Cancer and Metastasis Reviews

, Volume 23, Issue 1–2, pp 29–39

Epigenetic changes in colorectal cancer



Epigenetic silencing is now recognized as a ‘third pathway’ in Knudson's model of tumor-suppressor gene inactivation in cancer and can affect gene function without genetic changes. DNA methylation within gene promoters and alterations in histone modifications appear to be primary mediators of epigenetic inheritance in cancer cells. For selected genes, epigenetic changes are tightly related to neoplastic transformation in colorectal cancers (CRCs). In the colon, aberrant DNA methylation arises very early, initially in normal appearing mucosa, and may be part of the age-related field defect observed in sporadic CRCs. Aberrant methylation also contributes to later stages of colon cancer formation and progression through a hypermethylator phenotype termed CpG Island Methylator Phenotype (CIMP), which appears to be a defining event in about half of all sporadic tumors. CIMP+ CRCs are distinctly characterized by pathology, clinical and molecular genetic features. Histone modifications, recently recognized as a ‘histone code’ that affects chromatin structure and gene expression also play an important role in the establishment of gene silencing during tumorigenesis. DNA methylation and histone H3 lysine 9 hypoacetylation and methylation appear to form a mutually reinforcing silencing loop that contributes to tumor-suppressor gene inactivation in CRCs. Understanding epigenetic alterations as a driving force in neoplasia opens new fields of research in epidemiology, risk assessment, and treatment in CRCs.

colorectal cancer epigenetics DNA methylation CpG island methylator phenotype histones 


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  1. 1.
    Jemal A, Thomas A, Murray T, Thun M: Cancer statistics. CA Cancer J Clin 52: 23–47, 2002Google Scholar
  2. 2.
    Kinzler KW, Vogelstein B: Lessons form hereditary colorectal cancer. Cell 87: 159–170, 1996Google Scholar
  3. 3.
    Jones PA, Laird PW: Cancer epigenetics comes of age. Nat Genet 21: 163–167, 1999Google Scholar
  4. 4.
    Issa JP: The epigenetics of colorectal cancer. Ann NY Acad Sci 910: 140–153, 2000Google Scholar
  5. 5.
    Bestor TH: The DNA methyltransferases of mammals. Hum Mol Genet 9: 2395–2402, 2000Google Scholar
  6. 6.
    Li E, Bestor TH, Jaenisch R: Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69: 915–926, 1992Google Scholar
  7. 7.
    Bird AP, Wolffe AP: Methylation-induced repression-belts, braces, and chromatin. Cell 99: 451–454, 1999Google Scholar
  8. 8.
    Sakai T, Toguchida J, Ohtani N, Yandell DW, Rapaport JM, Dryja TP: Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene. Am J Hum Genet 48: 880–888, 1991Google Scholar
  9. 9.
    Santini V, Kantarjian HM, Issa JP: Changes in DNA methylation in neoplasia: Pathophysiology and therapeutic implications. Ann Intern Med 134: 573–586, 2001Google Scholar
  10. 10.
    Jenuwein T, Allis CD: Translating the histone code. Science 293: 1074–1080, 2001Google Scholar
  11. 11.
    Turker MS: The establishment and maintenance of DNA methylation patterns in mouse somatic cells. Semin Cancer Biol 9: 329–337, 1999Google Scholar
  12. 12.
    Cross SH, Bird AP: CpG islands and genes. Curr Opin Genet Dev 5: 309–314, 1995Google Scholar
  13. 13.
    Jones PA, Takai D: The role of DNA methylation in mammalian epigenetics. Science 293: 1068–1070, 2001Google Scholar
  14. 14.
    Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JPJ: Alterations in DNA methylation-A fundamental aspect of neoplasia. Adv Cancer Res 72: 141–196, 1998Google Scholar
  15. 15.
    Boyes J, Bird A: Repression of genes by DNA methylation depends on CpG density and promoter strength: Evidence for involvement of a methyl-CpG binding protein. EMBO J 11: 327–333, 1992Google Scholar
  16. 16.
    Ehrlich M: DNA hypomethylation, cancer, the immunode ficiency, centromeric region instability, facial anomalies syndrome and chromosomal rearrangements. J Nutr 132: 2424S–2429S, 2002Google Scholar
  17. 17.
    Okano M, Bell DW, Haber DA, Li E: DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99: 247–257, 1999Google Scholar
  18. 18.
    Chan MF, van Amerongen R, Nijjar T, Cuppen E, Jones PA, Laird PW: Reduced rates of gene loss, gene silencing, and gene mutation in Dnmt1-deficient embryonic stem cells. Mol Cell Biol 21: 7587–7600, 2001Google Scholar
  19. 19.
    Yoder JA, Walsh CP, Bestor TH: Cytosine methylation and the ecology of intragenomic parasites. Trends Genet 13: 335–340, 1997Google Scholar
  20. 20.
    Herman JG, Merlo A, Mao L, Lapidus RG, Issa JP, Davidson NE, Sidransky D, Baylin SB: Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res 55: 4525–4530, 1995Google Scholar
  21. 21.
    Robertson KD, Jones PA: The human ARF cell cycle regulatory gene promoter is a CpG island which can be silenced by DNA methylation and down-regulated by wildtype p53. Mol Cell Biol 18: 6457–6473, 1998Google Scholar
  22. 22.
    Sherr CJ: The INK4a/ARF network in tumor suppression. Nat Rev Mol Cell Biol 2: 731–737, 2001Google Scholar
  23. 23.
    Shen L, Kondo Y, Hamilton SR, Rashid A, Issa JP: p14ARF methylation in human colon cancer is associated with microsatellite instability and wild-type p53. Gastroenterology. In Press, 2003Google Scholar
  24. 24.
    Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, Jessup JM, Kolodner R: Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repairdefective human tumor cell lines. Cancer Res 57: 808–811, 1997Google Scholar
  25. 25.
    Costello JF, Futscher BW, Tano K, Graunke DM, Pieper RO: Graded methylation in the promoter and body of the o6-methylguanine dna methyltransferase (mgmt) gene correlates with mgmt expression in human glioma cells. J Biol Chem 269: 17228–17237, 1994Google Scholar
  26. 26.
    Esteller M, Sparks A, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, Gonzalez S, Tarafa G, Sidransky D, Meltzer SJ, Baylin SB, Herman JG: Analysis of adenomatous polyposis coli promoter hypermethylation in human cancer. Cancer Res 60: 4366–4371, 2000Google Scholar
  27. 27.
    Young J, Biden KG, Simms LA, Huggard P, Karamatic R, Eyre HJ, Sutherland GR, Herath N, Barker M, Anderson GJ, Fitzpatrick DR, Ramm GA, Jass JR, Leggett BA: HPP1: A transmembrane protein-encoding gene commonly methylated in colorectal polyps and cancers. Proc Natl Acad Sci USA 98: 265–270, 2001Google Scholar
  28. 28.
    Liang G, Robertson KD, Talmadge C, Sumegi J, Jones PA: The gene for a novel transmembrane protein containing epidermal growth factor and follistatin domains is frequently hypermethylated in human tumor cells. Cancer Res 60: 4907–4912, 2000Google Scholar
  29. 29.
    Du Y, Carling T, Fang W, Piao Z, Sheu JC, Huang S: Hypermethylation in human cancers of the RIZ1 tumor suppressor gene, a member of a histone/protein methyltransferase superfamily. Cancer Res 61: 8094–8099, 2001Google Scholar
  30. 30.
    Moinova HR, Chen WD, Shen L, Smiraglia D, Olechnowicz J, Ravi L, Kasturi L, Myeroff L, Plass C, Parsons R, Minna J, Willson JK, Green SB, Issa JP, Markowitz SD: HLTF gene silencing in human colon cancer. Proc Natl Acad Sci USA 99: 4562–4567, 2002Google Scholar
  31. 31.
    Toyota M, Shen L, Ohe-Toyota M, Hamilton SR, Sinicrope FA, Issa JP: Aberrant methylation of the Cyclooxygenase 2 CpG island in colorectal tumors. Cancer Res 60: 4044–4048, 2000Google Scholar
  32. 32.
    Devereux TR, Horikawa I, Anna CH, Annab LA, Afshari CA, Barrett JC: DNA methylation analysis of the promoter region of the human telomerase reverse transcriptase (hTERT) gene. Cancer Res 59: 6087–6090, 1999Google Scholar
  33. 33.
    Issa JP, Vertino PM, Wu J, Sazawal S, Celano P, Nelkin BD, Hamilton SR, Baylin SB: Increased cytosine DNAmethyltransferase activity during colon cancer progression. J Natl Cancer Inst 85: 1235–1240, 1993Google Scholar
  34. 34.
    Lee PJ, Washer LL, Law DJ, Boland CR, Horon IL, Feinberg AP: Limited up-regulation of DNA methyltransferase in human colon cancer reflecting increased cell proliferation. Proc Natl Acad Sci USA 93: 10366–10370, 1996Google Scholar
  35. 35.
    Eads CA, Danenberg KD, Kawakami K, Saltz LB, Danenberg PV, Laird PW: CpG island hypermethylation in human colorectal tumors is not associated with DNA methyltransferase overexpression. Cancer Res 59: 2302–2306, 1999Google Scholar
  36. 36.
    Issa JPJ: Aging, DNA methylation, and cancer. Crit Rev Oncol Hematol 32: 31–43, 1999Google Scholar
  37. 37.
    Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson NE, Baylin SB: Methylation of the oestrogen receptor CpG island links aging and neoplasia in human colon. Nat Genet 7: 536–540, 1994Google Scholar
  38. 38.
    Issa JPJ, Vertino PM, Boehm CD, Newsham IF, Baylin SB: Switch from mono-allelic to bi-allelic human IGF2 promoter methylation during aging and carcinogenesis. Proc Natl Acad Sci USA 93: 11757–11762, 1996Google Scholar
  39. 39.
    Ahuja N, Li Q, Mohan AL, Baylin SB, Issa JPJ: Aging and DNA methylation in colorectal mucosa and cancer. Cancer Res 58: 5489–5494, 1998Google Scholar
  40. 40.
    Toyota M, Issa JP: CpG island methylator phenotypes in aging and cancer. Semin Cancer Biol 9: 349–357, 1999Google Scholar
  41. 41.
    Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JPJ: CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA 96: 8681–8686, 1999Google Scholar
  42. 42.
    Chan AO, Broaddus RR, Houlihan PS, Issa JP, Hamilton SR, Rashid A: CpG island methylation in aberrant crypt foci of the colorectum. Am J Pathol 160: 1823–1830, 2002Google Scholar
  43. 43.
    Issa JP, Ahuja N, Toyota M, Bronner MP, Brentnall TA: Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res 61: 3573–3577, 2001Google Scholar
  44. 44.
    Shen L, Ahuja N, Shen Y, Habib NA, Toyota M, Rashid A, Issa JP: DNA methylation and environmental exposures in human hepatocellular carcinoma. J Natl Cancer Inst 94: 755–761, 2002Google Scholar
  45. 45.
    Eads CA, Lord RV, Wickramasinghe K, Long TI, Kurumboor SK, Bernstein L, Peters JH, DeMeester SR, DeMeester TR, Skinner KA, Laird PW: Epigenetic patterns in the progression of esophageal adenocarcinoma. Cancer Res 61: 3410–3418, 2001Google Scholar
  46. 46.
    Yatabe Y, Tavare S, Shibata D: Investigating stem cells in human colon by using methylation patterns. Proc Natl Acad Sci USA 98: 10839–10844, 2001Google Scholar
  47. 47.
    Nakagawa H, Nuovo GJ, Zervos EE, Martin EW Jr., Salovaara R, Aaltonen LA, de la CA: Age-related hypermethylation of the 50 region of MLH1 in normal colonic mucosa is associated with microsatellite-unstable colorectal cancer development. Cancer Res 61: 6991–6995, 2001Google Scholar
  48. 48.
    Issa JP: Epigenetic variation and human disease. J Nutr 132: 2388S–2392S, 2002Google Scholar
  49. 49.
    Whitehall VL, Wynter CV, Walsh MD, Simms LA, Purdie D, Pandeya N, Young J, Meltzer SJ, Leggett BA, Jass JR: Morphological and molecular heterogeneity within nonmicrosatellite instability-high colorectal cancer. Cancer Res 62: 6011–6014, 2002Google Scholar
  50. 50.
    van Rijnsoever M, Grieu F, Elsaleh H, Joseph D, Iacopetta B: Characterisation of colorectal cancers showing hypermethylation at multiple CpG islands. Gut 51: 797–802, 2002Google Scholar
  51. 51.
    Toyota M, Kopecky KJ, Toyota MO, Jair KW, Willman CL, Issa JP: Methylation profiling in acute myeloid leukemia. Blood 97: 2823–2829, 2001Google Scholar
  52. 52.
    Ueki T, Toyota M, Sohn T, Yeo CJ, Issa JP, Hruban RH, Goggins M: Hypermethylation of multiple genes in pancreatic adenocarcinoma. Cancer Res 60: 1835–1839, 2000Google Scholar
  53. 53.
    Toyota M, Ahuja N, Suzuki H, Itoh F, Ohe-Toyota M, Imai K, Baylin SB, Issa JP: Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype. Cancer Res 59: 5438–5442, 1999Google Scholar
  54. 54.
    Garcia-Manero G, Daniel J, Smith TL, Kornblau SM, Lee MS, Kantarjian HM, Issa JP: DNA methylation of multiple promoter-associated CpG islands in adult acute lymphocytic leukemia. Clin Cancer Res 8: 2217–2224, 2002Google Scholar
  55. 55.
    Strathdee G, Appleton K, Illand M, Millan DW, Sargent J, Paul J, Brown R: Primary ovarian carcinomas display multiple methylator phenotypes involving known tumor suppressor genes. Am J Pathol 158: 1121–1127, 2001Google Scholar
  56. 56.
    Toyota M, Ohe-Toyota M, Ahuja N, Issa JP: Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype. Proc Natl Acad Sci USA 97: 710–715, 2000Google Scholar
  57. 57.
    Malkhosyan SR, Yamamoto H, Piao Z, Perucho M: Late onset and high incidence of colon cancer of the mutator phenotype with hypermethylated hMLH1 gene in women. Gastroenterology 119: 598, 2000Google Scholar
  58. 58.
    Shannon BA, Iacopetta BJ: Methylation of the hMLH1, p16, and MDR1 genes in colorectal carcinoma: Associations with clinicopathological features. Cancer Lett 167: 91–97, 2001Google Scholar
  59. 59.
    Burri N, Shaw P, Bouzourene H, Sordat I, Sordat B, Gillet M, Schorderet D, Bosman FT, Chaubert P: Methylation silencing and mutations of the p14ARF and p16INK4a genes in colon cancer. Lab Invest 81: 217–229, 2001Google Scholar
  60. 60.
    Whitehall VL, Walsh MD, Young J, Leggett BA, Jass JR: Methylation of O-6-methylguanine DNA methyltransferase characterizes a subset of colorectal cancer with low-level DNA microsatellite instability. Cancer Res 61: 827–830, 2001Google Scholar
  61. 61.
    Esteller M, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, Watkins DN, Issa JP, Sidransky D, Baylin SB, Herman JG: Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. Cancer Res 60: 2368–2371, 2000Google Scholar
  62. 62.
    Rashid A, Shen L, Morris JS, Issa JP, Hamilton SR: Cpg island methylation in colorectal adenomas. Am J Pathol 159: 1129–1135, 2001Google Scholar
  63. 63.
    Chan AO, Issa JP, Morris JS, Hamilton SR, Rashid A: Concordant CpG island methylation in hyperplastic polyposis. Am J Pathol 160: 529–536, 2002Google Scholar
  64. 64.
    Jass JR: Serrated route to colorectal cancer: Back street or super highway? J Pathol 193: 283–285, 2001Google Scholar
  65. 65.
    Lachner M, Jenuwein T: The many faces of histone lysine methylation. Curr Opin Cell Biol 14: 286–298, 2002Google Scholar
  66. 66.
    Kondo Y, Shen L, Issa JP: Critical role of histone methylation in tumor suppressor gene silencing in colorectal cancer. Mol Cell Biol 23: 206–215, 2003Google Scholar
  67. 67.
    Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB: Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet 21: 103–107, 1999Google Scholar
  68. 68.
    Nguyen CT, Gonzales FA, Jones PA: Altered chromatin structure associated with methylation-induced gene silencing in cancer cells: Correlation of accessibility, methylation, MeCP2 binding and acetylation. Nucleic Acids Res 29: 4598–4606, 2001Google Scholar
  69. 69.
    Fahrner JA, Eguchi S, Herman JG, Baylin SB: Dependence of histone modifications and gene expression on DNA hypermethylation in cancer. Cancer Res 62: 7213–7218, 2002Google Scholar
  70. 70.
    Nguyen CT, Weisenberger DJ, Velicescu M, Gonzales FA, Lin JC, Liang G, Jones PA: 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, 2002Google Scholar
  71. 71.
    Mermoud JE, Popova B, Peters AH, Jenuwein T, Brockdorff N: Histone H3 lysine 9 methylation occurs rapidly at the onset of random X chromosome inactivation. Curr Biol 12: 247–251, 2002Google Scholar
  72. 72.
    Xin Z, Allis CD, Wagstaff J: Parent-specific complementary patterns of histone H3 lysine 9 and H3 lysine 4 methylation at the Prader-Willi syndrome imprinting center. Am J Hum Genet 69: 1389–1394, 2001Google Scholar
  73. 73.
    Gregory RI, Randall TE, Johnson CA, Khosla S, Hatada I, O'Neill LP, Turner BM, Feil R: DNA methylation is linked to deacetylation of histone H3, but not H4, on the imprinted genes Snrpn and U2af1-rs1. Mol Cell Biol 21: 5426–5436, 2001Google Scholar
  74. 74.
    Bird A: DNA methylation patterns and epigenetic memory. Genes Dev 16: 6–21, 2002Google Scholar
  75. 75.
    Magdinier F, Wolffe AP: Selective association of the methyl-CpG binding protein MBD2 with the silent p14/p16 locus in human neoplasia. Proc Natl Acad Sci USA 98: 4990–4995, 2001Google Scholar
  76. 76.
    El Osta A, Kantharidis P, Zalcberg JR, Wolffe AP: Precipitous release of methyl-CpG binding protein 2 and histone deacetylase 1 from the methylated human multidrug resistance gene (MDR1) on activation. Mol Cell Biol 22: 1844–1857, 2002Google Scholar
  77. 77.
    Fuks F, Hurd PJ, Wolf D, Nan X, Bird AP, Kouzarides T: The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. J Biol Chem 278: 4035–4040, 2003Google Scholar
  78. 78.
    Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A: Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393: 386–389, 1998Google Scholar
  79. 79.
    Rountree MR, Bachman KE, Baylin SB: DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet 25: 269–277, 2000Google Scholar
  80. 80.
    Tamaru H, Selker EU: A histone H3 methyltransferase controls DNA methylation in neurospora crassa. Nature 414: 277–283, 2001Google Scholar
  81. 81.
    Johnson L, Cao X, Jacobsen S: Interplay between two epigenetic marks. DNA methylation and histone H3 lysine 9 methylation. Curr Biol 20(12): 1360–1367, 2002Google Scholar
  82. 82.
    Malagnac F, Bartee L, Bender J: An Arabidopsis SET domain protein required for maintenance but not establishment of DNA methylation. EMBO J 21: 6842–6852, 2002Google Scholar
  83. 83.
    Richards EJ: Chromatin methylation: Who's on first? Curr Biol 12: R694–R695, 2002Google Scholar
  84. 84.
    Kaslow DC, Migeon BR: DNA methylation stabilizes X chromosome inactivation in eutherians but not in marsupials: Evidence for multistep maintenance of mammalian X dosage compensation. Proc Natl Acad Sci USA 84: 6210–6214, 1987Google Scholar
  85. 85.
    Zochbauer-Muller S, Fong KM, Virmani AK, Geradts J, Gazdar AF, Minna JD: Aberrant promoter methylation of multiple genes in non-small cell lung cancers. Cancer Res 61: 249–255, 2001Google Scholar
  86. 86.
    Wong DJ, Barrett MT, Stoger R, Emond MJ, Reid BJ: p16INK4a promoter is hypermethylated at a high frequency in esophageal adenocarcinomas. Cancer Res 57: 2619–2622, 1997Google Scholar
  87. 87.
    Sidransky D: Emerging molecular markers of cancer. Nat Rev Cancer 2: 210–219, 2002Google Scholar
  88. 88.
    Laird PW, Jackson-Grusby L, Fazeli A, Dickinson SL, Jung WE, Li E, Weinberg RA, Jaenisch R: Suppression of intestinal neoplasia by DNA hypomethylation. Cell 81: 197–205, 1995Google Scholar
  89. 89.
    Cormier RT, Dove WF: Dnmt1N/+ reduces the net growth rate and multiplicity of intestinal adenomas in C57BL/6-multiple intestinal neoplasia (Min)/+ mice independently of p53 but demonstrates strong synergy with the modifier of Min 1(AKR) resistance allele. Cancer Res 60: 3965–3970, 2000Google Scholar
  90. 90.
    Eads CA, Nickel AE, Laird PW: Complete genetic suppression of polyp formation and reduction of CpGisland hypermethylation in Apc(Min/+) Dnmt1-hypomorphic mice. Cancer Res 62: 1296–1299, 2002Google Scholar

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© Kluwer Academic Publishers 2004

Authors and Affiliations

  1. 1.Department of LeukemiaUniversity of Texas at M.D.Anderson Cancer CenterHouston

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