Carcinogenesis Advance Access originally published online on September 24, 2007
Carcinogenesis 2007 28(12):2434-2442; doi:10.1093/carcin/bgm206
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Alterations of DNA methylation associated with abnormalities of DNA methyltransferases in human cancers during transition from a precancerous to a malignant state
Pathology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
* To whom correspondence should be addressed. Tel: +81 3 3542 2511; Fax: +81 3 3248 2463; Email: ykanai{at}ncc.go.jp
Alterations of DNA methylation are one of the most consistent epigenetic changes in human cancers. Human cancers generally show global DNA hypomethylation accompanied by region-specific hypermethylation. Alterations of DNA methylation may result in chromosomal instability as a result of changes in chromatin structure. DNA hypermethylation of CpG islands silences various tumor-related genes. Alterations of DNA methylation are frequently observed in cancers associated with chronic inflammation and/or persistent infection with viruses or other pathogenic microorganisms, such as hepatitis B or C viruses, Epstein–Barr virus, human papillomavirus and Helicobacter pylori, or with cigarette smoking. Accumulating evidence suggests that alterations of DNA methylation are involved even in the early and precancerous stages. On the other hand, in patients with cancers, aberrant DNA methylation is significantly associated with poorer tumor differentiation, tumor aggressiveness and poor prognosis. Precancerous conditions showing alterations of DNA methylation may progress rapidly and generate more malignant cancers. DNA methyltransferase (DNMT) 1 over-expression is not a secondary result of increased cell proliferative activity but is significantly correlated with the CpG island methylator phenotype, which is defined as frequent DNA hypermethylation of C-type CpG islands that are usually methylated in a cancer-specific (not age-dependent) manner. Splicing alteration of DNMT3b may result in chromosomal instability through DNA hypomethylation of pericentromeric satellite regions. Alteration of DNA methylation may become an indicator for carcinogenetic risk estimation and early diagnosis of cancers and a biological predictor of poor prognosis in patients with cancers. Correction of DNA methylation status may offer a new strategy for prevention and therapy of cancers.
Abbreviations: CIMP, CpG island methylator phenotype; DNMT, DNA methyltransferase; HCC, hepatocellular carcinoma; LOH, loss of heterozygosity; MBD, methyl-CpG-binding protein; mRNA, messenger RNA; PanIN, pancreatic intra-epithelial neoplasia; PCR, polymerase chain reaction; PCNA, proliferating cell nuclear antigen; RCC, renal cell carcinoma; STAT, signal transducer and activator of transcription; TCC, transitional cell carcinoma
Received May 2, 2007; revised September 5, 2007; accepted September 12, 2007.
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