DNA Methylation in Cancer: A Gene Silencing Mechanism and the Clinical Potential of Its Biomarkers

被引：66

作者：

Fukushige, Shinichi ^{[1
,2
]}

Horii, Akira ^{[1
]}

机构：

[1] Tohoku Univ, Grad Sch Med, Dept Mol Pathol, Sendai, Miyagi 9808575, Japan

[2] Tohoku Univ, Grad Sch Med, Ctr Regulatory Epigenome & Dis, Sendai, Miyagi 9808575, Japan

来源：

TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE | 2013年 / 229卷 / 03期

基金：

日本学术振兴会;

关键词：

biomarker; cancer; CpG island; DNA methylation; gene silencing; ENHANCER-BLOCKING ACTIVITY; PROSTATE-CANCER; CPG ISLANDS; COLORECTAL-CANCER; PROMOTER HYPERMETHYLATION; REPRESSES TRANSCRIPTION; GLYCOSYLASE MBD4; MAMMALIAN DNA; TET PROTEINS; HUMAN BREAST;

D O I：

10.1620/tjem.229.173

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Initiation and progression of human caner not only depends on genetic alterations but also on epigenetic changes such as DNA methylation and histone modifications. Aberrant DNA hypermethylation in the promoter regions of genes is the most well-defined epigenetic change in tumors and is associated with inappropriate gene silencing. This feature can be utilized to search for tumor-specific DNA methylation biomarkers and to examine candidate DNA biomarkers for clinical use. DNA methylation biomarker is defined as a molecular target that undergoes DNA methylation changes in carcinogenesis. Such a biomarker is useful for early detection of cancer, predicting and/or monitoring the therapeutic response, and detection of recurrent cancer. In this review, we describe the mechanism that establishes and maintains DNA methylation patterns as well as the mechanism of aberrant gene silencing in cancer, and then we introduce methods to isolate the DNA methylation biomarkers. We also summarize the current status of clinical implementation for some of the most widely studied and well-validated DNA methylation biomarkers, including tissue factor pathway inhibitor 2 (TFPI2), septin 9 (SEPT9), glutathione S-transferase pi 1 (GSTP1), and O-6-methylguanine-DNA methyltransferase (MGMT), and assess the clinical potential of these biomarkers for risk assessment, early diagnosis, prognosis, treatment, and the prevention of cancer. Finally we describe the possible involvement of 5-hydroxymethylcytosine in cancer; this is a recently discovered 5-methylcytosine oxidation derivative and might have a diagnostic potential in certain cancers. Abnormal DNA methylations are leading candidates for the development of specific markers for cancer diagnosis and therapy.

引用

页码：173 / 185

页数：13

共 108 条

[1] Next-Generation Stool DNA Test Accurately Detects Colorectal Cancer and Large Adenomas [J].

Ahlquist, David A. ;

Zou, Hongzhi ;

Domanico, Michael ;

Mahoney, Douglas W. ;

Yab, Tracy C. ;

Taylor, William R. ;

Butz, Malinda L. ;

Thibodeau, Stephen N. ;

Rabeneck, Linda ;

Paszat, Lawrence F. ;

Kinzler, Kenneth W. ;

Vogelstein, Bert ;

Bjerregaard, Niels Chr. ;

Laurberg, Soren ;

Sorensen, Henrik Toft ;

Berger, Barry M. ;

Lidgard, Graham P. .

GASTROENTEROLOGY, 2012, 142 (02) :248-256

[2] GATA-4 and GATA-5 transcription factor genes and potential downstream antitumor target genes are epigenetically silenced in colorectal and gastric cancer [J].

Akiyama, Y ;

Watkins, N ;

Suzuki, H ;

Jair, KW ;

van Engeland, M ;

Esteller, M ;

Sakai, H ;

Ren, CY ;

Yuasa, Y ;

Herman, JG ;

Baylin, SB .

MOLECULAR AND CELLULAR BIOLOGY, 2003, 23 (23) :8429-8439

[3] MS-qFRET: A quantum dot-based method for analysis of DNA methylation [J].

Bailey, Vasudev J. ;

Easwaran, Hariharan ;

Zhang, Yi ;

Griffiths, Elizabeth ;

Belinsky, Steven A. ;

Herman, James G. ;

Baylin, Stephen B. ;

Carraway, Hetty E. ;

Wang, Tza-Huei .

GENOME RESEARCH, 2009, 19 (08) :1455-1461

[4] A decade of exploring the cancer epigenome - biological and translational implications [J].

Baylin, Stephen B. ;

Jones, Peter A. .

NATURE REVIEWS CANCER, 2011, 11 (10) :726-734

[5] The protein CTCF is required for the enhancer blocking activity of vertebrate insulators [J].

Bell, AC ;

West, AG ;

Felsenfeld, G .

CELL, 1999, 98 (03) :387-396

[6] Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene [J].

Bell, AC ;

Felsenfeld, G .

NATURE, 2000, 405 (6785) :482-485

[7] DNA methylation patterns and epigenetic memory [J].

Bird, A .

GENES & DEVELOPMENT, 2002, 16 (01) :6-21

[8]

BIRD A, 1985, CELL, V40, P91, DOI 10.1016/0092-8674(85)90312-5

[9] Methylation-induced repression - Belts, braces, and chromatin [J].

Bird, AP ;

Wolffe, AP .

CELL, 1999, 99 (05) :451-454

[10] Quantitative Sequencing of 5-Methylcytosine and 5-Hydroxymethylcytosine at Single-Base Resolution [J].

Booth, Michael J. ;

Branco, Miguel R. ;

Ficz, Gabriella ;

Oxley, David ;

Krueger, Felix ;

Reik, Wolf ;

Balasubramanian, Shankar .

SCIENCE, 2012, 336 (6083) :934-937

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