Methylomics analysis identifies epigenetically silenced genes and implies an activation of β‐catenin signaling in cervical cancer. Issue 1 (17th December 2013)

• Record Type: Journal Article
• Authors: Chen, Yu‐Chih; Huang, Rui‐Lan; Huang, Yung‐Kai; Liao, Yu‐Ping; Su, Po‐Hsuan; Wang, Hui‐Chen; Chang, Cheng‐Chang; Lin, Ya‐Wen; Yu, Mu‐Hsien; Chu, Tang‐Yuan; Lai, Hung‐Cheng
• Is Part Of: International journal of cancer. Volume 135:Issue 1(2014:Jul. 01)
• Page Start: 117
• Page End: 127
• Publication Date: 2013-12-17
• Subjects: Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.28658
• Languages: English
• ISSNs: 0020-7136

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 (<italic>n</italic> = 19) and a pool of DNA from cervical cancer tissues (<italic>n</italic> = 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 <italic>ADRA1D</italic>, <italic>AJAP1</italic>, <italic>COL6A2</italic>, <italic>EDN3</italic>, <italic>EPO</italic>, <italic>HS3ST2</italic>, <italic>MAGI2</italic>, <italic>POU4F3</italic>, <italic>PTGDR</italic>, <italic>SOX8</italic>, <italic>SOX17</italic>, <italic>ST6GAL2</italic>, <italic>SYT9</italic>, and <italic>ZNF614</italic>, were significantly hypermethylated in CIN3+ lesions. The sensitivity, specificity, and accuracy of <italic>POU4F3</italic> 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.</p> </abstract>