The epigenetic progenitor origin of human cancer

Key Points

  • Cancer is fundamentally a disease of stem cells; we argue that the epigenome is a logical target for early events in carcinogenesis, given that stem cells are defined epigenetically and that epigenetic alterations in cancer modify stem/progenitor cell properties.

  • An epigenetic disruption of progenitor cells might be a common early event in human cancer.

  • Epigenetic alterations include global hypomethylation, site-specific hypomethylation and hypermethylation, and chromatin modification that is linked to tumour-suppressor-gene silencing and oncogene activation.

  • Epigenetic changes also promote chromosomal instability.

  • Cancer is proposed to involve three steps: an epigenetic alteration of stem cells, a gatekeeper mutation, and genetic instability during tumour progression.

  • Epigenetic changes, including loss of imprinting, are found in normal cells of patients with cancer and are associated with cancer risk.

  • We propose that cancer stem cells arise from misregulation of 'tumour-progenitor genes', which can include stem cell regulatory genes, imprinted genes, DNA deaminases and chromatin modifying genes.

  • The epigenetic progenitor model can help to explain tumour latency, progression, heterogeneity and environmental effects in cancer.

  • The model suggests that greater attention be paid to the apparently normal cells of patients with cancer or who are at risk of cancer, as they might be crucial targets for epigenetic alteration, and might be an important target for chemoprevention and screening.


Cancer is widely perceived as a heterogeneous group of disorders with markedly different biological properties, which are caused by a series of clonally selected genetic changes in key tumour-suppressor genes and oncogenes. However, recent data suggest that cancer has a fundamentally common basis that is grounded in a polyclonal epigenetic disruption of stem/progenitor cells, mediated by 'tumour-progenitor genes'. Furthermore, tumour cell heterogeneity is due in part to epigenetic variation in progenitor cells, and epigenetic plasticity together with genetic lesions drives tumour progression. This crucial early role for epigenetic alterations in cancer is in addition to epigenetic alterations that can substitute for genetic variation later in tumour progression. Therefore, non-neoplastic but epigenetically disrupted stem/progenitor cells might be a crucial target for cancer risk assessment and chemoprevention.

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Figure 1: The clonal genetic model of cancer.
Figure 2: The epigenetic progenitor model of cancer.
Figure 3: The epigenetic progenitor model in the context of a stem cell niche.


  1. 1

    Pitot, H. C. Fundamentals of Oncology (Marcel Dekker, New York, 1986).

  2. 2

    Boveri, T. & Boveri, M. The Origin of Malignant Tumors (Williams and Wilkins, Baltimore, 1929).

  3. 3

    Sawyers, C. Targeted cancer therapy. Nature 432, 294–297 (2004).

  4. 4

    Feinberg, A. P. & Tycko, B. The history of cancer epigenetics. Nature Rev. Cancer 4, 143–153 (2004).

  5. 5

    Schmid, M., Haaf, T. & Grunert, D. 5-Azacytidine-induced undercondensations in human chromosomes. Hum. Genet. 67, 257–263 (1984).

  6. 6

    Eden, A., Gaudet, F., Waghmare, A. & Jaenisch, R. Chromosomal instability and tumors promoted by DNA hypomethylation. Science 300, 455 (2003). A mouse DNA methyltransferase I knockout supports a causal role for global hypomethylation in cancer, which is mediated in part by increased recombination.

  7. 7

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

  8. 8

    Holm, T. M. et al. Global loss of imprinting leads to widespread tumorigenesis in adult mice. Cancer Cell 8, 275–285 (2005). A mouse transient DNA methyltransferase I knockout supports a causal role for loss of imprinting in cancer.

  9. 9

    Nishigaki, M. et al. Discovery of aberrant expression of R-RAS by cancer-linked DNA hypomethylation in gastric cancer using microarrays. Cancer Res. 65, 2115–2124 (2005). A good example of CpG hypomethylation leading to oncogene activation.

  10. 10

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

  11. 11

    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).

  12. 12

    Cho, M. et al. Activation of the MN/CA9 gene is associated with hypomethylation in human renal cell carcinoma cell lines. Mol. Carcinog. 27, 184–189 (2000).

  13. 13

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

  14. 14

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

  15. 15

    Jones, P. A. & Baylin, S. B. The fundamental role of epigenetic events in cancer. Nature Rev. Genet. 3, 415–428 (2002).

  16. 16

    Herman, J. G. & Baylin, S. B. Gene silencing in cancer in association with promoter hypermethylation. N. Engl. J. Med. 349, 2042–2054 (2003).

  17. 17

    Bjornsson, H. T., Fallin, M. D. & Feinberg, A. P. An integrated epigenetic and genetic approach to common human disease. Trends Genet. 20, 350–358 (2004).

  18. 18

    Nowell, P. C. The clonal nature of neoplasia. Cancer Cells 1, 29–30 (1989).

  19. 19

    US National Cancer Advisory Board Working Group on Biomedical Technology. Recommendation for a Human Cancer Genome Project. Report to National Cancer Advisory Board [online], <> (2005).

  20. 20

    Rowley, J. D. The Philadelphia chromosome translocation. A paradigm for understanding leukemia. Cancer 65, 2178–2184 (1990).

  21. 21

    Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).

  22. 22

    de la Chapelle, A. Genetic predisposition to colorectal cancer. Nature Rev. Cancer 4, 769–780 (2004).

  23. 23

    Kaelin, W. G. Jr. The von Hippel–Lindau tumor suppressor gene and kidney cancer. Clin. Cancer Res. 10, S6290—S6295 (2004).

  24. 24

    Druker, B. J. et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells. Nature Med. 2, 561–566 (1996).

  25. 25

    Welm, A. L., Kim, S., Welm, B. E. & Bishop, J. M. MET and MYC cooperate in mammary tumorigenesis. Proc. Natl Acad. Sci. USA 102, 4324–4329 (2005).

  26. 26

    Kim, S. J. et al. Reduced c-Met expression by an adenovirus expressing a c-Met ribozyme inhibits tumorigenic growth and lymph node metastases of PC3-LN4 prostate tumor cells in an orthotopic nude mouse model. Clin. Cancer Res. 9, 5161–5170 (2003).

  27. 27

    Yang, J. et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927–939 (2004).

  28. 28

    Tachimori, A. et al. Up regulation of ICAM-1 gene expression inhibits tumour growth and liver metastasis in colorectal carcinoma. Eur. J. Cancer 41, 1802–1810 (2005).

  29. 29

    Wang, T. L. et al. Prevalence of somatic alterations in the colorectal cancer cell genome. Proc. Natl Acad. Sci. USA 99, 3076–3080 (2002).

  30. 30

    Egger, G., Liang, G., Aparicio, A. & Jones, P. A. Epigenetics in human disease and prospects for epigenetic therapy. Nature 429, 457–463 (2004).

  31. 31

    Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 16, 6–21 (2002).

  32. 32

    Brandeis, M. et al. Sp1 elements protect a CpG island from de novo methylation. Nature 371, 435–438 (1994).

  33. 33

    Feinberg, A. P. & Vogelstein, B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301, 89–92 (1983). The first report that documents widespread hypomethylation in human cancer.

  34. 34

    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).

  35. 35

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

  36. 36

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

  37. 37

    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).

  38. 38

    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).

  39. 39

    Hiltunen, M. O. et al. Hypermethylation of the APC (adenomatous polyposis coli) gene promoter region in human colorectal carcinoma. Int. J. Cancer 70, 644–648 (1997).

  40. 40

    Suzuki, H. et al. Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nature Genet. 36, 417–422 (2004).

  41. 41

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

  42. 42

    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).

  43. 43

    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).

  44. 44

    Wu, H. et al. Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis. Nature (in the press).

  45. 45

    Yamada, Y. et al. Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis. Proc. Natl Acad. Sci. USA 102, 13580–13585 (2005).

  46. 46

    Cui, H. et al. Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science 299, 1753–1755 (2003). The authors provide evidence that epigenetic change in normal cells is linked to increased risk of human cancer.

  47. 47

    Sakatani, T. et al. Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice. Science 307, 1976–1978 (2005). The authors use a mouse model to demonstrate the causal role of LOI and involvement of stem cells in predisposing to colon cancer.

  48. 48

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

  49. 49

    Stirzaker, C., Song, J. Z., Davidson, B. & Clark, S. J. Transcriptional gene silencing promotes DNA hypermethylation through a sequential change in chromatin modifications in cancer cells. Cancer Res. 64, 3871–3877 (2004).

  50. 50

    Mutskov, V. & Felsenfeld, G. Silencing of transgene transcription precedes methylation of promoter DNA and histone H3 lysine 9. EMBO J. 23, 138–149 (2004). This article shows that hypermethylation of promoters arises secondarily to transcriptional inactivation.

  51. 51

    Wolffe, A. Chromatin: Structure and Function (Academic, San Diego, 1995).

  52. 52

    Luger, K., Mader, A. W., Richmond, R. K., Sargent, D. F. & Richmond, T. J. Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 389, 251–260 (1997).

  53. 53

    Ringrose, L. & Paro, R. Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu. Rev. Genet. 38, 413–443 (2004).

  54. 54

    Freitas, M. A., Sklenar, A. R. & Parthun, M. R. Application of mass spectrometry to the identification and quantification of histone post-translational modifications. J Cell Biochem 92, 691–700 (2004).

  55. 55

    Brower-Toland, B. et al. Specific contributions of histone tails and their acetylation to the mechanical stability of nucleosomes. J Mol Biol 346, 135–46 (2005).

  56. 56

    Lachner, M., O'Carroll, D., Rea, S., Mechtler, K. & Jenuwein, T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116–120 (2001).

  57. 57

    Turner, B. M. Cellular memory and the histone code. Cell 111, 285–291 (2002).

  58. 58

    Hess, J. L. Mechanisms of transformation by MLL. Crit. Rev. Eukaryot. Gene Expr. 14, 235–254 (2004).

  59. 59

    Sellers, W. R. & Loda, M. The EZH2 polycomb transcriptional repressor — a marker or mover of metastatic prostate cancer? Cancer Cell 2, 349–350 (2002).

  60. 60

    Fraga, M. F. et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nature Genet. 37, 391–400 (2005). The authors provide evidence that epigenome-wide changes, in particular histone modifications, are characteristic of nearly all tumours examined, revealing an unexpected connection between epigenetics and cancer.

  61. 61

    Malik, H. S. & Henikoff, S. Phylogenomics of the nucleosome. Nature Struct. Biol. 10, 882–891 (2003).

  62. 62

    Tomonaga, T. et al. Overexpression and mistargeting of centromere protein-A in human primary colorectal cancer. Cancer Res. 63, 3511–3516 (2003).

  63. 63

    Feinberg, A. P. in The Genetic Basis of Human Cancer (eds Vogelstein, B. & Kinzler, K. W.) 43–55 (McGraw-Hill, New York, 2002).

  64. 64

    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).

  65. 65

    Woodson, K. et al. Loss of insulin-like growth factor-II imprinting and the presence of screen-detected colorectal adenomas in women. J. Natl Cancer Inst. 96, 407–410 (2004).

  66. 66

    Nakanishi, H. et al. Loss of imprinting of PEG1/MEST in lung cancer cell lines. Oncol. Rep. 12, 1273–1278 (2004).

  67. 67

    Sato, N., Matsubayashi, H., Abe, T., Fukushima, N. & Goggins, M. Epigenetic down-regulation of CDKN1C/p57KIP2 in pancreatic ductal neoplasms identified by gene expression profiling. Clin. Cancer Res. 11, 4681–4688 (2005).

  68. 68

    Yu, Y. et al. NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas. Proc. Natl Acad. Sci. USA 96, 214–219 (1999).

  69. 69

    Kang, M. J. et al. Loss of imprinting and elevated expression of wild-type p73 in human gastric adenocarcinoma. Clin. Cancer Res. 6, 1767–1771 (2000).

  70. 70

    Hanada, M., Delia, D., Aiello, A., Stadtmauer, E. & Reed, J. C. bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood 82, 1820–1828 (1993).

  71. 71

    Nakagawa, T. et al. DNA hypomethylation on pericentromeric satellite regions significantly correlates with loss of heterozygosity on chromosome 9 in urothelial carcinomas. J. Urol. 173, 243–246 (2005).

  72. 72

    Pardal, R., Clarke, M. F. & Morrison, S. J. Applying the principles of stem-cell biology to cancer. Nature Rev. Cancer 3, 895–902 (2003).

  73. 73

    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).

  74. 74

    Sachs, L. Hematopoietic growth and differentiation factors and the reversibility of malignancy: cell differentiation and by-passing of genetic defects in leukemia. Med. Oncol. Tumor Pharmacother. 3, 165–176 (1986).

  75. 75

    Lotem, J. & Sachs, L. Epigenetics wins over genetics: induction of differentiation in tumor cells. Semin. Cancer Biol. 12, 339–346 (2002).

  76. 76

    Yuspa, S. H. Molecular and cellular basis for tumor promotion in mouse skin. Princess Takamatsu Symp. 14, 315–326 (1983).

  77. 77

    Lorincz, M. C., Schubeler, D., Hutchinson, S. R., Dickerson, D. R. & Groudine, M. DNA methylation density influences the stability of an epigenetic imprint and Dnmt3a/b-independent de novo methylation. Mol. Cell Biol. 22, 7572–7580 (2002).

  78. 78

    Holst, C. R. et al. Methylation of p16INK4a promoters occurs in vivo in histologically normal human mammary epithelia. Cancer Res. 63, 1596–1601 (2003). This paper demonstrates that epigenetic lesions, that is, DNA hypermethylation, in normal breast tissue, are common in healthy women.

  79. 79

    Crawford, Y. G. et al. Histologically normal human mammary epithelia with silenced p16INK4a overexpress COX-2, promoting a premalignant program. Cancer Cell 5, 263–273 (2004).

  80. 80

    Hochedlinger, K. et al. Reprogramming of a melanoma genome by nuclear transplantation. Genes Dev. 18, 1875–1885 (2004).

  81. 81

    Kim, C. F. et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121, 823–835 (2005).

  82. 82

    Singh, S. et al. Identification of human brain tumour initiating cells. Nature 432, 396–401 (2004). This paper demonstrates that a small subpopulation of stem cells in a brain tumour propagates the cancer phenotype when serially transmitted from mouse to mouse.

  83. 83

    Zhu, Y. et al. Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell 8, 119–130 (2005).

  84. 84

    Michor, F. et al. Dynamics of chronic myeloid leukaemia. Nature 435, 1267–1270 (2005).

  85. 85

    Ren, R. Mechanisms of BCR–ABL in the pathogenesis of chronic myelogenous leukaemia. Nature Rev. Cancer 5, 172–183 (2005).

  86. 86

    Maitra, A. et al. Genomic alterations in cultured human embryonic stem cells. Nature Genet. 37, 1099–1103 (2005).

  87. 87

    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).

  88. 88

    Olumi, A. F. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999).

  89. 89

    Karhadkar, S. S. et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431, 707–712 (2004).

  90. 90

    Schreiber, S. L. & Bernstein, B. E. Signaling network model of chromatin. Cell 111, 771–778 (2002).

  91. 91

    Li, E., Bestor, T. H. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915–926 (1992).

  92. 92

    Pham, P., Bransteitter, R. & Goodman, M. F. Reward versus risk: DNA cytidine deaminases triggering immunity and disease. Biochemistry 44, 2703–2715 (2005).

  93. 93

    Beale, R. C. et al. Comparison of the differential context-dependence of DNA deamination by APOBEC enzymes: correlation with mutation spectra in vivo. J. Mol. Biol. 337, 585–596 (2004).

  94. 94

    Okazaki, I. M. et al. Constitutive expression of AID leads to tumorigenesis. J. Exp. Med. 197, 1173–1181 (2003).

  95. 95

    Pasqualucci, L. et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412, 341–346 (2001).

  96. 96

    Nussenzweig, M. C. & Alt, F. W. Antibody diversity: one enzyme to rule them all. Nature Med. 10, 1304–1305 (2004).

  97. 97

    Petersen-Mahrt, S. DNA deamination in immunity. Immunol. Rev. 203, 80–97 (2005). This article points out that the similarity between the range in mutations of APOBEC-class deaminases and of gatekeeper mutations in cancer indicates that misregulation of these enzymes has a causal role in cancer.

  98. 98

    Nichols, J. et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95, 379–391 (1998).

  99. 99

    Hanna, L. A., Foreman, R. K., Tarasenko, I. A., Kessler, D. S. & Labosky, P. A. Requirement for Foxd3 in maintaining pluripotent cells of the early mouse embryo. Genes Dev. 16, 2650–2661 (2002).

  100. 100

    Chambers, I. et al. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 113, 643–655 (2003).

  101. 101

    Ezeh, U. I., Turek, P. J., Reijo, R. A. & Clark, A. T. Human embryonic stem cell genes OCT4, NANOG, STELLAR, and GDF3 are expressed in both seminoma and breast carcinoma. Cancer 104, 2255–2265 (2005).

  102. 102

    Monk, M. & Holding, C. Human embryonic genes re-expressed in cancer cells. Oncogene 20, 8085–8091 (2001). This paper describes how genes that encode stemness functions are often overexpressed in human tumours.

  103. 103

    Varambally, S. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002). The authors propose a potential mechanism for epigenetic silencing in cancer that does not directly involve DNA methylation.

  104. 104

    Cha, T. L. et al. Akt-mediated phosphorylation of EZH2 suppresses methylation of lysine 27 in histone H3. Science 310, 306–310 (2005).

  105. 105

    Yoshiura, K. et al. Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas. Proc. Natl Acad. Sci. USA 92, 7416–7419 (1995).

  106. 106

    Rattis, F. M., Voermans, C. & Reya, T. Wnt signaling in the stem cell niche. Curr. Opin. Hematol. 11, 88–94 (2004).

  107. 107

    Ruiz i Altaba, A., Sanchez, P. & Dahmane, N. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nature Rev. Cancer 2, 361–372 (2002).

  108. 108

    Sapienza, C. Imprinted gene expression, transplantation medicine, and the 'other' human embryonic stem cell. Proc. Natl Acad. Sci. USA 99, 10243–10245 (2002).

  109. 109

    Sancho, E., Batlle, E. & Clevers, H. Signaling pathways in intestinal development and cancer. Annu. Rev. Cell Dev. Biol. 20, 695–723 (2004).

  110. 110

    Yamashita, Y., Jones, D. & Fuller, M. Orientation of asymmetric stem cell division by the APC tumor suppressor and centrosome. Science 301, 1547–1550 (2003).

  111. 111

    Hirohashi, S. Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. Am. J. Pathol. 153, 333–339 (1998).

  112. 112

    Singal, R., Tu, Z. J., Vanwert, J. M., Ginder, G. D. & Kiang, D. T. Modulation of the connexin26 tumor suppressor gene expression through methylation in human mammary epithelial cell lines. Anticancer Res. 20, 59–64 (2000).

  113. 113

    Futreal, P. A. et al. A census of human cancer genes. Nature Rev. Cancer 4, 177–183 (2004).

  114. 114

    Fearon, E. R. in The Genetic Basis of Human Cancer (eds Vogelstein, B. & Kinzler, K. W.) 197–206 (McGraw-Hill, New York, 2002).

  115. 115

    Lengauer, C., Kinzler, K. W. & Vogelstein, B. Genetic instabilities in human cancers. Nature 396, 643–649 (1998).

  116. 116

    Ohlsson, R. et al. Epigenetic variability and the evolution of human cancer. Adv. Cancer Res. 88, 145–168 (2003).

  117. 117

    Artandi, S. E. et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406, 641–645 (2000).

  118. 118

    Sharpless, N. E. & DePinho, R. A. Telomeres, stem cells, senescence, and cancer. J. Clin. Invest. 113, 160–168 (2004).

  119. 119

    Tanaka, H., Bergstrom, D. A., Yao, M. C. & Tapscott, S. J. Widespread and nonrandom distribution of DNA palindromes in cancer cells provides a structural platform for subsequent gene amplification. Nature Genet. 37, 320–327 (2005).

  120. 120

    Tomonaga, T. et al. Centromere protein H is up-regulated in primary human colorectal cancer and its overexpression induces aneuploidy. Cancer Res. 65, 4683–4689 (2005). The authors show that experimental misregulation of a centromere protein causes aneuploidy, indicating that the common elevation of centromere proteins in cancer underlies chromosome instability seen in cancer.

  121. 121

    Kirschmann, D. A. et al. Down-regulation of HP1Hsα expression is associated with the metastatic phenotype in breast cancer. Cancer Res. 60, 3359–3363 (2000).

  122. 122

    Kuzmichev, A., Jenuwein, T., Tempst, P. & Reinberg, D. Different EZH2-containing complexes target methylation of histone H1 or nucleosomal histone H3. Mol. Cell 14, 183–193 (2004).

  123. 123

    Rutherford, S. L. & Lindquist, S. Hsp90 as a capacitor for morphological evolution. Nature 396, 336–342 (1998).

  124. 124

    Rutherford, S. L. & Henikoff, S. Quantitative epigenetics. Nature Genet. 33, 6–8 (2003).

  125. 125

    Sollars, V. et al. Evidence for an epigenetic mechanism by which HSP90 acts as a capacitor for morphological evolution. Nature Genet. 33, 70–74 (2003). The authors use a sensitive phenotypic assay to show that when the chaperone protein Hsp90 is mutated or inhibited, highly inbred flies show unexpected epigenetic variation.

  126. 126

    Berenblum, I. in General Pathology (ed. Florey, H.) (Saunders, Philadelphia, 1962).

  127. 127

    Klein, G. Epigenetics: surveillance team against cancer. Nature 434, 150 (2005).

  128. 128

    Wilson, M. J., Shivapurkar, N. & Poirier, L. A. Hypomethylation of hepatic nuclear DNA in rats fed with a carcinogenic methyl-deficient diet. Biochem. J. 218, 987–990 (1984). This is an early study showing that dietary methylation deficiency alone can cause cancer in animals.

  129. 129

    Poirier, L. A. The effects of diet, genetics and chemicals on toxicity and aberrant DNA methylation: an introduction. J. Nutr. 132, S2336–S2339 (2002).

  130. 130

    Pogribny, I. P. & James, S. J. De novo methylation of the p16INK4A gene in early preneoplastic liver and tumors induced by folate/methyl deficiency in rats. Cancer Lett. 187, 69–75 (2002).

  131. 131

    Giovannucci, E. et al. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J. Natl Cancer Inst. 85, 875–884 (1993).

  132. 132

    Hamamoto, R. et al. SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nature Cell Biol. 6, 731–740 (2004).

  133. 133

    Ruden, D. M., Xiao, L., Garfinkel, M. D. & Lu, X. Hsp90 and environmental impacts on epigenetic states: a model for the trans-generational effects of diethylstibesterol on uterine development and cancer. Hum. Mol. Genet. 14, R149–R155 (2005).

  134. 134

    Ohlsson, R. et al. Mosaic allelic insulin-like growth factor 2 expression patterns reveal a link between Wilms' tumorigenesis and epigenetic heterogeneity. Cancer Res. 59, 3889–3892 (1999).

  135. 135

    Miranti, C. K. & Brugge, J. S. Sensing the environment: a historical perspective on integrin signal transduction. Nature Cell Biol. 4, e83–e90 (2002).

  136. 136

    Mueller, M. M. & Fusenig, N. E. Friends or foes — bipolar effects of the tumour stroma in cancer. Nature Rev. Cancer 4, 839–849 (2004).

  137. 137

    Hendrix, M. J., Seftor, E. A., Hess, A. R. & Seftor, R. E. Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nature Rev. Cancer 3, 411–421 (2003).

  138. 138

    Fisher, B. et al. Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer. N. Engl. J. Med. 328, 1581–1586 (1993).

  139. 139

    Esteller, M. DNA methylation and cancer therapy: new developments and expectations. Curr. Opin. Oncol. 17, 55–60 (2005).

  140. 140

    Jouvenot, Y. et al. Targeted regulation of imprinted genes by synthetic zinc-finger transcription factors. Gene Ther. 10, 513–522 (2003).

  141. 141

    Poy, M. N. et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432, 226–230 (2004).

  142. 142

    Aaltonen, L. A. et al. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N. Engl. J. Med. 338, 1481–1487 (1998).

  143. 143

    Claus, E. B., Petruzella, S., Matloff, E. & Carter, D. Prevalence of BRCA1 and BRCA2 mutations in women diagnosed with ductal carcinoma in situ. JAMA 293, 964–969 (2005).

  144. 144

    Luo, Z., Ronai, D. & Scharff, M. D. The role of activation-induced cytidine deaminase in antibody diversification, immunodeficiency, and B-cell malignancies. J. Allergy Clin. Immunol. 114, 726–735 (2004).

  145. 145

    Garcia-Echeverria, C. et al. In vivo antitumor activity of NVP-AEW541 — A novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell 5, 231–239 (2004).

  146. 146

    Hu M, et al. Distinct epigenetic changes in the stromal cells of breast cancers. Nature Genet. 37, 899–905 (2005).

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We thank A. Gondor, P. Onyango, S. Petersen-Mahrt, B. Vogelstein, H. Bjornsson and C. Iacobuzio-Donahue for helpful comments. This article is largely focused on the idea of early epigenetic events in stem cells before tumours are apparent. For this reason we have referred the reader to several excellent reviews for detailed discussions of later events in tumorigenesis, and apologize to authors whose work we were unable to discuss owing to space limitations. Work discussed here was supported by a US National Institutes of Health grant to A.F.

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Correspondence to Andrew P. Feinberg.

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colorectal cancer

Wilms tumour



A benign epithelial tumour.


A class of repetitive DNA that is made up of repeats that are 2–8 nucleotides in length. They can be highly polymorphic and are frequently used as molecular markers in population genetics studies.


A mutant allele that has reduced function, or an organism that carries such a mutation.


A tumour of the lymphoid system.

Genomic imprinting

The parent-of-origin-specific silencing of a specific allele of a gene; loss of imprinting of IGF2 increases cancer risk and shifts the balance of normal intestinal epithelium to a less differentiated state.


Arising from multiple cells.


Severe combined immunodeficiency disorder. Mice that have this disorder are used as hosts for tumour xenografts.


An early stage brain tumour.

Stem/progenitor cells

Stem cells are pluripotent cells that have an unlimited capacity for self-renewal, but limited replication frequency, that live within a tissue-specific compartment or niche. Tissue-specific progenitor cells are derived from stem cells and have a limited capacity for self-renewal.


A DNA sequence that is followed by its inverted repeat.


A protein that assists in protein folding.


Arising from a single cell.

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Feinberg, A., Ohlsson, R. & Henikoff, S. The epigenetic progenitor origin of human cancer. Nat Rev Genet 7, 21–33 (2006).

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