It is abundantly clear that mutations, whether inherited throughthe germ line or, more commonly, arising in somatic tissueslater in life,1 can cause cancer. These mutations abnormallyenhance the function of some genes, the oncogenes, or causeother genes, the tumor-suppressor genes, to lose function.1Students of the neoplastic process, however, have argued fordecades about whether the initiation and progression of cancerare due only to mutations or, as well, to epigenetic changesthat are not caused by alterations in the primary nucleotidesequence of DNA. Recent investigations have proved not onlythat both views are correct, but . . . [Full Text of this Article]
What is DNA Methylation?
The Molecular Role of DNA Methylation
Maintenance of Genes in a Transcriptionally Silent State
CpG Islands
DNA Methylation in Cancer
Losses of DNA Methylation in Cancer
Gains in DNA Methylation in Gene Promoters
Biologic Effects of Promoter Hypermethylation
Proteins That Mediate DNA Methylation
DNMTS
Methyl Cytosine–Binding Proteins, Nucleosomes, and Histone Acetylation
Gene Silencing and Chromatin
Nucleosomes
Histone Acetylation
The Histone Code
Clinical Implications of Gene Silencing in Cancer
Reversal of Gene Silencing to Prevent or Treat Cancer
Inhibitors of Histone Deacetylases
Inhibition of DNMTs
Hypermethylation of CpG Islands as a Molecular Marker for Cancer
Early Detection of Cancer
Confounding Issues
Hypermethylation and Prognosis in Cancer
Source Information
From the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (J.G.H.) and the Departments of Oncology (J.G.H.) and Medicine (S.B.B.), Johns Hopkins Medical Institutions, Baltimore.
Address reprint requests to Dr. Herman at hermanji@jhmi.edu or to Dr. Baylin at sbaylin@jhmi.edu.
Related Letters:
Gene Silencing
Kirk J., Herman J. G., Baylin S. B.
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N Engl J Med 2004;
350:947-948, Feb 26, 2004.
Correspondence
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(2008). T{beta}RIII suppresses non-small cell lung cancer invasiveness and tumorigenicity. Carcinogenesis
29: 528-535
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Potapova, A., Hoffman, A. M., Godwin, A. K., Al-Saleem, T., Cairns, P.
(2008). Promoter Hypermethylation of the PALB2 Susceptibility Gene in Inherited and Sporadic Breast and Ovarian Cancer. Cancer Res.
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Fan, J., Stanfield, J., Guo, Y., Karam, J. A., Frenkel, E., Sun, X., Hsieh, J.-T.
(2008). Effect of Trans-2,3-Dimethoxycinnamoyl Azide on Enhancing Antitumor Activity of Romidepsin on Human Bladder Cancer. Clin. Cancer Res.
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Liu, S., Liu, Z., Xie, Z., Pang, J., Yu, J., Lehmann, E., Huynh, L., Vukosavljevic, T., Takeki, M., Klisovic, R. B., Baiocchi, R. A., Blum, W., Porcu, P., Garzon, R., Byrd, J. C., Perrotti, D., Caligiuri, M. A., Chan, K. K., Wu, L.-C., Marcucci, G.
(2008). Bortezomib induces DNA hypomethylation and silenced gene transcription by interfering with Sp1/NF-{kappa}B-dependent DNA methyltransferase activity in acute myeloid leukemia. Blood
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Rodriguez, J., Vives, L., Jorda, M., Morales, C., Munoz, M., Vendrell, E., Peinado, M. A.
(2008). Genome-wide tracking of unmethylated DNA Alu repeats in normal and cancer cells. Nucleic Acids Res
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Palii, S. S., Van Emburgh, B. O., Sankpal, U. T., Brown, K. D., Robertson, K. D.
(2008). DNA Methylation Inhibitor 5-Aza-2'-Deoxycytidine Induces Reversible Genome-Wide DNA Damage That Is Distinctly Influenced by DNA Methyltransferases 1 and 3B. Mol. Cell. Biol.
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Ongenaert, M., Van Neste, L., De Meyer, T., Menschaert, G., Bekaert, S., Van Criekinge, W.
(2008). PubMeth: a cancer methylation database combining text-mining and expert annotation. Nucleic Acids Res
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Jin, Z., Hamilton, J. P., Yang, J., Mori, Y., Olaru, A., Sato, F., Ito, T., Kan, T., Cheng, Y., Paun, B., David, S., Beer, D. G., Agarwal, R., Abraham, J. M., Meltzer, S. J.
(2008). Hypermethylation of the AKAP12 Promoter is a Biomarker of Barrett's-Associated Esophageal Neoplastic Progression. Cancer Epidemiol. Biomarkers Prev.
17: 111-117
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Yamashita, K., Kim, M. S., Park, H. L., Tokumaru, Y., Osada, M., Inoue, H., Mori, M., Sidransky, D.
(2008). HOP/OB1/NECC1 Promoter DNA Is Frequently Hypermethylated and Involved in Tumorigenic Ability in Esophageal Squamous Cell Carcinoma. Mol Cancer Res
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Carvalho, A. L., Jeronimo, C., Kim, M. M., Henrique, R., Zhang, Z., Hoque, M. O., Chang, S., Brait, M., Nayak, C. S., Jiang, W.-W., Claybourne, Q., Tokumaru, Y., Lee, J., Goldenberg, D., Garrett-Mayer, E., Goodman, S., Moon, C.-s., Koch, W., Westra, W. H., Sidransky, D., Califano, J. A.
(2008). Evaluation of Promoter Hypermethylation Detection in Body Fluids as a Screening/Diagnosis Tool for Head and Neck Squamous Cell Carcinoma. Clin. Cancer Res.
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Jacinto, F. V., Ballestar, E., Ropero, S., Esteller, M.
(2007). Discovery of Epigenetically Silenced Genes by Methylated DNA Immunoprecipitation in Colon Cancer Cells. Cancer Res.
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Linhart, H. G., Lin, H., Yamada, Y., Moran, E., Steine, E. J., Gokhale, S., Lo, G., Cantu, E., Ehrich, M., He, T., Meissner, A., Jaenisch, R.
(2007). Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing. Genes Dev.
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Fini, L., Selgrad, M., Fogliano, V., Graziani, G., Romano, M., Hotchkiss, E., Daoud, Y. A., De Vol, E. B., Boland, C. R., Ricciardiello, L.
(2007). Annurca Apple Polyphenols Have Potent Demethylating Activity and Can Reactivate Silenced Tumor Suppressor Genes in Colorectal Cancer Cells. J. Nutr.
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Zhang, C., Li, K., Wei, L., Li, Z., Yu, P., Teng, L., Wu, K., Zhu, J.
(2007). p300 expression repression by hypermethylation associated with tumour invasion and metastasis in oesophageal squamous cell carcinoma. J. Clin. Pathol.
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Jin, Z., Olaru, A., Yang, J., Sato, F., Cheng, Y., Kan, T., Mori, Y., Mantzur, C., Paun, B., Hamilton, J. P., Ito, T., Wang, S., David, S., Agarwal, R., Beer, D. G., Abraham, J. M., Meltzer, S. J.
(2007). Hypermethylation of Tachykinin-1 Is a Potential Biomarker in Human Esophageal Cancer. Clin. Cancer Res.
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