Skip to main content
SpringerLink
Log in

CpG Island Hypermethylation of Tumor Suppressor Genes in Human Cancer

Concepts, Methodologies and Uses

  • Chapter
DNA Methylation and Cancer Therapy

Part of the book series: Medical Intelligence Unit ((MIUN))

  • 1094 Accesses

Abstract

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, p16INK4a, VHL, 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 development of new technologies for the careful study of the DNA methylation patterns, and their genetic partners in accomplishing gene silencing, may also provide us with new drugs for the epigenetic treatment of human tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Bird AP. CpG-rich islands and the function of DNA methylation. Nature 1986; 321:209–213.

    Article  PubMed  CAS  Google Scholar 

  2. Nguyen C, Liang G, Nguyen TT et al. Susceptibility of nonpromoter CpG islands to de novo methylation in normal and neoplastic cells. J Natl Cancer Inst 2001; 93:1465–72.

    Article  PubMed  CAS  Google Scholar 

  3. Esteller M, Corn PG, Baylin SB et al. A gene hypermethylation profile of human cancer. Cancer Res. 2001; 61:3225–3229.

    PubMed  CAS  Google Scholar 

  4. Greger V, Passarge E, Hopping W et al Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum Genet 1989; 83:155–8.

    Article  PubMed  CAS  Google Scholar 

  5. Herman JG, Latif F, Weng Y et al. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci USA 1994; 91:9700–4.

    Article  PubMed  CAS  Google Scholar 

  6. Merlo A, Herman JG, Mao L et al. 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med 1995; 1:686–692.

    Article  PubMed  CAS  Google Scholar 

  7. Herman JG, Merlo A, Mao L et al. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res 1995; 55:4525–30.

    PubMed  CAS  Google Scholar 

  8. Gonzalez-Zulueta M, Bender CM, Yang AS 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.

    Google Scholar 

  9. Clark SJ, Harrison J, Paul CL et al. High sensitivity mapping of methylated cytosines. Nucleic Acids Res 1994; 22:2990–2997.

    Article  PubMed  CAS  Google Scholar 

  10. Herman JG, Graff JR, Myohanen S et al. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 1996; 93:9821–6.

    Article  PubMed  CAS  Google Scholar 

  11. Esteller M, Fraga MF, Guo M et al. DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis. Hum Mol Genet 2001; 10:3001–7.

    Article  PubMed  CAS  Google Scholar 

  12. Myohanen SK, Baylin SB, Herman JG. Hypermethylation can selectively silence individual p16ink4A alleles in neoplasia. Cancer Res 1998; 58:591–3.

    PubMed  CAS  Google Scholar 

  13. Herman JG, Umar A, Polyak K et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 1998; 95:6870–68:5.

    Article  PubMed  CAS  Google Scholar 

  14. Esteller M, Levine R, Baylin SB et al. MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas. Oncogene 1998; 17:2413–2417.

    Article  PubMed  CAS  Google Scholar 

  15. Esteller M, Hamilton SR, Burger PC et al. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 1999; 59:793–797.

    PubMed  CAS  Google Scholar 

  16. Lee WH, Morton RA, Epstein JI et al. Cytidine methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic carcinogenesis. Proc Natl Acad Sci USA 1994; 91, 11733–7.

    Article  PubMed  CAS  Google Scholar 

  17. Esteller M, Corn PG, Urena JM et al. Inactivation of glutathione S-transferase P1 gene by promoter hypermethylation in human neoplasia. Cancer Res 1998; 58:4515–4518.

    PubMed  CAS  Google Scholar 

  18. Esteller M, Silva JM, Dominguez G et al. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst 2000; 92:564–9.

    Article  PubMed  CAS  Google Scholar 

  19. Di Croce L, Raker VA, Corsaro M et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 2002; 295:1079–1082.

    Article  PubMed  Google Scholar 

  20. Esteller M, Fraga MF, Paz MF et al. Cancer epigenetics and methylation. Science 2002; 297:1807–1808.

    Article  PubMed  Google Scholar 

  21. Paz MF, Avila S, Fraga MF et al. Germ-line variants in methyl-group metabolism genes and susceptibility to DNA methylation in normal tissues and human primary tumors. Cancer Res 2002; 62:4519–4524.

    PubMed  CAS  Google Scholar 

  22. Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet 1999; 21:163–7.

    Article  PubMed  CAS  Google Scholar 

  23. Baylin SB, Esteller M, Rountree MR et al. Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum Mol Genet 2001; 10:687–92.

    Article  PubMed  CAS  Google Scholar 

  24. Graff JR, Herman JG, Myohanen S et al. 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; 272:22322–9.

    Article  PubMed  CAS  Google Scholar 

  25. Song JZ, Stirzaker C, Harrison J et al. Hypermethylation trigger of the glutathione-S-transferase gene (GSTP1) in prostate cancer cells. Oncogene 2002, 21, 1048–61.

    Article  PubMed  CAS  Google Scholar 

  26. Robertson KD, Uzvolgyi E, Liang G et al. The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res 1999; 27:2291–8.

    Article  PubMed  CAS  Google Scholar 

  27. Feinberg AP, Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 1983; 301:89–92.

    Article  PubMed  CAS  Google Scholar 

  28. Ehrlich M, DNA hypomethylation and cancer. In: Melanie Ehrlich, ed. DNA Alterations in Cancer: Genetic and Epigenetic Changes. Natick: Eaton Publishing, 2000:273–291.

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  30. Lewis JD, Meehan RR, Henzel WJ et al. Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 1992; 69:905–914.

    Article  PubMed  CAS  Google Scholar 

  31. 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 2001; 98:4990–4995.

    Article  PubMed  CAS  Google Scholar 

  32. Nan X, Ng HH, Johnson CA et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 1998; 393:386–389.

    Article  PubMed  CAS  Google Scholar 

  33. Jones PL, Veenstra GJ, Wade PA et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 1989; 19:187–191.

    Article  Google Scholar 

  34. Ballestar E, Esteller M. The impact of chromatin in human cancer: linking DNA methylation to gene silencing. Carcinogenesis 2002; 23:1103–9.

    Article  PubMed  CAS  Google Scholar 

  35. Esteller M, Sparks A, Toyota M et al. Analysis of adenomatous polyposis coli promoter hypermethylation in human cancer. Cancer Res 2000; 60:4366–71.

    PubMed  CAS  Google Scholar 

  36. Wolffe AP, Jones PL, Wade PA DN.A d emethylation. Proc Natl Acad Sci USA 1999; 96:5894–5896.

    Article  PubMed  CAS  Google Scholar 

  37. Stirzaker C, Millar DS, Paul PM et al. Extensive DNA methylation spanning the Rb promoter in retinoblastoma tumors. Cancer Res 1997; 57:2229–2237.

    PubMed  CAS  Google Scholar 

  38. Xiong Z, Laird PW. COBRA: a sensitive and quantitative DNA methylation assay. Nucleic Acids Res 1997; 25:2532–2534.

    Article  PubMed  CAS  Google Scholar 

  39. Gonzalgo ML, Bender CM, You EH et al. Low frequency of p16/CDKN2A methylation in sporadic melanoma: comparative approaches for methylation analysis of primary tumors. Cancer Res 1997; 57:5336–5347.

    PubMed  CAS  Google Scholar 

  40. Bianco T, Hussey D, Dobrovic A. Methylation-sensitive, single-strand conformation analysis (MS-SSCA): A rapid method to screen for and analyze methylation. Hum Mutat 1999; 14:289–293.

    Article  PubMed  CAS  Google Scholar 

  41. Fraga MF, Rodriguez R, Canal MJ. Rapid quantification of DNA methylation by high performance capillary electrophoresis. Electrophoresis 2000; 14:2990–4.

    Article  Google Scholar 

  42. Fraga MF, Uriol E, Borja Diego L et al. High-performance capillary electrophoretic method for the quantification of 5-methyl 2′-deoxycytidine in genomic DNA: application to plant, animal and human cancer tissues. Electrophoresis 2002; 23:1677–1681.

    Article  PubMed  CAS  Google Scholar 

  43. Fraga MF, Esteller M. DNA methylation: a profile of methods and applications. Biotechniques 2002; 33:632–649.

    PubMed  CAS  Google Scholar 

  44. Wu J, Issa JP, Herman J et al. Expression of an exogenous eukaryotic DNA methyltransferase gene induces transformation of NIH 3T3 cells. Proc Natl Acad Sci USA 1993; 90:8891–8895.

    Article  PubMed  CAS  Google Scholar 

  45. Miller OJ, Schnedl W, Allen J et al. 5-Methylcytosine localised in mammalian constitutive heterochromatin. Nature 1974; 251:636–637.

    Article  PubMed  CAS  Google Scholar 

  46. Cedar H, Solage A, Glaser G et al. Direct detection of methylated cytosine in DNA by use of the restriction enzyme MspI. Nucleic Acids Res 1979; 6:2125–2132.

    Article  PubMed  CAS  Google Scholar 

  47. Butkus V, Petrauskiene L, Maneliene Z et al. Cleavage of methylated CCCGGG sequences containing either N4-methylcytosine or 5-methylcytosine with MspI, HpaII, SmaI, XmaI and Cfr9I restriction endonucleases. Nucleic Acids Res 1987; 15:7091–7102.

    Article  PubMed  CAS  Google Scholar 

  48. McClelland M, Nelson M, Raschke E. Effect of site-specific modification on restriction endonucleases and DNA modification methyltransferases. Nucleic Acids Res 1994; 22:3640–3659.

    Article  PubMed  CAS  Google Scholar 

  49. Hatada I, Hayashizaki Y, Hirotsune S et al. A genomic scanning method for higher organisms using restriction sites as landmarks. Proc Natl Acad Sci USA 1991; 88:9523–9527.

    Article  PubMed  CAS  Google Scholar 

  50. Kawai J, Hirotsune S, Hirose K et al. Methylation profiles of genomic DNA of mouse developmental brain detected by restriction landmark genomic scanning (RLGS) method. Nucleic Acids Res 1993; 21:5604–5608.

    Article  PubMed  CAS  Google Scholar 

  51. Toyota M, Ahuja N, Ohe-Toyota M et al. CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA 1999; 96:8681–6.

    Article  PubMed  CAS  Google Scholar 

  52. Shiraishi M, Chuu YH, Sekiya T. Isolation of DNA fragments associated with methylated CpG islands in human adenocarcinomas of the lung using a methylated DNA binding column and denaturing gradient gel electrophoresis. Proc Natl Acad Sci USA 1999; 96:2913–2918.

    Article  PubMed  CAS  Google Scholar 

  53. Huang TH, Perry MR, Laux DE. Methylation profiling of CpG islands in human breast cancer cells. Hum Mol Genet 1999; 8:459–470.

    Article  PubMed  CAS  Google Scholar 

  54. Gitan RS, Shi H, Chen CM et al. Methylation-specific oligonucleotide microarray: a new potential for high-throughput methylation analysis. Genome Res 2002; 12:158–164.

    Article  PubMed  CAS  Google Scholar 

  55. Esteller M, Sanchez-Cespedes M, Rosell R et al. Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from nonsmall cell lung cancer patients. Cancer Res 1999; 59:67–70.

    PubMed  CAS  Google Scholar 

  56. Tang X, Khuri FR, Lee JJ et al. Hypermethylation of the death-associated protein (DAP) kinase promoter and aggressiveness in stage I nonsmall-cell lung cancer. J Natl Cancer Inst 2000; 92:1511–6.

    Article  PubMed  CAS  Google Scholar 

  57. Esteller M, Gonzalez S, Risques RA et al. K-ras and p16 aberrations confer poor prognosis in human colorectal cancer. J Clin Oncol 2001; 19:299–304.

    PubMed  CAS  Google Scholar 

  58. Esteller M, Garcia-Foncillas J, Andion E et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 2000; 343:1350–1354.

    Article  PubMed  CAS  Google Scholar 

  59. Esteller M, Gaidano G, Goodman SN et al. Hypermethylation of the DNA repair gene O(6)-methylguanine DNA methyltransferase and survival of patients with diffuse large B-cell lymphoma. J Natl Cancer Inst 2002; 94:6–7.

    Google Scholar 

  60. Wijermans PW, Krulder JW, Huijgens PC et al. Continuous infusion of low-dose 5-Aza-2′-deoxycytidine in elderly patients with high-risk myelodysplastic syndrome. Leukemia 1997; 11:1–5.

    Article  PubMed  CAS  Google Scholar 

  61. Schwartsmann G, Fernandes MS, Schaan MD et al. 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):S28–31.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cancer Epigenerics Laboratory, Spanish National Cancer Center (CNIO), Madrid, Spain

    Michel Herranz & Manel Esteller

Authors
  1. Michel Herranz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manel Esteller
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

Copyright information

© 2005 Eurekah.com and Kluwer Academic/Plenum Publishers

About this chapter

Cite this chapter

Herranz, M., Esteller, M. (2005). CpG Island Hypermethylation of Tumor Suppressor Genes in Human Cancer. In: DNA Methylation and Cancer Therapy. Medical Intelligence Unit. Springer, Boston, MA. https://doi.org/10.1007/0-387-27443-X_6

Download citation

Publish with us

Policies and ethics

Search

Navigation