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  • Review Article
  • Published:

The fundamental role of epigenetic events in cancer

Nature Reviews Genetics volume 3, pages 415–428 (2002)Cite this article

Key Points

  • Tumour-related genes can be silenced by heritable epigenetic changes that involve DNA-methylation and chromatin-remodelling events.

  • Epigenetic silencing should be regarded as one of the pathways that is necessary to satisfy Knudson's hypothesis that two hits are required for a phenotypic consequence of tumour-suppressor gene loss.

  • Recent advances in the field of chromatin structure are beginning to link the 'histone code' with the DNA 'cytosine-methylation code', which indicates that these two processes are intimately linked.

  • Methylated cytosine contributes directly to the genetic inactivation of tumour-suppressor genes by virtue of its enhanced mutability and by altering how cytosine residues interact with ultraviolet light and aromatic hydrocarbons. Cytosine methylation can also inactivate DNA-repair genes, therefore increasing the rate of mutagenesis.

  • The mechanisms by which changes in DNA methylation are interpreted in normal and malignant cells are being deciphered rapidly. These alterations silence transcriptional initiation but do not block transcriptional elongation.

  • The DNA-methyltransferase enzymes, which establish and maintain DNA-cytosine-methylation patterns, can also act as direct transcriptional repressors and interact with crucial chromatin-remodelling factors. These enzymes cooperate to maintain DNA-methylation patterns, and the roles of these multi-functional proteins are now beginning to be understood.

  • DNA methylation and heterochromatin both have a propensity to spread from one region to another. This gradual spreading process can result in the permanent silencing of genes and presumably takes place when a breakdown occurs in the mechanisms that normally protect CpG islands from the DNA-methyltransferase enzymes.

  • Genes that are silenced by inappropriate promoter hypermethylation can be relatively easily reactivated by treatment with DNA-methylation inhibitors, such as 5-aza nucleosides. New evidence shows that the activities of these inhibitors are enhanced by histone deacetylase inhibitors, which provides further evidence for a close interconnection between chromatin structure and DNA methylation.

  • The altered methylation of CpG islands in DNA can be detected using highly sensitive techniques. This might allow for the development of new technologies to detect cancer cells and to provide prognostic information.

Abstract

Patterns of DNA methylation and chromatin structure are profoundly altered in neoplasia and include genome-wide losses of, and regional gains in, DNA methylation. The recent explosion in our knowledge of how chromatin organization modulates gene transcription has further highlighted the importance of epigenetic mechanisms in the initiation and progression of human cancer. These epigenetic changes — in particular, aberrant promoter hypermethylation that is associated with inappropriate gene silencing — affect virtually every step in tumour progression. In this review, we discuss these epigenetic events and the molecular alterations that might cause them and/or underlie altered gene expression in cancer.

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Figure 1: How epigenetics affects genetics.
Figure 2: A map of the human genome.
Figure 3: Typical chromatin configuration of transcriptionally silent pericentromeric DNA.
Figure 4: A CpG-poor promoter in transcriptionally active and transcriptionally repressed states.
Figure 5: A CpG-rich promoter in transcriptionally active and transcriptionally repressed states.
Figure 6: Progressive methylation changes in epithelial carcinogenesis.

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References

  1. Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 16, 6–21 (2002).An excellent review of mammalian DNA methylation.

    CAS  PubMed  Google Scholar 

  2. Takai, D. & Jones, P. A. Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc. Natl Acad. Sci. USA 99, 3740–3745 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Baylin, S. B. & Herman, J. G. DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet. 16, 168–174 (2000).

    CAS  PubMed  Google Scholar 

  4. Jones, P. A. & Laird, P. W. Cancer epigenetics comes of age. Nature Genet. 21, 163–167 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Esteller, M. et al. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. Cancer Res. 60, 2368–2371 (2000).

    CAS  PubMed  Google Scholar 

  6. Herman, J. G. et al. Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies. Cancer Res. 57, 837–841 (1997).

    CAS  PubMed  Google Scholar 

  7. Burbee, D. G. et al. Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. J. Natl Cancer Inst. 93, 691–699 (2001).

    CAS  PubMed  Google Scholar 

  8. Dammann, R. et al. Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nature Genet. 25, 315–319 (2000).

    CAS  PubMed  Google Scholar 

  9. Herman, J. G. et al. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc. Natl Acad. Sci. USA 91, 9700–9704 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Esteller, M. et al. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J. Natl Cancer Inst. 92, 564–569 (2000).

    CAS  PubMed  Google Scholar 

  11. Esteller, M. et al. Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz–Jeghers syndrome. Oncogene 19, 164–168 (2000).

    CAS  PubMed  Google Scholar 

  12. Hedenfalk, I. et al. Gene-expression profiles in hereditary breast cancer. N. Engl. J. Med. 344, 539–548 (2001).

    CAS  PubMed  Google Scholar 

  13. Van't Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002).

    CAS  Google Scholar 

  14. Knudson, A. G. Chasing the cancer demon. Annu. Rev. Genet. 34, 1–19 (2000).

    CAS  PubMed  Google Scholar 

  15. Myohanen, S. K., Baylin, S. B. & Herman, J. G. Hypermethylation can selectively silence individual p16ink4A alleles in neoplasia. Cancer Res. 58, 591–593 (1998).

    CAS  PubMed  Google Scholar 

  16. Grady, W. M. et al. Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer. Nature Genet. 26, 16–17 (2000).

    CAS  PubMed  Google Scholar 

  17. Esteller, M. et al. DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis. Hum. Mol. Genet. 10, 3001–3007 (2001).

    CAS  PubMed  Google Scholar 

  18. Kane, M. F. et al. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 57, 808–811 (1997).

    CAS  PubMed  Google Scholar 

  19. Herman, J. G. et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc. Natl Acad. Sci. USA 95, 6870–6875 (1998).References 18 and 19 provided an important link between epigenetic and genetic changes in colon cancer. Reference 19 illustrates how demethylation of an aberrantly silenced gene in cancer can restore gene expression and function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nakagawa, H. et al. Age-related hypermethylation of the 5′ region of MLH1 in normal colonic mucosa is associated with microsatellite-unstable colorectal cancer development. Cancer Res. 61, 6991–6995 (2001).

    CAS  PubMed  Google Scholar 

  21. Esteller, M. et al. hMLH1 promoter hypermethylation is an early event in human endometrial tumorigenesis. Am. J. Pathol. 155, 1767–1772 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Esteller, M., Hamilton, S. R., Burger, P. C., Baylin, S. B. & Herman, J. G. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res. 59, 793–797 (1999).

    CAS  PubMed  Google Scholar 

  23. Esteller, M. et al. Promoter hypermethylation of the DNA repair gene O(6)-methylguanine-DNA methyltransferase is associated with the presence of G:C to A:T transition mutations in p53 in human colorectal tumorigenesis. Cancer Res. 61, 4689–4692 (2001).

    CAS  PubMed  Google Scholar 

  24. Wales, M. M. et al. p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. Nature Med. 1, 570–577 (1995).

    CAS  PubMed  Google Scholar 

  25. Huang, T. H., Perry, M. R. & Laux, D. E. Methylation profiling of CpG islands in human breast cancer cells. Hum. Mol. Genet. 8, 459–470 (1999).

    CAS  PubMed  Google Scholar 

  26. Toyota, M. et al. Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification. Cancer Res. 59, 2307–2312 (1999).

    CAS  PubMed  Google Scholar 

  27. Costello, J. F. et al. Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nature Genet. 24, 132–138 (2000).

    CAS  PubMed  Google Scholar 

  28. Gonzalgo, M. L. et al. Identification and characterization of differentially methylated regions of genomic DNA by methylation-sensitive arbitrarily primed PCR. Cancer Res. 57, 594–599 (1997).

    CAS  PubMed  Google Scholar 

  29. Gitan, R. S., Shi, H., Chen, C. M., Yan, P. S. & Huang, T. H. Methylation-specific oligonucleotide microarray: a new potential for high-throughput methylation analysis. Genome Res. 12, 158–164 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Suzuki, H. et al. A genomic screen for genes upregulated by demethylation and HDAC inhibition in human colorectal cancer. Nature Genet. May 6 [epub ahead of print] 2002.

  31. Coulondre, C., Miller, J. H., Farabaugh, P. J. & Gilbert, W. Molecular basis of base substitution hotspots in Escherichia coli. Nature 274, 775–780 (1978).

    CAS  PubMed  Google Scholar 

  32. Rideout, W. M. III, Coetzee, G. A., Olumi, A. F. & Jones, P. A. 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science 249, 1288–1290 (1990).This paper provides an example of how the base methylcytosine provides an endogenous site of mutagenic potential in the coding region of important genes.

    CAS  PubMed  Google Scholar 

  33. Pfeifer, G. P., Tang, M. & Denissenko, M. F. Mutation hotspots and DNA methylation. Curr. Top. Microbiol. Immunol. 249, 1–19 (2000).

    CAS  PubMed  Google Scholar 

  34. Yoon, J. H. et al. Methylated CpG dinucleotides are the preferential targets for G-to-T transversion mutations induced by benzo[a]pyrene diol epoxide in mammalian cells: similarities with the p53 mutation spectrum in smoking-associated lung cancers. Cancer Res. 61, 7110–7117 (2001).

    CAS  PubMed  Google Scholar 

  35. Magewu, A. N. & Jones, P. A. Ubiquitous and tenacious methylation of the CpG site in codon 248 of the p53 gene may explain its frequent appearance as a mutational hotspot in human cancer. Mol. Cell. Biol. 14, 4225–4232 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Feinberg, A. P. & Vogelstein, B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301, 89–92 (1983).

    CAS  PubMed  Google Scholar 

  37. Feinberg, A. P., Gehrke, C. W., Kuo, K. C. & Ehrlich, M. Reduced genomic 5-methylcytosine content in human colonic neoplasia. Cancer Res. 48, 1159–1161 (1988).These two papers outline the presence of DNA hypomethylation in human tumours.

    CAS  PubMed  Google Scholar 

  38. Xu, G. L. et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402, 187–191 (1999).

    CAS  PubMed  Google Scholar 

  39. Okano, M., Bell, D. W., Haber, D. A. & Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247–257 (1999).An important paper that discusses the function of the mammalian DNMTs in establishing and maintaining DNA methylation patterns.

    CAS  PubMed  Google Scholar 

  40. Hansen, R. S. et al. The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc. Natl Acad. Sci. USA 96, 14412–14417 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Qu, G. Z., Grundy, P. E., Narayan, A. & Ehrlich, M. Frequent hypomethylation in Wilms tumors of pericentromeric DNA in chromosomes 1 and 16. Cancer Genet. Cytogenet. 109, 34–39 (1999).

    CAS  PubMed  Google Scholar 

  42. Chen, R. Z., Pettersson, U., Beard, C., Jackson-Grusby, L. & Jaenisch, R. DNA hypomethylation leads to elevated mutation rates. Nature 395, 89–93 (1998).

    CAS  PubMed  Google Scholar 

  43. Chan, M. F. et al. Reduced rates of gene loss, gene silencing, and gene mutation in Dnmt1-deficient embryonic stem cells. Mol. Cell. Biol. 21, 7587–7600 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Kass, S. U., Landsberger, N. & Wolffe, A. P. DNA methylation directs a time-dependent repression of transcription initiation. Curr. Biol. 7, 157–165 (1997).

    CAS  PubMed  Google Scholar 

  45. Wutz, A., Rasmussen, T. P. & Jaenisch, R. Chromosomal silencing and localization are mediated by different domains of Xist RNA. Nature Genet. 30, 167–174 (2002).

    CAS  PubMed  Google Scholar 

  46. Jones, P. A. & Taylor, S. M. Cellular differentiation, cytidine analogs and DNA methylation. Cell 20, 85–93 (1980).This paper was the first to show that 5-azacytidine can induce demethylation of DNA.

    CAS  PubMed  Google Scholar 

  47. Murzina, N., Verreault, A., Laue, E. & Stillman, B. Heterochromatin dynamics in mouse cells: interaction between chromatin assembly factor 1 and HP1 proteins. Mol. Cell 4, 529–540 (1999).

    CAS  PubMed  Google Scholar 

  48. Struhl, K. Histone acetylation and transcriptional regulatory mechanisms. Genes Dev. 12, 599–606 (1998).

    CAS  PubMed  Google Scholar 

  49. Taddei, A., Maison, C., Roche, D. & Almouzni, G. Reversible disruption of pericentric heterochromatin and centromere function by inhibiting deacetylases. Nature Cell Biol. 3, 114–120 (2001).

    CAS  PubMed  Google Scholar 

  50. Bird, A. P. & Wolffe, A. P. Methylation-induced repression – belts, braces, and chromatin. Cell 99, 451–454 (1999).

    CAS  PubMed  Google Scholar 

  51. Jones, P. L. et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nature Genet. 19, 187–191 (1998).

    CAS  PubMed  Google Scholar 

  52. Ng, H. H. et al. MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nature Genet. 23, 58–61 (1999).

    CAS  PubMed  Google Scholar 

  53. Wade, P. A. et al. Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nature Genet. 23, 62–66 (1999).References 51–53 were the first to link DNA methylation with gene silencing by identifying the chromatin-remodelling proteins with which methylcytosine-binding proteins associate.

    CAS  PubMed  Google Scholar 

  54. Bell, A. C. & Felsenfeld, G. Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405, 482–485 (2000).

    CAS  PubMed  Google Scholar 

  55. Hark, A. T. et al. CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature 405, 486–489 (2000).

    CAS  PubMed  Google Scholar 

  56. Mikovits, J. A. et al. Infection with human immunodeficiency virus type 1 upregulates DNA methyltransferase, resulting in de novo methylation of the gamma interferon (IFN-γ) promoter and subsequent downregulation of IFN-γ production. Mol. Cell. Biol. 18, 5166–5177 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Graff, J. R., Herman, J. G., Myohanen, S., Baylin, S. B. & Vertino, P. M. Mapping patterns of CpG island methylation in normal and neoplastic cells implicates both upstream and downstream regions in de novo methylation. J. Biol. Chem. 272, 22322–22329 (1997).

    CAS  PubMed  Google Scholar 

  58. Graff, J. R., Gabrielson, E., Fujii, H., Baylin, S. B. & Herman, J. G. Methylation patterns of the E-cadherin 5′ CpG island are unstable and reflect the dynamic, heterogeneous loss of E-cadherin expression during metastatic progression. J. Biol. Chem. 275, 2727–2732 (2000).

    CAS  PubMed  Google Scholar 

  59. Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).An important review of the latest thinking on the histone code, which marks and/or establishes regions of transcriptionally repressive versus transcriptionally active chromatin.

    CAS  PubMed  Google Scholar 

  60. Bannister, A. J. et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410, 120–124 (2001).

    CAS  PubMed  Google Scholar 

  61. Nakayama, J., Rice, J. C., Strahl, B. D., Allis, C. D. & Grewal, S. I. Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science 292, 110–113 (2001).

    CAS  PubMed  Google Scholar 

  62. Noma, K., Allis, C. D. & Grewal, S. I. Transitions in distinct histone H3 methylation patterns at the heterochromatin domain boundaries. Science 293, 1150–1155 (2001).

    CAS  PubMed  Google Scholar 

  63. Zhang, Y. & Reinberg, D. Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev. 15, 2343–2360 (2001).

    CAS  PubMed  Google Scholar 

  64. Tamaru, H. & Selker, E. U. A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 414, 277–283 (2001).

    CAS  PubMed  Google Scholar 

  65. Jackson, J. P., Lindroth, A. M., Cao, X. & Jacobsen, S. E. Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase. Nature 416, 556–560 (2002).References 64 and 65 provide the exciting concept that a specific site of histone methylation might specify where DNA methylation occurs.

    CAS  PubMed  Google Scholar 

  66. Cameron, E. E., Bachman, K. E., Myohanen, S., Herman, J. G. & Baylin, S. B. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nature Genet. 21, 103–107 (1999).This paper illustrates the synergy between DNA methylation and histone deacetylation in the aberrant silencing of tumour-suppressor genes and the dominant role of DNA methylation.

    CAS  PubMed  Google Scholar 

  67. Nguyen, C. T., Gonzales, F. A. & Jones, P. A. Altered chromatin structure associated with methylation-induced gene silencing in cancer cells: correlation of accessibility, methylation, MeCP2 binding and acetylation. Nucleic Acids Res. 29, 4598–4606 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Magdinier, F. & Wolffe, A. P. Selective association of the methyl-CpG binding protein MBD2 with the silent p14/p16 locus in human neoplasia. Proc. Natl Acad. Sci. USA 98, 4990–4995 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. El-Osta, A., Kantharidis, P., Zalcberg, J. R. & Wolffe, A. P. Precipitous release of methyl-CpG binding protein 2 and histone deacetylase 1 from the methylated human multidrug resistance gene (MDR1) on activation. Mol. Cell. Biol. 22, 1844–1857 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Robertson, K. D. et al. The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res. 27, 2291–2298 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. De Marzo, A. M. et al. Abnormal regulation of DNA methyltransferase expression during colorectal carcinogenesis. Cancer Res. 59, 3855–3860 (1999).

    CAS  PubMed  Google Scholar 

  72. Wu, J. et al. Expression of an exogenous eukaryotic DNA methyltransferase gene induces transformation of NIH 3T3 cells. Proc. Natl Acad. Sci. USA 90, 8891–8895 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Bakin, A. V. & Curran, T. Role of DNA 5-methylcytosine transferase in cell transformation by fos. Science 283, 387–390 (1999).

    CAS  PubMed  Google Scholar 

  74. Laird, P. W. et al. Suppression of intestinal neoplasia by DNA hypomethylation. Cell 81, 197–205 (1995).This paper presented a role for DNMT1 in tumorigenesis and the concept that decreasing the action of this enzyme could be a therapeutic goal for treating cancer.

    CAS  PubMed  Google Scholar 

  75. Fuks, F., Burgers, W. A., Brehm, A., Hughes-Davies, L. & Kouzarides, T. DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nature Genet. 24, 88–91 (2000).

    CAS  PubMed  Google Scholar 

  76. Robertson, K. D. et al. DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nature Genet. 25, 338–342 (2000).

    CAS  PubMed  Google Scholar 

  77. Rountree, M. R., Bachman, K. E. & Baylin, S. B. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nature Genet. 25, 269–277 (2000).

    CAS  PubMed  Google Scholar 

  78. Fuks, F., Burgers, W. A., Godin, N., Kasai, M. & Kouzarides, T. Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription. EMBO J. 20, 2536–2544 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Bachman, K. E., Rountree, M. R. & Baylin, S. B. Dnmt3a and Dnmt3b are transcriptional repressors that exhibit unique localization properties to heterochromatin. J. Biol. Chem. 276, 32282–32287 (2001).References 75–79 report that mammalian DNMTs probably have additional roles in transcriptional silencing by recruiting histone deacetylases, acting as transcriptional repressors and serving as binding platforms for transcriptional co-repressors.

    CAS  PubMed  Google Scholar 

  80. Taddei, A., Roche, D., Sibarita, J. B., Turner, B. M. & Almouzni, G. Duplication and maintenance of heterochromatin domains. J. Cell Biol. 147, 1153–1166 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Liang, G. et al. Cooperativity between DNA methyltransferases in the maintenance methylation of repetitive elements. Mol. Cell. Biol. 22, 480–491 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Velicescu, M. et al. Cell division is required for de novo methylation of CpG islands in bladder cancer cells. Cancer Res. 62, 2378–2384 (2002).

    CAS  PubMed  Google Scholar 

  83. Di Croce, L. et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295, 1079–1082 (2002).

    CAS  PubMed  Google Scholar 

  84. Rhee, I. et al. CpG methylation is maintained in human cancer cells lacking DNMT1. Nature 404, 1003–1007 (2000).

    CAS  PubMed  Google Scholar 

  85. Rhee, I. et al. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 416, 552–556 (2002).References 83–85 report that the DNMTs might act cooperatively in maintaining aberrant gene silencing. Reference 85 provides evidence for epigenetics in the silencing of the tumour-suppressor gene CDKN2A.

    CAS  PubMed  Google Scholar 

  86. Panning, B. & Jaenisch, R. DNA hypomethylation can activate Xist expression and silence X-linked genes. Genes Dev. 10, 1991–2002 (1996).

    CAS  PubMed  Google Scholar 

  87. Jackson-Grusby, L. et al. Loss of genomic methylation causes p53-dependent apoptosis and epigenetic deregulation. Nature Genet. 27, 31–39 (2001).

    CAS  PubMed  Google Scholar 

  88. Sun, F. L. & Elgin, S. C. Putting boundaries on silence. Cell 99, 459–462 (1999).

    CAS  PubMed  Google Scholar 

  89. Turker, M. S. & Bestor, T. H. Formation of methylation patterns in the mammalian genome. Mutat. Res. 386, 119–130 (1997).

    CAS  PubMed  Google Scholar 

  90. Issa, J. P. et al. Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nature Genet. 7, 536–540 (1994).

    CAS  PubMed  Google Scholar 

  91. Issa, J. P. Aging, DNA methylation and cancer. Crit. Rev. Oncol. Hematol. 32, 31–43 (1999).Papers 90 and 91 discuss a possible link between aberrant DNA methylation, ageing and cancer.

    CAS  PubMed  Google Scholar 

  92. Cairns, J. Cancer: Science and Society (W. H. Freeman & Co., San Francisco, California, 1978).

    Google Scholar 

  93. Cameron, E. E., Baylin, S. B. & Herman, J. G. p15(INK4B) CpG island methylation in primary acute leukemia is heterogeneous and suggests density as a critical factor for transcriptional silencing. Blood 94, 2445–2451 (1999).

    CAS  PubMed  Google Scholar 

  94. Greller, L. D., Tobin, F. L. & Poste, G. Tumor heterogeneity and progression: conceptual foundations for modeling. Invasion Metastasis 16, 177–208 (1996).

    CAS  PubMed  Google Scholar 

  95. Fidler, I. J. The biology of cancer metastasis, or 'you cannot fix it if you do not know how it works'. Bioessays 13, 551–554 (1991).

    CAS  PubMed  Google Scholar 

  96. Nuovo, G. J., Plaia, T. W., Belinsky, S. A., Baylin, S. B. & Herman, J. G. In situ detection of the hypermethylation-induced inactivation of the p16 gene as an early event in oncogenesis. Proc. Natl Acad. Sci. USA 96, 12754–12759 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Wong, D. J., Foster, S. A., Galloway, D. A. & Reid, B. J. Progressive region-specific de novo methylation of the p16 CpG island in primary human mammary epithelial cell strains during escape from M(0) growth arrest. Mol. Cell. Biol. 19, 5642–5651 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Kiyono, T. et al. Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature 396, 84–88 (1998).

    CAS  PubMed  Google Scholar 

  99. Issa, J. P., Ahuja, N., Toyota, M., Bronner, M. P. & Brentnall, T. A. Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res. 61, 3573–3577 (2001).

    CAS  PubMed  Google Scholar 

  100. Comijn, J. et al. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol. Cell 7, 1267–1278 (2001).

    CAS  PubMed  Google Scholar 

  101. Mareel, M., Bracke, M. & Van Roy, F. Cancer metastasis: negative regulation by an invasion-suppressor complex. Cancer Detect. Prev. 19, 451–464 (1995).

    CAS  PubMed  Google Scholar 

  102. Cihak, A. Biological effects of 5-azacytidine in eukaryotes. Oncology 30, 405–422 (1974).

    CAS  PubMed  Google Scholar 

  103. Lubbert, M. DNA methylation inhibitors in the treatment of leukemias, myelodysplastic syndromes and hemoglobinopathies: clinical results and possible mechanisms of action. Curr. Top. Microbiol. Immunol. 249, 135–164 (2000).

    CAS  PubMed  Google Scholar 

  104. Lin, X. et al. Reversal of GSTP1 CpG island hypermethylation and reactivation of pi-class glutathione S-transferase (GSTP1) expression in human prostate cancer cells by treatment with procainamide. Cancer Res. 61, 8611–8616 (2001).

    CAS  PubMed  Google Scholar 

  105. Wolf, S. F. & Migeon, B. R. Studies of X chromosome DNA methylation in normal human cells. Nature 295, 667–671 (1982).

    CAS  PubMed  Google Scholar 

  106. Mohandas, T., Sparkes, R. S. & Shapiro, L. J. Reactivation of an inactive X human chromosome: evidence for X inactivation by DNA methylation. Science 211, 393–396 (1981).

    CAS  PubMed  Google Scholar 

  107. Jaenisch, R., Schnieke, A. & Harbers, K. Treatment of mice with 5-azacytidine efficiently activates silent retroviral genomes in different tissues. Proc. Natl Acad. Sci. USA 82, 1451–1455 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Liang, G., Gonzales, F. A., Jones, P. A., Orntoft, T. F. & Thykjaer, T. Analysis of gene induction in human fibroblasts and bladder cancer cells exposed to the methylation inhibitor 5-aza-2′-deoxycytidine. Cancer Res. 62, 961–966 (2002).

    CAS  PubMed  Google Scholar 

  109. Soengas, M. S. et al. Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature 409, 207–211 (2001).

    CAS  PubMed  Google Scholar 

  110. Bender, C. M. et al. Roles of cell division and gene transcription in the methylation of CpG islands. Mol. Cell. Biol. 19, 6690–6698 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Sidransky, D. Emerging molecular markers of cancer. Nature Rev. Cancer 2, 210–219 (2002).

    CAS  Google Scholar 

  112. Esteller, M., Corn, P. G., Baylin, S. B. & Herman, J. G. A gene hypermethylation profile of human cancer. Cancer Res. 61, 3225–3229 (2001).

    CAS  PubMed  Google Scholar 

  113. Adorjan, P. et al. Tumour class prediction and discovery by microarray-based DNA methylation analysis. Nucleic Acids Res. 30, e21 (2002).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

P.A.J. thanks C. Nguyen for help with some of the figures. P.A.J. and S.B.B. are supported by grants from the National Cancer Institute and the National Institute of Environmental Health Sciences. Peter A. Jones is a shareholder and consultant for Epigenomics AG, a company with interests in the development of methylation-based diagnosis and detection technologies. Stephen B. Baylin is a consultant for Tibotech-Virco, which is developing methylation-based diagnosis technologies and is eligible for royalties from the sales of any products that are marketed.

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Authors and Affiliations

  1. Departments of Urology, USC/Norris Comprehensive Cancer Center, Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, MS 8302L, Los Angeles, 90089-9181, California, USA

    Peter A. Jones

  2. Departments of Oncology and Medicine, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, 1650 East Orleans Street, Baltimore, 21231, Maryland, USA

    Stephen B. Baylin

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DATABASES

CancerNet

breast cancer

colon cancer

leukaemia

lung cancer

prostate cancer

LocusLink

ATM

APC

BRCA1

BRCA2

CBX5

CDH1

CDKN2A

CDKN2B

DNMT1

Dnmt1

DNMT3A

Dnmt3a

DNMT3B

Dnmt3b

ESR1

FHIT

FOS

GSTP1

HDAC2

HIC1

Hp1α

MBD1

MBD2

MDR1

MECP2

MGMT

MLH1

MSH2

NF1

NF2

PML

PTCH

PTEN

RARα

RARB

RB1

SMAD4

SMARCA3

SMARCB1

STK11

TIMP3

TP53

TP73

Trp53

VHL

XIST

Medscape DrugInfo

procanamide

Mouse Genome Informatics

min

OMIM

ICF syndrome

promyelocytic leukaemia

FURTHER INFORMATION

Cancer Genetics Web

Encyclopedia of Life Sciences

Cancer

DNA methylation

Guide to Internet Resources for Cancer

Glossary

MICROSATELLITE INSTABILITY

(min). In diploid tumours, genetic instability that is due to a high mutation rate, primarily in short nucleotide repeats. Cancers with the min phenotype are associated with defects in DNA-mismatch-repair genes.

KNUDSON'S TWO-HIT MODEL

In 1971, Alfred Knudson proposed that two successive genetic 'hits' are required to turn a normal cell into a tumour cell and that, in familial cancers, one hit was inherited. Two inactivating 'hits' are therefore required to cause the loss of function of tumour-suppressor genes.

CDKN2A

Two tumour-suppressor transcripts are encoded by the CDKN2A locus. P16INK4A inhibits the cyclin-dependent kinases 4 and 6, blocking them from phosphorylating RB1 and so preventing cells from exiting G1. P14ARF is encoded from an alternative reading frame (arf), helps regulate nuclear location of TP53 and putatively causes cell-cycle arrest at G1 and G2. Loss of heterozygosity of either transcript is associated with cancer.

5-AZA-2′-DEOXYCYTIDINE

A potent and specific inhibitor of DNA methylation.

PERICENTROMERIC HETEROCHROMATIN

The late-replicating, gene-sparse, transcriptionally inactive, condensed chromatin regions that are rich in repeated sequence and occur near the centromeres of chromosomes.

NUCLEOSOME

The fundamental unit into which DNA and histones are packaged in eukaryotic cells. It is the basic structural subunit of chromatin and consists of ∼200 bp of DNA and an octamer of histone proteins.

CHROMODOMAIN

A highly conserved sequence motif that has been identified in various animal and plant species. Chromodomain proteins are often structural components of large macromolecular chromatin complexes or involved in remodelling chromatin structure. Hp1α is a chromodomain-containing protein.

EUCHROMATIN

The lightly staining regions of the nucleus that generally contain decondensed, transcriptionally active regions of the genome.

MYELOSUPPRESSION

The depressed production of blood cells that are derived from the myeloid lineage, including platelets, some leukocytes and erythrocytes. Myelosuppression is a common side effect of many anticancer drugs as they suppress the growth or proliferation of rapidly dividing cells.

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Jones, P., Baylin, S. The fundamental role of epigenetic events in cancer. Nat Rev Genet 3, 415–428 (2002). https://doi.org/10.1038/nrg816

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