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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.

Abstract

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.

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References

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

    Google Scholar 

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

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  14. 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 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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], <http://deainfo.nci.nih.gov/Advisory/ncab/sub-bt/NCABReport_Feb05.pdf> (2005).

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

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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DATABASES

OMIM

colorectal cancer

Wilms tumour

Glossary

Adenoma

A benign epithelial tumour.

Microsatellite

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.

Hypomorph

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

Lymphoma

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.

Polyclonal

Arising from multiple cells.

SCID

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

Astrocytoma

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.

Palindrome

A DNA sequence that is followed by its inverted repeat.

Chaperone

A protein that assists in protein folding.

Monoclonal

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). https://doi.org/10.1038/nrg1748

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