Prognostic CpG methylation biomarkers identified by methylation array in esophageal squamous cell carcinoma patients.

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Abstract

Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with poor prognosis. We aimed to identify a panel of CpG methylation biomarkers for prognosis prediction of ESCC patients.

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Most cited references 25

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Aberrant CpG-island methylation has non-random and tumour-type-specific patterns.

J. Costello, M Frühwald, D Smiraglia … (2000)

CpG islands frequently contain gene promoters or exons and are usually unmethylated in normal cells. Methylation of CpG islands is associated with delayed replication, condensed chromatin and inhibition of transcription initiation. The investigation of aberrant CpG-island methylation in human cancer has primarily taken a candidate gene approach, and has focused on less than 15 of the estimated 45,000 CpG islands in the genome. Here we report a global analysis of the methylation status of 1,184 unselected CpG islands in each of 98 primary human tumours using restriction landmark genomic scanning (RLGS). We estimate that an average of 600 CpG islands (range of 0 to 4,500) of the 45,000 in the genome were aberrantly methylated in the tumours, including early stage tumours. We identified patterns of CpG-island methylation that were shared within each tumour type, together with patterns and targets that displayed distinct tumour-type specificity. The expression of many of these genes was reactivated by experimental demethylation in cultured tumour cells. Thus, the methylation of particular subsets of CpG islands may have consequences for specific tumour types.

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High-throughput DNA methylation profiling using universal bead arrays.

Marina Bibikova, Zhenwu Lin, Lixin Zhou … (2006)

We have developed a high-throughput method for analyzing the methylation status of hundreds of preselected genes simultaneously and have applied it to the discovery of methylation signatures that distinguish normal from cancer tissue samples. Through an adaptation of the GoldenGate genotyping assay implemented on a BeadArray platform, the methylation state of 1536 specific CpG sites in 371 genes (one to nine CpG sites per gene) was measured in a single reaction by multiplexed genotyping of 200 ng of bisulfite-treated genomic DNA. The assay was used to obtain a quantitative measure of the methylation level at each CpG site. After validating the assay in cell lines and normal tissues, we analyzed a panel of lung cancer biopsy samples (N = 22) and identified a panel of methylation markers that distinguished lung adenocarcinomas from normal lung tissues with high specificity. These markers were validated in a second sample set (N = 24). These results demonstrate the effectiveness of the method for reliably profiling many CpG sites in parallel for the discovery of informative methylation markers. The technology should prove useful for DNA methylation analyses in large populations, with potential application to the classification and diagnosis of a broad range of cancers and other diseases.

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Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer.

S B Baylin, M. Esteller, M Rountree … (2001)

Gene function in cancer can be disrupted either through genetic alterations, which directly mutate or delete genes, or epigenetic alterations, which alter the heritable state of gene expression. The latter events are mediated by formation of transcriptionally repressive chromatin states around gene transcription start sites and an associated gain of methylation in normally unmethylated CpG islands in these regions. The genes affected include over half of the tumor suppressor genes that cause familial cancers when mutated in the germline; the selective advantage for genetic and epigenetic dysfunction in these genes is very similar. The aberrant methylation can begin very early in tumor progression and mediate most of the important pathway abnormalities in cancer including loss of cell cycle control, altered function of transcription factors, altered receptor function, disruption of normal cell-cell and cell-substratum interaction, inactivation of signal transduction pathways, loss of apoptotic signals and genetic instability. The active role of the aberrant methylation in transcriptional silencing of genes is becoming increasingly understood and involves a synergy between the methylation and histone deacetylase (HDAC) activity. This synergy can be mediated directly by HDAC interaction with DNA methylating enzymes and by recruitment through complexes involving methyl-cytosine binding proteins. In the translational arena, the promoter hypermethylation changes hold great promise as DNA tumor markers and their potentially reversible state creates a target for cancer therapeutic strategies involving gene reactivation.

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Author and article information

Journal

Journal ID (iso-abbrev): Int J Med Sci

Title: International journal of medical sciences

Publisher: Ivyspring International Publisher

ISSN (Electronic): 1449-1907

ISSN (Print): 1449-1907

Publication date (Electronic): 2014

Volume: 11

Issue: 8

Affiliations

[1 ] 1. Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan;

[2 ] 2. Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan; ; 3. Department of Surgery, Chia-Yi Christian Hospital, Chiayi, Taiwan;

[3 ] 4. National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan;

[4 ] 5. Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan;

[5 ] 2. Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan;

[6 ] 6. Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan;

[7 ] 1. Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan; ; 2. Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan; ; 7. Department of Pharmacology, National Cheng Kung University, Tainan, Taiwan.

Article

Publisher Item ID: ijmsv11p0779

DOI: 10.7150/ijms.7405

PMC ID: 4057483

PubMed ID: 24936140

SO-VID: 5fd8d4c2-b869-478f-8315-90ccde893ffe

History

Keywords: CpG methylation,DNA methylation array,esophageal squamous cell carcinoma,prognosis.,pyrosequencing

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Keywords: CpG methylation, DNA methylation array, esophageal squamous cell carcinoma, prognosis., pyrosequencing

Prognostic CpG methylation biomarkers identified by methylation array in esophageal squamous cell carcinoma patients.

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Abstract

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International Journal of Applied Technology in Medical Sciences

Most cited references 25

Aberrant CpG-island methylation has non-random and tumour-type-specific patterns.

High-throughput DNA methylation profiling using universal bead arrays.

Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer.

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