Cancer Epigenetics: DNA Methylation and Chromatin Alterations in Human Cancer

  • Manel Esteller


Aberrations in the DNA methylation patterns are nowadays recognized as a hallmark of human cancer One of the most characteristic changes is the hypermethylation of CpG islands of tumor suppressor genes associated with their transcriptional silencing The target genes are distributed in all cellular pathways (apoptosis, DNA repair, cell cycle, cell adherence, etc) They are “classical” tumor suppressor genes with associated familial cancers (BRCA1, hMLH1, p16lNK4aVHL, etc) and putative new tumor suppressor genes which loss may contribute to the transformed phenotype (MGMT, p14ARF, GSTP1, RARB2, etc) A tumor-type specific profile of CpG island hypermethylation exist in human cancer that allows the use of these aberrantly hypermethylated loci as biomarkers of the malignant disease The irruption of new technologies for the careful study of the DNA methylation patterns, and their genetic partners in accomplishing gene silencing, it may also provide us with new drugs for the epigenetic treatment of human tumors


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  1. 1.
    Bird, AP CpG-rich islands and the function of DNA methylation Nature 1986, 321:209–213PubMedCrossRefGoogle Scholar
  2. 2.
    Nguyen C, Liang G Nguyen TT, Tsao-Wei D, Groshen S, Lubbert M, Zhou JH, Benedict WF, Jones PA Susceptibility of nonpromoter CpG islands to de novo methylation in normal and neoplastic cells J Nail Cancer Inst 2001, 93,1465–72CrossRefGoogle Scholar
  3. 3.
    Esteller, M, Corn, PG, Baylin, SB, and Herman, JG A gene hypermethylation profile of human cancer Cancer Res, 2001, 61, 3225–3229PubMedGoogle Scholar
  4. 4.
    Greger V, Passarge E, Hopping W, Messmer E, Horsthernke B Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma Hum Genet 1989, 83,155–8PubMedCrossRefGoogle Scholar
  5. 5.
    Herman JG, Latif F, Weng Y, Lerman MI, Zbar B, Liu S, Samid D, Duan DS, Gnarra JR, Linehan WM Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma Proc Natl Acad Sci U S A 1994, 91,9700–4PubMedCrossRefGoogle Scholar
  6. Merlo, A Herman, JG, Mao, L, Lee, DJ, Gabrielson, E, Burger, PC, Baylin, SB, and Sidransky, D 5 CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers Nat Med 1995, 1: 686–692PubMedCrossRefGoogle Scholar
  7. 7.
    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 1995, 55,4525–30PubMedGoogle Scholar
  8. Gonzalez-Zulueta, M, Bender, CM, Yang, AS, Nguyen, T, Beart, RW, Van Tornout, JM, and Jones PA Methylation of the 5’ CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencingGoogle Scholar
  9. 9.
    Clark, SJ, J Harrison, CL Paul and M Frommer High sensitivity mapping of methylated cytosines Nucleic Acids Res 1994, 22:2990–2997PubMedCrossRefGoogle Scholar
  10. 10.
    Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands Proc Natl Acad Sci U S A 1996, 93,9821–6PubMedCrossRefGoogle Scholar
  11. 11.
    Esteller M, Fraga MF, Guo M, Garcia-Foncillas J, Hedelfank I, Godwin AK, Trojan J, Vaurs-Barrière C, Bignon Y-J, Ramus S, Benitez J, Akiyama Y, Caldes T, Canal MJ, Rodriguez R, Capella G, Peinado MA, Borg A, Aaltonen LA, Ponder BA, Baylin SB, Herman JG DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis Human Molecular Genetics, 2001, 10, 3001–7PubMedCrossRefGoogle Scholar
  12. 12.
    Myohanen SK, Baylin SB, Herman JG Hypermethylation can selectively silence individual pl6ink4A alleles in neoplasia Cancer Res 1998, 58,591–3PubMedGoogle Scholar
  13. 13.
    Herman, JG, Umar, A, Polyak, K, Graft, JR, Ahuja, N, Issa, JP, Markowitz, S, Willson, JK, Hamilton, SR, Kinzler, KW, Kane, MF, Kolodner, RD, Vogelstein, B, Kunkel, TA, and Baylin, SB Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma Proc Natl Acad Sci U S A 1998, 95: 6870–6875PubMedCrossRefGoogle Scholar
  14. 14.
    Esteller M, Levine R, Baylin SB, Ellenson LH, Herman JG MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas Oncogene, 1998,17,2413–2417PubMedCrossRefGoogle Scholar
  15. 15.
    Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG Inactivation of the DNA repair gene 06methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia Cancer Research, 1999, 59, 793–797PubMedGoogle Scholar
  16. 16.
    Lee WH, Morton RA, Epstein JI, Brooks JD, Campbell PA, Bova GS, Hsieh WS, Isaacs WB, Nelson WG Cytidine methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic carcinogenesis Proc Natl Acad Sci U S A 1994, 91,11733–7PubMedCrossRefGoogle Scholar
  17. 17.
    Esteller M, Corn PG, Urena JM, Gabrielson E, Baylin SB, Herman JG Inactivation of glutathione Stransferase P1 gene by promoter hypermethylation in human neoplasia Cancer Research, 1998, 58, 4515–4518PubMedGoogle Scholar
  18. 18.
    Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Bussaglia E, Lerma E, Prat J, Harkes IC, Repasky EA, Gabrielson E, Schutte M, Baylin SB, Herman JG Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors Journal of the National Cancer Institute 2000, 92, 5649CrossRefGoogle Scholar
  19. 19.
    Di Croce L, Raker VA, Corsaro M, Fazi F, Fanelli M, Faretta M, Fuks F, Lo Coco F, Kouzarides T, Nervi C, Minucci S, Pelicci PG Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor Science 2002, 295, 1079–1082PubMedCrossRefGoogle Scholar
  20. 20.
    Esteller M, Fraga MF, Paz MF, Campo E, Colomer D, Novo FJ, Calsanz MJ, Galm 0, Guo M, Benitez J, Herman JG Cancer epigenetics and methylation Science 2002, 297, 1807–1808PubMedCrossRefGoogle Scholar
  21. 21.
    Paz MF, Avila S, Fraga MF, Pollan M, Capella G, Peinado MA, Sanchez-Cespedes M, Herman JG, Esteller M Germ-line variants in methyl-group metabolism genes and susceptibility to DNA methylation in normal tissues and human primary tumors Cancer Res 2002, 62, 4519–4524PubMedGoogle Scholar
  22. 22.
    Jones PA, Laird PW Cancer epigenetics comes of age Nat Genet 1999, 21,163–7PubMedCrossRefGoogle Scholar
  23. 23.
    Baylin SB, Esteller M, Rountree MR, Bachman KE, Schuebel K, Herman JG Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer Hum Mol Genet 2001, 10, 687–92PubMedCrossRefGoogle Scholar
  24. 24.
    Graff JR, Herman JG, Myohanen S, Baylin SB, Vertino PM Mapping patterns of CpG island methylation in normal and neoplastic cells implicates both upstream and downstream regions in de novo methylation J Biol Chem 1997, 272: 22322–9PubMedCrossRefGoogle Scholar
  25. 25.
    Song JZ, Stirzaker C, Harrison J, Melki JR, Clark SJ Hypermethylation trigger of the glutathione-Stransferase gene (GSTPI) in prostate cancer cells Oncogene 2002, 21, 1048–61PubMedCrossRefGoogle Scholar
  26. 26.
    Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA, Jones PA xThe human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors Nucleic Acids Res 1999, 27,2291–8Google Scholar
  27. 27.
    Feinberg AP, Vogelstein B Hypomethylation distinguishes genes of some human cancers from their normal counterparts Nature 1983, 301,89–92PubMedCrossRefGoogle Scholar
  28. 28.
    Ehrlich M DNA hypomethylation and cancer In: DNA alterations in cancer: genetic and epigenetic changes Edited by Melanie Ehrlich, Eaton Publishing, Natick, Pages 273–291, 2000Google Scholar
  29. 29.
    Keshet, I, Lieman-Hurwitz, J and Cedar, H DNA methylation affects the formation of active chromatin Cell 1986, 44, 535–543PubMedCrossRefGoogle Scholar
  30. 30.
    Lewis, JD, Meehan, RR, Henzel, WJ, Maurer-Fogy, I, Jeppesen, P, Klein, F and Bird A Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA Cell 1992, 69, 905–914PubMedCrossRefGoogle Scholar
  31. 31.
    Magdinier, F and 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 2001, 98, 4990–4995PubMedCrossRefGoogle Scholar
  32. 32.
    Nan, X, Ng, HH, Johnson, CA, Laherty, CD, Turner, BM, Eisenman, RN and Bird A Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex Nature 1998, 393, 386–389PubMedCrossRefGoogle Scholar
  33. 33.
    Jones, PL, Veenstra, GJ, Wade, PA, Vermaak, D, Kass, SU, Landsberger, N, Strouboulis, J and Wolffe, AP Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription Nat Genet, 1989, 19, 187–191CrossRefGoogle Scholar
  34. 34.
    Ballestar E and Esteller M The impact of chromatin in human cancer: linking DNA methylation to gene silencing Carcinogenesis 2002, 23: 1103–9PubMedCrossRefGoogle Scholar
  35. 35.
    Esteller M, Sanchez-Cespedes M, Rosell R, Sidransky D, Baylin SB, Herman JG Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from non-small cell lung cancer patients Cancer Research, 1999, 59, 67–70PubMedGoogle Scholar
  36. 36.
    Tang X, Khuri FR, Lee JJ, Kemp BL, Liu D, Hong WK, Mao L Hypermethylation of the death-associated protein (DAP) kinase promoter and aggressiveness in stage I non-small-cell lung cancer J Nat! Cancer Inst 2000, 92,1511–6PubMedCrossRefGoogle Scholar
  37. 37.
    Esteller M, Gonzalez S, Risques RA, Marcuello E, Mangues R, Germa JR, Herman JG, Capella G, Peinado MA K-ras and p16 aberrations confer poor prognosis in human colorectal cancer J Clin Oncol, 2001,19, 299–304PubMedGoogle Scholar
  38. 38.
    Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, Baylin SB, Herman JG Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents N Engl J Med, 2000, 343, 1350–1354PubMedCrossRefGoogle Scholar
  39. 39.
    Esteller M, Gaidano G, Goodman SN, Zagonel V, Capello D, Botto B, Rossi D, Gloghini A, Vitolo U, Carbone A, Baylin SB, Herman JG Hypermethylation of the DNA repair gene O(6)-methylguanine DNA methyltransferase and survival of patients with diffuse large B-cell lymphoma J Nat! Cancer Inst 2002, 94, 6–7CrossRefGoogle Scholar
  40. 40.
    Wijermans PW, Krulder JW, Huijgens PC, Neve P Continuous infusion of low-dose 5-Aza-2’deoxycytidine in elderly patients with high-risk myelodysplastic syndrome Leukemia 1997, 11,1–5PubMedCrossRefGoogle Scholar
  41. 41.
    Schwartsmann G, Fernandes MS, Schaan MD, Moschen M, Gerhardt LM, Di Leone L, Loitzembauer B, Kalakun L Decitabine (5-Aza-2’-deoxycytidine; DAC) plus daunorubicin as a first line treatment in patients with acute myeloid leukemia: preliminary observations Leukemia 1997, 11 Suppl 1:528–31Google Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Manel Esteller
    • 1
  1. 1.Cancer Epigenetics LaboratorySpanish National Cancer Center (CNIO)MadridSpain

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