Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The history of cancer epigenetics

Abstract

Since its discovery in 1983, the epigenetics of human cancer has been in the shadows of human cancer genetics. But this area has become increasingly visible with a growing understanding of specific epigenetic mechanisms and their role in cancer, including hypomethylation, hypermethylation, loss of imprinting and chromatin modification. This timeline traces the field from its conception to the present day. It also addresses the genetic basis of epigenetic changes — an emerging area that promises to unite cancer genetics and epigenetics, and might serve as a model for understanding the epigenetic basis of human disease more generally.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Gatekeeper role for loss of imprinting of IGF2 in Wilms tumour.
Figure 2: Co-operative and self-reinforcing organization of the chromatin and DNA-modifying machinery responsible for gene silencing in normal and malignant cells.

References

  1. 1

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

    CAS  Google Scholar 

  2. 2

    Gama-Sosa, M. A. et al. The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res. 11, 6883–6894 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Goelz, S. E., Vogelstein, B., Hamilton, S. R. & Feinberg, A. P. Hypomethylation of DNA from benign and malignant human colon neoplasms. Science 228, 187–190 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    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).

    CAS  PubMed  Google Scholar 

  5. 5

    Strichman-Almashanu, L. Z. et al. A genome-wide screen for normally methylated human CgG islands that can identify novel imprinted genes. Genome Res. 12, 543–554 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Feinberg, A. P. & Vogelstein, B. Hypomethylation of ras oncogenes in primary human cancers. Biochem. Biophys. Res. Commun. 111, 47–54 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    De Smet, C. et al. The activation of human gene MAGE-1 in tumor cells is correlated with genome-wide demethylation. Proc. Natl Acad. Sci. USA 93, 7149–7153 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Cho, B. et al. Promoter hypomethylation of a novel cancer/testis antigen gene CAGE is correlated with its aberrant expression and is seen in premalignant stage of gastric carcinoma. Biochem. Biophys. Res. Commun. 307, 52–63 (2003)

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    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 

  10. 10

    Iacobuzio-Donahue, C. A. et al. Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays. Am. J. Pathol. 162, 1151–1162 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Oshimo, Y. et al. Promoter methylation of cyclin D2 gene in gastric carcinoma. Int. J. Oncol. 23, 1663–1670 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Akiyama, Y., Maesawa, C., Ogasawara, S., Terashima, M. & Masuda, T. Cell-type-specific repression of the maspin gene is disrupted frequently by demethylation at the promoter region in gastric intestinal metaplasia and cancer cells. Am. J. Pathol. 163, 1911–1919 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Cho, M. et al. Hypomethylation of the MN/CA9 promoter and upregulated MN/CA9 expression in human renal cell carcinoma. Br. J. Cancer 85, 563–567 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Nakamura, N. & Takenaga, K. Hypomethylation of the metastasis-associated S100A4 gene correlates with gene activation in human colon adenocarcinoma cell lines. Clin. Exp. Metastasis 16, 471–479 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Badal, V. et al. CpG methylation of human papillomavirus type 16 DNA in cervical cancer cell lines and in clinical specimens: genomic hypomethylation correlates with carcinogenic progression. J. Virol. 77, 6227–6234 (2003).

    PubMed  PubMed Central  Google Scholar 

  16. 16

    De Capoa, A. et al. DNA demethylation is directly related to tumour progression: evidence in normal, pre-malignant and malignant cells from uterine cervix samples. Oncol. Rep. 10, 545–549 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Sato, N. et al. Frequent hypomethylation of multiple genes overexpressed in pancreatic ductal adenocarcinoma. Cancer Res. 63, 4158–4166 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Piyathilake, C. J. et al. Race- and age-dependent alterations in global methylation of DNA in squamous cell carcinoma of the lung (United States). Cancer Causes Control 14, 37–42 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Lengauer, C., Kinzler, K. W. & Vogelstein, B. DNA methylation and genetic instability in colorectal cancer cells. Proc. Natl Acad. Sci. USA 94, 2545–2550 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Pao, M. M. et al. DNA methylator and mismatch repair phenotypes are not mutually exclusive in colorectal cancer cell lines. Oncogene 19, 943–952 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    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  PubMed Central  Google Scholar 

  22. 22

    Cui, H., Horon, I. L., Ohlsson, R., Hamilton, S. R. & Feinberg, A. P. Loss of imprinting in normal tissue of colorectal cancer patients with microsatellite instability. Nature Med. 4, 1276–1280 (1998).

    CAS  PubMed  Google Scholar 

  23. 23

    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  PubMed Central  Google Scholar 

  24. 24

    Yeh, A. et al. Chromosome arm 16q in Wilms tumors: unbalanced chromosomal translocations, loss of heterozygosity, and assessment of the CTCF gene. Genes Chromosomes Cancer 35, 156–163 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    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 

  26. 26

    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  PubMed Central  Google Scholar 

  27. 27

    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).

    CAS  PubMed  Google Scholar 

  28. 28

    Eden, A., Gaudet, F., Waghmare, A. & Jaenisch, R. Chromosomal instability and tumors promoted by DNA hypomethylation. Science 300, 455 (2003).

    CAS  PubMed  Google Scholar 

  29. 29

    Suter, C. M., Martin, D. I. & Ward, R. L. Hypomethylation of L1 retrotransposons in colorectal cancer and adjacent normal tissue. Int. J. Colorectal Dis. 8 Oct 2003 (doi: 10.1007/s00384-003-0539-3).

  30. 30

    Nakayama, M. et al. Hypomethylation status of CpG sites at the promoter region and overexpression of the human MDR1 gene in acute myeloid leukemias. Blood 92, 4296–4307 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Takaguchi, M., Achanzar, W. E., Qu, W., Li, G. & Waalkes, M. P. Effects of cadmium on DNA-(Cytosine-5) methyltransferase activity and DNA methylation status during cadmium-induced cellular transformation. Exp. Cell Res. 286, 355–365 (2003).

    Google Scholar 

  32. 32

    Okoji, R. S., Yu, R. C., Maronpot, R. R. & Froines, J. R. Sodium arsenite administration via drinking water increases genome-wide and Ha-ras DNA hypomethylation in methyl-deficient C57BL/6J mice. Carcinogenesis 23, 777–785 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Li, H. & Minarovits, J. Host cell-dependent expression of latent Epstein–Barr virus genomes: regulation by DNA methylation. Adv. Cancer Res. 89, 133–156 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Heijmans, B. T. et al. A common variant of the methylenetetrahydrofolate reductase gene (1p36) is associated with an increased risk of cancer. Cancer Res. 63, 1249–1253 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Chen, J. et al. A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res. 56, 4862–4864 (1996).

    CAS  Google Scholar 

  36. 36

    Pufulete, M. et al. Folate status, genomic DNA hypomethylation, and risk of colorectal adenoma and cancer: a case control study. Gastroenterology 124, 1240–1248 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Poirier, L. A. Folate deficiency in rats bearing the Walker tumor 256 and the Novikoff hepatoma. Cancer Res. 33, 2109–2113 (1973).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Gibbons, R. J. et al. Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation. Nature Genet. 24, 368–371 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Versteege, I. et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203–206 (1998).

    CAS  Google Scholar 

  40. 40

    Fan, T. et al. Lsh-deficient murine embryonal fibroblasts show reduced proliferation with signs of abnormal mitosis. Cancer Res. 63, 4677–4683 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Saito, Y. et al. Overexpression of a splice variant of DNA methyltransferase 3b, DNMT3b4, associated with DNA hypomethylation on pericentromeric satellite regions during human hepatocarcinogenesis. Proc. Natl Acad. Sci. USA 99, 10060–10065 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Baylin, S. B. et al. DNA methylation patterns of the calcitonin gene in human lung cancers and lymphomas. Cancer Res. 46, 2917–2922 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Greger, V., Passarge, E., Hopping, W., Messmer, E. & Horsthemke, B. Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum. Genet. 83, 155–158 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Sakai, T. et al. Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene. Am. J. Hum. Genet. 48, 880–888 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Ohtani-Fujita, N. et al. CpG methylation inactivates the promoter activity of the human retinoblastoma tumor-suppressor gene. Oncogene 8, 1063–1067 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Greger, V. et al. Frequency and parental origin of hypermethylated RB1 alleles in retinoblastoma. Hum. Genet. 94, 491–496 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Gonzalez-Zulueta, M. et al. Methylation of the 5′ Cpg island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing. Cancer Res. 55, 4531–4535 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Graff, J. R. et al. E-Cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res. 55, 5195–5199 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    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 

  50. 50

    Merlo, A. et al. 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nature Med. 1, 686–692 (1995).

    CAS  Article  Google Scholar 

  51. 51

    Cunningham, J. M. et al. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res. 58, 3455–3460 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Veigl, M. L. et al. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc. Natl Acad. Sci. USA 95, 8698–8702 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Toyota, M. et al. CpG island methylator phenotype in colorectal cancer. Proc. Natl Acad. Sci. USA 96, 8681–8686 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    West, R. W. & Barrett, J. C. Inactivation of a tumor suppressor function in immortal Syrian hamster cells by N-methyl-N′-nitro-N-nitrosoguanidine and by 5-aza-2′-deoxycytidine. Carcinogenesis 14, 285–289 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Rhee, I. et al. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 416, 552–556 (2002).

    CAS  PubMed  Google Scholar 

  56. 56

    Robert, M. F. et al. DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells. Nature Genet. 33, 61–65 (2003).

    CAS  PubMed  Google Scholar 

  57. 57

    Bestor, T. H. Unanswered questions about the role of promoter methylation in carcinogenesis. Ann. NY Acad. Sci. 983, 22–27 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Hajra, K. M., Ji, X. & Fearon, E. R. Extinction of E-cadherin expression in breast cancer via a dominant repression pathway acting on proximal promoter elements. Oncogene 18, 7274–7279 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Bachman, K. E. et al. Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell 3, 89–95 (2003).

    CAS  Google Scholar 

  60. 60

    Clark, S. J. & Melki, J. DNA methylation and gene silencing in cancer: which is the guilty party? Oncogene 21, 5380–5387 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Ehrlich, M. et al. Hypomethylation and hypermethylation of DNA in Wilms tumors. Oncogene 21, 6694–6702 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Van Zee, K. J., Calvano, J. E. & Bisogna, M. Hypomethylation and increased gene expression of p16INK4a in primary and metastatic breast carcinoma as compared to normal breast tissue. Oncogene 16, 2723–2727 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Surani, M. A., Barton, S. C. & Norris, M. L. Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature 308, 548–550 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    McGrath, J. & Solter, D. Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell 37, 179–183 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Kajii, T. & Ohama, K. Androgenetic origin of hydatidiform mole. Nature 268, 633 (1977).

    CAS  PubMed  Google Scholar 

  66. 66

    Linder, D., McCaw, B., Kaiser, X. & Hecht, F. Parthenogenetic origin of benign ovarian teratomas. N. Engl. J. Med. 292, 63–66 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Pal, N. et al. Preferential loss of maternal alleles in sporadic Wilms' tumor. Oncogene 5, 1665–1668 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Schroeder, W. T. et al. Nonrandom loss of maternal chromosome 11 alleles in Wilms tumors. Am. J. Hum. Genet. 40, 413–420 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Scrable, H. et al. A model for embryonal rhabdomyosarcoma tumorigenesis that involves genome imprinting. Proc. Natl Acad. Sci. USA 86, 7480–7484 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Williams, J. C., Brown, K. W., Mott, M. G. & Maitland, N. J. Maternal allele loss in Wilms' tumor. Lancet 1, 283–284 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Brown, K. W., Williams, J. C., Maitland, N. J. & Mott, M. G. Genomic imprinting and the Beckwith–Wiedemann syndrome. Am. J. Hum. Genet. 46, 1000–1001 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Koufos, A. et al. Familial Wiedemann–Beckwith syndrome and a second Wilms tumor locus both map to 11p15.5. Am. J. Hum. Genet. 44, 711–719 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Ping, A. J. et al. Genetic linkage of Beckwith–Wiedemann syndrome to 11p15. Am. J. Hum. Genet. 44, 720–723 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Mannens, M. et al. Parental imprinting of human chromosome region 11p15.3-pter involved in the Beckwith–Wiedemann syndrome and various human neoplasia. Eur. J. Hum. Genet. 2, 3–23 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Zhang, Y. & Tycko, B. Monoallelic expression of the human H19 gene. Nature Genet. 1, 40–44 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Giannoukakis, N., Deal, C., Paquette, J., Goodyer, C. G. & Polychronakos, C. Parental genomic imprinting of the human IGF2 gene. Nature Genet. 4, 98–101 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Ohlsson, R. et al. IGF2 is parentally imprinted during human embryogenesis and in the Beckwith–Wiedemann syndrome. Nature Genet. 4, 94–97 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Rainier, S. et al. Relaxation of imprinted genes in human cancer. Nature 362, 747–749 (1993).

    CAS  PubMed  Google Scholar 

  79. 79

    Ogawa, O. et al. Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms' tumour. Nature 362, 749–751 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Barlow, D. P., Stoger, R., Herrmann, B. G., Saito, K. & Schweifer, N. The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus. Nature 349, 84–87 (1991).

    CAS  PubMed  Google Scholar 

  81. 81

    Bartolomei, M., Zemel, S. & Tilghman, S. M. Parental imprinting of the mouse H19 gene. Nature 351, 153–155 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    DeChiara, T. M., Robertson, E. J. & Efstratiadis, A. Parental imprinting of the mouse insulin-like growth factor-2 gene. Cell 64, 849–859 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Glenn, C. C., Porter, K. A., Jong, M. T., Nicholls, R. D. & Driscoll, D. J. Functional imprinting and epigenetic modification of the human SNRPN gene. Hum Mol. Genet. 2, 2001–2005 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Leff, S. E. et al. Maternal imprinting of the mouse Snrpn gene and conserved linkage homology with the human Prader–Willi syndrome region. Nature Genet. 2, 259–264 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Li, E., Beard, C. & Jaenisch, R. Role for DNA methylation in genomic imprinting. Nature 366, 362–365 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Onyango, P. et al. Sequence and comparative analysis of the mouse 1 megabase region orthologous to the human 11p15 imprinted domain. Genome Res. 10, 1697–1710 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Paulsen, M. et al. Syntenic organization of the mouse distal chromosome 7 imprinting cluster and the Beckwith–Wiedemann syndrome region in chromosome 11p15.5. Hum. Mol. Genet. 7, 1149–1159 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Qian, N. et al. The IPL gene on chromosome 11p15.5 is imprinted in humans and mice and is similar to TDAG51, implicated in Fas expression and apoptosis. Hum. Mol. Genet. 6, 2021–2029 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Dao, D. et al. IMPT1, an imprinted gene similar to polyspecific transporter and multi-drug resistance genes. Hum. Mol. Genet. 7, 597–608 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Moulton, T. et al. Epigenetic lesions at the H19 locus in Wilms' tumour patients. Nature Genet. 7, 440–447 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Steenman, M. J. et al. Loss of imprinting of IGF2 is linked to reduced expression and abnormal methylation of H19 in Wilms' tumour. Nature Genet 7, 433–439 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Okamoto, K., Morison, I. M., Taniguchi, T. & Reeve, A. E. Epigenetic changes at the insulin-like growth factor II/H19 locus in developing kidney is an early event in Wilms tumorigenesis. Proc. Natl Acad. Sci. USA 94, 5367–5371 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Hao, Y., Crenshaw, T., Moulton, T., Newcomb, E. & Tycko, B. Tumor-suppressor activity of H19 RNA. Nature 365, 764–767 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Christofori, G., Naik, P. & Hanahan, D. Deregulation of both imprinted and expressed alleles of the insulin-like growth factor 2 gene during β-cell tumorigenesis. Nature Genet. 10, 196–201 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Christofori, G., Naik, P. & Hanahan, D. A second signal supplied by insulin-like growth factor II in oncogene-induced tumorigenesis. Nature 369, 414–418 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Ravenel, J. D. et al. Loss of imprinting of insulin-like growth factor-II (IGF2) gene in distinguishing specific biologic subtypes of Wilms tumor. J. Natl Cancer Inst. 93, 1698–1703 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Sanson, M., Leuraud, P., Marie, Y., Delattre, J. Y. & Hoang-Xuan, K. Preferential loss of paternal 19q, but not 1p, alleles in oligodendrogliomas. Ann. Neurol. 52, 105–107 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Maegawa, S. et al. Epigentic silencing of PEG3 gene expression in human glioma cell lines. Mol. Carcinogen. 31, 1–9 (2001).

    CAS  Google Scholar 

  99. 99

    Jenkins, R. B., Curran, W., Scott, C. B. & Cairncross, G. Pilot evaluation of 1p and 19q deletions in anaplastic oligodendrogliomas collected by a national cooperative cancer treatment group. Am. J. Clin. Oncol. 24, 506–508 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Li, L. et al. Regulation of maternal behavior and offspring growth by paternally expressed Peg3. Science 284, 330–333 (1999).

    CAS  Google Scholar 

  101. 101

    Kohda, T. et al. Tumour suppressor activity of human imprinted gene PEG3 in a glioma cell line. Genes Cells 6, 237–247 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Maegawa, S. et al. Epigenetic silencing of PEG3 gene expression in human glioma cell lines. Mol. Carcinogen. 31, 1–9 (2001).

    CAS  Google Scholar 

  103. 103

    Caron, H. et al. Chromosome bands 1p35-36 contain two distinct neuroblastoma tumor suppressor loci, one of which is imprinted. Genes Chromosomes Cancer 30, 168–174 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Morison, I. M., Ellis, L. M., Teague, L. R. & Reeve, A. E. Preferential loss of maternal 9p alleles in childhood acute lymphoblastic leukemia. Blood 99, 375–377 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Yuan, J. et al. Aberrant methylation and silencing of ARHI, an imprinted tumor suppressor gene in which the function is lost in breast cancers. Cancer Res. 63, 4174–4180 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Lee, M. P. et al. Loss of imprinting of a paternally expressed transcript, with antisense orientation to KVLQT1, occurs frequently in Beckwith–Wiedemann syndrome and is independent of insulin-like growth factor II imprinting. Proc. Natl Acad. Sci. USA 96, 5203–5208 (1999).

    CAS  PubMed  Google Scholar 

  107. 107

    Smilinich, N. J. et al. A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith–Wiedemann syndrome. Proc. Natl Acad. Sci. USA 96, 8064–8069 (1999).

    CAS  PubMed  Google Scholar 

  108. 108

    Buschhausen, G., Wittig, B., Graessmann, M. & Graessmann, A. Chromatin structure is required to block transcription of the methylated herpes simplex virus thymidine kinase gene. Proc. Natl Acad. Sci. USA 84, 1177–1181 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Keshet, I., Lieman-Hurwitz, J. & Cedar, H. DNA methylation affects the formation of active chromatin. Cell 44, 535–543 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Lewis, J. D. et al. Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 69, 905–914 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Meehan, R. R., Lewis, J. D. & Bird, A. P. Characterization of MeCP2, a vertebrate DNA binding protein with affinity for methylated DNA. Nucleic Acids Res. 20, 5085–5092 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

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

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Nan, X. et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386–389 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    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  PubMed Central  Google Scholar 

  115. 115

    Wade, P. A. et al. Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nature Genet. 23, 62–66 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Roder, K. et al. Transcriptional repression by Drosophila methyl-CpG-binding proteins. Mol. Cell Biol. 20, 7401–7409 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Strahl, B. D., Ohba, R., Cook, R. G. & Allis, C. D. Methylation of histone H3 at lysine 4 is highly conserved and correlates with transcriptionally active nuclei in Tetrahymena. Proc. Natl Acad. Sci. USA 96, 14967–14972 (1999).

    CAS  PubMed  Google Scholar 

  119. 119

    Nguyen, C. T. et al. Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2′-deoxycytidine. Cancer Res. 62, 6456–6461 (2002).

    CAS  PubMed  Google Scholar 

  120. 120

    Yoder, J. A., Walsh, C. P. & Bestor, T. H. Cytosine methylation and the ecology of intragenomic parasites. Trends Genet. 13, 335–340 (1997).

    CAS  Google Scholar 

  121. 121

    Ahmad, K. & Henikoff, S. Histone H3 variants specify modes of chromatin assembly. Proc. Natl Acad. Sci. USA 99, S16477–S16484 (2002).

    Google Scholar 

  122. 122

    Bannister, A. J., Schneider, R. & Kouzarides, T. Histone methylation: dynamic or static? Cell 109, 801–806 (2002).

    CAS  PubMed  Google Scholar 

  123. 123

    Lobanenkov, V. V., Nicolas, R. H., Plumb, M. A., Wright, C. A. & Goodwin, G. H. Sequence-specific DNA-binding proteins which interact with (G + C)-rich sequences flanking the chicken c-myc gene. Eur. J. Biochem. 159, 181–188 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Holmgren, C. et al. CpG methylation regulates the Igf2/H19 insulator. Curr. Biol. 11, 1128–1130 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    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 

  126. 126

    Bell, A. C., West, A. G. & Felsenfeld, G. The protein CTCF is required for the enhancer blocking activity of vertebrate insulators. Cell 98, 387–396 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Cui, H. et al. Loss of imprinting of insulin-like growth factor-II in Wilms' tumor commonly involves altered methylation but not mutations of CTCF or its binding site. Cancer Res. 61, 4947–4950 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Cui, H. et al. Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2. Cancer Res. 62, 6442–6446 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Nakagawa, H. et al. Loss of imprinting of the insulin-like growth factor II gene occurs by biallelic methylation in a core region of H19-associated CTCF-binding sites in colorectal cancer. Proc. Natl Acad. Sci. USA 98, 591–596 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Loukinov, D. I. et al. BORIS, a novel male germ-line-specific protein associated with epigenetic reprogramming events, shares the same 11-zinc-finger domain with CTCF, the insulator protein involved in reading imprinting marks in the soma. Proc. Natl Acad. Sci. USA 99, 6806–6811 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Varambally, S. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    DeBaun, M. R. & Tucker, M. A. Risk of cancer during the first four years of life in children from The Beckwith–Wiedemann Syndrome Registry. J. Pediatr. 132, 398–400 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Weksberg, R., Shen, D. R., Fei, Y. L., Song, Q. L., & Squire, J. Disruption of insulin-like growth factor 2 imprinting in Beckwith–Wiedemann syndrome. Nature Genet. 5, 143–150 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Hatada, I. et al. An imprinted gene p57KIP2 is mutated in Beckwith–Wiedemann syndrome. Nature Genet. 14, 171–1733 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Tycko, B. Genomic imprinting and cancer. Results Probl. Cell. Differ. 25, 133–169 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Engel, J. R. et al. Epigenotype-phenotype correlations in Beckwith–Wiedemann syndrome. J. Med. Genet. 37, 921–926 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Bliek, J. et al. Increased tumour risk for BWS patients correlates with aberrant H19 and not KCNQ1OT1 methylation: occurrence of KCNQ1OT1 hypomethylation in familial cases of BWS. Hum. Mol. Genet. 10, 467–476 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Weksberg, R. et al. Tumor development in the Beckwith–Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1. Hum. Mol. Genet. 10, 2989–3000 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    DeBaun, M. R. et al. Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith–Wiedemann syndrome with cancer and birth defects. Am. J. Hum. Genet. 70, 604–611 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    DeBaun, M. R., Niemitz, E. L. & Feinberg, A. P. Association of in vitro fertilization with Beckwith–Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am. J. Hum. Genet. 72, 156–160 (2002).

    PubMed  PubMed Central  Google Scholar 

  141. 141

    Maher, E. R. et al. Beckwith–Wiedemann syndrome and assisted reproduction technology (ART). J. Med. Genet. 40, 62–64 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Cui, H. et al. Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science 299, 6442–6446 (2003).

    Google Scholar 

  143. 143

    Belinsky, S. A. et al. Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. Proc. Natl Acad. Sci. USA 95, 11891–11896 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Sandovici, I. et al. Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions. Hum. Mol. Genet. 12, 1569–1578 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Laird, P. W. et al. Suppression of intestinal neoplasia by DNA hypomethylation. Cell 81, 197–205 (1995).

    CAS  Google Scholar 

  146. 146

    Gaudet, F. et al. Induction of tumors in mice by genomic hypomethylation. Science 300, 489–492 (2003).

    CAS  PubMed  Google Scholar 

  147. 147

    Chen, W. Y. et al. Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors. Nature Genet. 33, 197–202 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Ziemin-van der Poel, S. et al. Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemias. Proc. Natl Acad. Sci. USA 88, 10735–10739 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149

    Tkachuk, D. C., Kohler, S. & Cleary, M. L. Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell 71, 691–700 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150

    Gu, Y. et al. The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene. Cell 71, 701–708 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Nakamura, T. et al. ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Mol. Cell 10, 1119–1128 (2002).

    CAS  PubMed  Google Scholar 

  152. 152

    El-Deiry, W. S. et al. High expression of the DNA methyltransferase gene characterizes human neoplastic cells and progression stages of colon cancer. Proc. Natl Acad. Sci. USA 88, 3470–3474 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Lee, P. J. et al. Limited upregulation of DNA methyltransferase in human colon cancer reflecting increased cell proliferation. Proc. Natl Acad. Sci. USA 93, 10366–10370 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154

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

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155

    Eads, C. A. et al. CpG island hypermethylation in human colorectal tumors is not associated with DNA methyltransferase overexpression. Cancer Res. 59, 2302–2306 (1999).

    CAS  PubMed  Google Scholar 

  156. 156

    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  PubMed Central  Google Scholar 

  157. 157

    Esteller, M. et al. Cancer epigenetics and methylation. Science 297, 1807–1808 (2002).

    PubMed  PubMed Central  Google Scholar 

  158. 158

    Hajra, K. M., Chen, D. Y. & Fearon, E. R. The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res. 62, 1613–1618 (2002).

    CAS  Google Scholar 

  159. 159

    Dunaief, J. L. et al. The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest. Cell 79, 119–130 (1994).

    CAS  Google Scholar 

  160. 160

    Luo, R. X., Postigo, A. A. & Dean, D. C. Rb interacts with histone deacetylase to repress transcription. Cell 92, 463–473 (1998).

    CAS  PubMed  Google Scholar 

  161. 161

    Magnaghi-Jaulin, L. et al. Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature 391, 601–605 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162

    Dahiya, A., Wong, S., Gonzalo, S., Gavin, M. & Dean, D. C. Linking the Rb and polycomb pathways. Mol. Cell 8, 557–569 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. 163

    Pradhan, S. & Kim, G. D. The retinoblastoma gene product interacts with maintenance human DNA (cytosine-5) methyltransferase and modulates its activity. EMBO J. 21, 779–788 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164

    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  PubMed Central  Google Scholar 

  165. 165

    Steele-Perkins, G. et al. Tumor formation and inactivation of RIZ1, an Rb-binding member of a nuclear protein-methyltransferase superfamily. Genes Dev. 15, 2250–2262 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166

    Hsiao, W. -L., Gattoni-Celli, S. & Weinstein, I. B. Effects of 5-azacytidine on the progressive nature of cell transformation. Mol. Cell. Biol. 5, 1800–1803 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167

    Taylor, S. M. & Jones, P. A. Multiple new phenotypes induced in 10T 1/2 and 3T3 cells treated with 5-azacytidine. Cell 17, 771–779 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168

    Daskalakis, M. et al. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-aza-2′-deoxycytidine (decitabine) treatment. Blood 100, 2957–2964 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169

    Juttermann, R., Li, E. & Jaenisch, R. Toxicity of 5-aza-2′-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation. Proc. Natl Acad. Sci. USA 91, 11797–11801 (1994).

    CAS  PubMed  Google Scholar 

  170. 170

    Cheng, J. C. et al. Inhibition of DNA methylation and reactivation of silenced genes by zebularine. J. Natl Cancer Inst. 95, 399–409 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171

    Barletta, J. M., Rainier, S. & Feinberg, A. P. Reversal of loss of imprinting in tumor cells by 5-aza-2′-deoxycytidine. Cancer Res. 57, 48–50 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172

    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).

    CAS  Google Scholar 

  173. 173

    Shaker, S., Bernstein, M., Momparler, L. F. & Momparler, R. L. Preclinical evaluation of antineoplastic activity of inhibitors of DNA methylation (5-aza-2′-deoxycytidine) and histone deacetylation (trichostatin A, depsipeptide) in combination against myeloid leukemic cells. Leuk. Res. 27, 437–444 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174

    Eden, A., Gaudet, F. & Jaenisch, R. Response to comment on “Chromosomal instability and tumors promoted by dna hypomethylation” and “Induction of tumors in mice by genomic hypomethylation”. Science 302, 1153 (2003).

    CAS  Google Scholar 

  175. 175

    Yang, A. S., Estecio, M. R., Garcia–Manero, G., Kantarjian, H. M. & Issa, J. P. Comment on “Chromosomal instability and tumors promoted by DNA hypomethylation” and “Induction of tumors in nice by genomic hypomethylation”. Science 302, 1153 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176

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

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177

    Wolf, S. F., Jolly, D. J., Lunnen, K. D., Friedmann, T., & Migeon, B. R. Methylation of the hypoxanthine phosphoribosyltransferase locus on the human X chromosome: implications for X-chromosome inactivation. Proc. Natl Acad. Sci. USA 81, 2806–2810 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178

    Antequera, F., Macleod, D. & Bird, A. P. Specific protection of methylated CpGs in mammalian nuclei. Cell 58, 509–517 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 179

    Hansen, R. S. & Gartler, S. M. 5-azacytidine-induced reactivation of the human X chromosome-linked PGK1 gene is associated with a large region of cytosine demethylation in the 5′ CpG island. Proc. Natl Acad. Sci. USA 87, 4174–4178 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180

    Jeppesen, P. & Turner, B. M. The inactive X chromosome in female mammals is distinguished by a lack of histone H4 acetylation, a cytogenetic marker for gene expression. Cell 74, 281–289 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank E. Fearon, B. Vogelstein, R. Ohlsson and G. Klein for reading the manuscript. This work was supported by grants from the National Institutes of Health. We apologize in advance for any errors of omission or commission.

Author information

Affiliations

Authors

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Cancer.gov

acute lymphoblastic leukaemias

acute myelogenous leukaemia

cervical cancer

colon cancer

liver cancer

lung cancer

malignant rhabdoid tumour

pancreatic cancer

stomach cancer

uterine cancer

Wilms tumour

LocusLink

ALL1

ARHI

ATRX

BORIS

CAGE

calcitonin

CDKN1C

CTCF

DNMT1

DNMT3A

DNMT3B

EZH2

H19

HP1

HRAS

IGF2

LIT1

Lsh

MBD2

MDR1

MECP2

MLH1

Nf1

PEG3

PML

RARα

RARB2

RB

SLUG

SNF5

SUV39H1

Trp53

WT1

FURTHER INFORMATION

DNA Methylation Society

Imprinted Gene Catalogue

Imprinting

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Feinberg, A., Tycko, B. The history of cancer epigenetics. Nat Rev Cancer 4, 143–153 (2004). https://doi.org/10.1038/nrc1279

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing