. Department of Pathology, University of Erlangen, Germany
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  • Albert Roessner MD,

    1. Department of Pathology, Otto-von-Guericke University Magdeburg, Germany
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  • Regine Schneider-Stock PhD,

    1. Department of Pathology, University of Erlangen, Germany
    2. Department of Pathology, Otto-von-Guericke University Magdeburg, Germany
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  • Wael El-Rifai MD, PhD

    Corresponding author
    1. Department of Surgery, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
    2. Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
    • Department of Surgery, Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 1255 Light Hall, 2215 Garland Avenue, Nashville, TN 37232
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    • Fax: (615) 322-7852


  • The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute or Vanderbilt University.

Abstract

BACKGROUND:

The checkpoint with forkhead-associated domain and RING-finger domain (CHFR) is a mitotic checkpoint protein with tumor-suppressor functions. In this study, the authors investigated the epigenetic and genetic mechanisms that regulate CHFR expression in esophageal adenocarcinomas (EACs).

METHODS:

Quantitative reverse transcriptase polymerase chain reaction analysis demonstrated downregulation of CHFR transcript in 79% of EACs (44 of 56) compared with 41 normal samples (P < .001). Immunohistochemical analysis of CHFR protein expression showed absence or weak immunostaining for CHFR in 75% of EACs (56 of 75) compared with normal tissue samples. The authors next examined the promoter DNA hypermethylation of CHFR by using quantitative bisulfite pyrosequencing technology. They detected significant CHFR promoter DNA hypermethylation in 31% of tumor samples (18 of 58) compared with normal samples (P < .001). Treatment of OE33 cells with 5-Aza-deoxycytidine led to reduction in the promoter DNA methylation levels with restoration of the CHFR mRNA expression, which confirmed promoter DNA methylation as an epigenetic mechanism regulating CHFR expression. However, they identified several EACs where the CHFR mRNA expression was silenced in the absence of notable methylation. Therefore, the authors examined the relative DNA copy number level of CHFR compared with normal samples.

RESULTS:

The results confirmed a decrease or absence of the relative CHFR DNA copy number levels in 59% of tumor samples. Nine tumors that showed loss of CHFR mRNA expression, in absence of promoter DNA hypermethylation, demonstrated a significant loss of relative CHFR DNA copy numbers.

CONCLUSIONS:

Taken together, their findings demonstrated that both epigenetic and genetic mechanisms were involved in silencing CHFR expression in EACs. Cancer 2010. © 2010 American Cancer Society.

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