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Epigenetic and genetic silencing of CHFR in esophageal adenocarcinomas

Mohammed Soutto1, Dunfa Peng, Mohammad Razvi

  • 1Department of Surgery, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37323, USA.

Cancer
|June 22, 2010
PubMed
Abstract

Insights

Checkpoint with forkhead-associated domain and RING-finger domain (CHFR) expression is silenced in esophageal adenocarcinomas by both epigenetic DNA hypermethylation and genetic DNA copy number loss.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The checkpoint with forkhead-associated domain and RING-finger domain (CHFR) is a crucial mitotic checkpoint protein with demonstrated tumor-suppressor functions.
  • Dysregulation of CHFR is implicated in various cancers, highlighting its importance in maintaining genomic stability.

Purpose of the Study:

  • To investigate the epigenetic and genetic mechanisms responsible for regulating CHFR expression in esophageal adenocarcinomas (EACs).
  • To determine the frequency and interplay of DNA hypermethylation and copy number alterations in CHFR silencing in EACs.

Main Methods:

  • Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) were used to assess CHFR transcript and protein levels.
  • Quantitative bisulfite pyrosequencing was employed to analyze CHFR promoter DNA methylation.
  • DNA copy number analysis was performed to evaluate genetic alterations of the CHFR locus.

Main Results:

  • CHFR transcript was downregulated in 79% of EACs, with absent or weak protein expression in 75%.
  • Significant CHFR promoter DNA hypermethylation was detected in 31% of EACs, and its reduction with 5-Aza-deoxycytidine restored CHFR mRNA expression.
  • Loss or decrease of CHFR DNA copy number was observed in 59% of EACs, with nine tumors showing copy number loss in the absence of promoter hypermethylation.

Conclusions:

  • Both epigenetic silencing via promoter DNA hypermethylation and genetic mechanisms involving DNA copy number loss contribute to the downregulation of CHFR expression in esophageal adenocarcinomas.
  • These findings elucidate the multifaceted regulation of CHFR in EAC development and progression.

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