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Epigenetic and genetic silencing of CHFR in esophageal adenocarcinomas
Author(s) -
Soutto Mohammed,
Peng DunFa,
Razvi Mohammad,
Ruemmele Petra,
Hartmann Arndt,
Roessner Albert,
SchneiderStock Regine,
ElRifai Wael
Publication year - 2010
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.25151
Subject(s) - dna methylation , epigenetics , bisulfite sequencing , cancer research , methylation , biology , medicine , microbiology and biotechnology , genetics , dna , gene expression , gene
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.