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Methylomics analysis identifies epigenetically silenced genes and implies an activation of β‐catenin signaling in cervical cancer
Author(s) -
Chen YuChih,
Huang RuiLan,
Huang YungKai,
Liao YuPing,
Su PoHsuan,
Wang HuiChen,
Chang ChengChang,
Lin YaWen,
Yu MuHsien,
Chu TangYuan,
Lai HungCheng
Publication year - 2013
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28658
Subject(s) - dna methylation , methylation , epigenetics , biology , carcinogenesis , cancer research , cervical cancer , gene , population , cancer , genetics , medicine , gene expression , environmental health
Using DNA methylation biomarkers in cancer detection is a potential direction in clinical testing. Some methylated genes have been proposed for cervical cancer detection; however, more reliable methylation markers are needed. To identify new hypermethylated genes in the discovery phase, we compared the methylome between a pool of DNA from normal cervical epithelium ( n = 19) and a pool of DNA from cervical cancer tissues ( n = 38) using a methylation bead array. We integrated the differentially methylated genes with public gene expression databases, which resulted in 91 candidate genes. Based on gene expression after demethylation treatment in cell lines, we confirmed 61 genes for further validation. In the validation phase, quantitative MSP and bisulfite pyrosequencing were used to examine their methylation level in an independent set of clinical samples. Fourteen genes, including ADRA1D , AJAP1 , COL6A2 , EDN3 , EPO , HS3ST2 , MAGI2 , POU4F3 , PTGDR , SOX8 , SOX17 , ST6GAL2 , SYT9 , and ZNF614 , were significantly hypermethylated in CIN3+ lesions. The sensitivity, specificity, and accuracy of POU4F3 for detecting CIN3+ lesions were 0.88, 0.82, and 0.85, respectively. A bioinformatics function analysis revealed that AJAP1, EDN3, EPO, MAGI2, and SOX17 were potentially implicated in β‐catenin signaling, suggesting the epigenetic dysregulation of this signaling pathway during cervical cancer development. The concurrent methylation of multiple genes in cancers and in subsets of precancerous lesions suggests the presence of a driver of methylation phenotype in cervical carcinogenesis. Further validation of these new genes as biomarkers for cervical cancer screening in a larger population‐based study is warranted.