Advertisement

Genome-Wide Epigenetic Modifications in Cancer

  • Yoon Jung Park
  • Rainer Claus
  • Dieter Weichenhan
  • Christoph Plass
Chapter
Part of the Progress in Drug Research book series (PDR, volume 67)

Abstract

Epigenetic alterations in cancer include changes in DNA methylation and associated histone modifications that influence the chromatin states and impact gene expression patterns. Due to recent technological advantages, the scientific community is now obtaining a better picture of the genome-wide epigenetic changes that occur in a cancer genome. These epigenetic alterations are associated with chromosomal instability and changes in transcriptional control which influence the overall gene expression differences seen in many human malignancies. In this review, we will briefly summarize our current knowledge of the epigenetic patterns and mechanisms of gene regulation in healthy tissues and relate this to what is known for cancer genomes. Our focus will be on DNA methylation. We will review the current standing of technologies that have been developed over recent years. This field is experiencing a revolution in the strategies used to measure epigenetic alterations, which includes the incorporation of next generation sequencing tools. We also will review strategies that utilize epigenetic information for translational purposes, with a special emphasis on the potential use of DNA methylation marks for early disease detection and prognosis. The review will close with an outlook on challenges that this field is facing.

Keywords

Chronic Lymphocytic Leukemia Epigenetic Alteration Germ Cell Development Padlock Probe Restriction Landmark Genomic Scanning 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The authors would like to thank Christopher Oakes for critical reading of the review. Work in the Division is funded in part by NIH grants CA101956 and DE013123 (C.P.). R.C. is supported by a fellowship of the Deutsche Forschungsgemeinschaft and YJ. P. holds a Roman Herzog Stipend of the Alexander von Humboldt-Stiftung.

References

  1. 1.
    Li E, Bestor TH, Jaenisch R (1992) Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69(6):915–926PubMedGoogle Scholar
  2. 2.
    Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99(3):247–257PubMedGoogle Scholar
  3. 3.
    Tachibana M, Sugimoto K, Nozaki M et al (2002) G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev 16(14):1779–1791PubMedGoogle Scholar
  4. 4.
    O’Carroll D, Erhardt S, Pagani M, Barton SC, Surani MA, Jenuwein T (2001) The polycomb-group gene Ezh2 is required for early mouse development. Mol Cell Biol 21(13):4330–4336PubMedGoogle Scholar
  5. 5.
    Sasaki H, Matsui Y (2008) Epigenetic events in mammalian germ-cell development: reprogramming and beyond. Nat Rev Genet 9(2):129–140PubMedGoogle Scholar
  6. 6.
    Ooi SK, Bestor TH (2008) The colorful history of active DNA demethylation. Cell 133(7):1145–1148PubMedGoogle Scholar
  7. 7.
    Kriaucionis S, Heintz N (2009) The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324(5929):929–930PubMedGoogle Scholar
  8. 8.
    Tahiliani M, Koh KP, Shen Y et al (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324(5929):930–935PubMedGoogle Scholar
  9. 9.
    Suzuki MM, Bird A (2008) DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet 9(6):465–476PubMedGoogle Scholar
  10. 10.
    Illingworth RS, Bird AP (2009) CpG islands – ‘a rough guide’. FEBS Lett 583(11):1713–1720PubMedGoogle Scholar
  11. 11.
    Kurdistani SK, Tavazoie S, Grunstein M (2004) Mapping global histone acetylation patterns to gene expression. Cell 117(6):721–733PubMedGoogle Scholar
  12. 12.
    Schotta G, Lachner M, Sarma K et al (2004) A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev 18(11):1251–1262PubMedGoogle Scholar
  13. 13.
    Li B, Carey M, Workman JL (2007) The role of chromatin during transcription. Cell 128(4):707–719PubMedGoogle Scholar
  14. 14.
    Heintzman ND, Hon GC, Hawkins RD et al (2009) Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459(7243):108–112PubMedGoogle Scholar
  15. 15.
    Cedar H, Bergman Y (2009) Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet 10(5):295–304PubMedGoogle Scholar
  16. 16.
    Gibbons RJ, McDowell TL, Raman S et al (2000) Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation. Nat Genet 24(4):368–371PubMedGoogle Scholar
  17. 17.
    Knoepfler PS, Eisenman RN (1999) Sin meets NuRD and other tails of repression. Cell 99(5):447–450PubMedGoogle Scholar
  18. 18.
    Eckhardt F, Lewin J, Cortese R et al (2006) DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet 38(12):1378–1385PubMedGoogle Scholar
  19. 19.
    Rakyan VK, Down TA, Thorne NP et al (2008) An integrated resource for genome-wide identification and analysis of human tissue-specific differentially methylated regions (tDMRs). Genome Res 18(9):1518–1529PubMedGoogle Scholar
  20. 20.
    Yoon B, Herman H, Hu B et al (2005) Rasgrf1 imprinting is regulated by a CTCF-dependent methylation-sensitive enhancer blocker. Mol Cell Biol 25(24):11184–11190PubMedGoogle Scholar
  21. 21.
    Bell AC, Felsenfeld G (2000) Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene [see comments]. Nature 405(6785):482–485PubMedGoogle Scholar
  22. 22.
    Illingworth R, Kerr A, Desousa D et al (2008) A novel CpG island set identifies tissue-specific methylation at developmental gene loci. PLoS Biol 6(1):e22PubMedGoogle Scholar
  23. 23.
    Irizarry RA, Ladd-Acosta C, Wen B et al (2009) The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 41(2):178–186PubMedGoogle Scholar
  24. 24.
    Bernstein BE, Mikkelsen TS, Xie X et al (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125(2):315–326PubMedGoogle Scholar
  25. 25.
    Mikkelsen TS, Ku M, Jaffe DB et al (2007) Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448(7153):553–560PubMedGoogle Scholar
  26. 26.
    Fouse SD, Shen Y, Pellegrini M et al (2008) Promoter CpG methylation contributes to ES cell gene regulation in parallel with Oct4/Nanog, PcG complex, and histone H3 K4/K27 trimethylation. Cell Stem Cell 2(2):160–169PubMedGoogle Scholar
  27. 27.
    Surani MA, Durcova-Hills G, Hajkova P, Hayashi K, Tee WW (2008) Germ line, stem cells, and epigenetic reprogramming. Cold Spring Harb Symp Quant Biol 73:9–15PubMedGoogle Scholar
  28. 28.
    Hemberger M, Dean W, Reik W (2009) Epigenetic dynamics of stem cells and cell lineage commitment: digging Waddington’s canal. Nat Rev Mol Cell Biol 10(8):526–537PubMedGoogle Scholar
  29. 29.
    Plass C, Soloway PD (2002) DNA methylation, imprinting and cancer. Eur J Hum Genet 10(1):6–16PubMedGoogle Scholar
  30. 30.
    Hark AT, Schoenherr CJ, Katz DJ, Ingram RS, Levorse JM, Tilghman SM (2000) CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus [see comments]. Nature 405(6785):486–489PubMedGoogle Scholar
  31. 31.
    Umlauf D, Goto Y, Cao R et al (2004) Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes. Nat Genet 36(12):1296–1300PubMedGoogle Scholar
  32. 32.
    Wagschal A, Sutherland HG, Woodfine K et al (2008) G9a histone methyltransferase contributes to imprinting in the mouse placenta. Mol Cell Biol 28(3):1104–1113PubMedGoogle Scholar
  33. 33.
    Jelinic P, Shaw P (2007) Loss of imprinting and cancer. J Pathol 211(3):261–268PubMedGoogle Scholar
  34. 34.
    Payer B, Lee JT (2008) X chromosome dosage compensation: how mammals keep the balance. Annu Rev Genet 42:733–772PubMedGoogle Scholar
  35. 35.
    Lee TI, Jenner RG, Boyer LA et al (2006) Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125(2):301–313PubMedGoogle Scholar
  36. 36.
    Goll MG, Bestor TH (2005) Eukaryotic cytosine methyltransferases. Annu Rev Biochem 74:481–514PubMedGoogle Scholar
  37. 37.
    Lees-Murdock DJ, De Felici M, Walsh CP (2003) Methylation dynamics of repetitive DNA elements in the mouse germ cell lineage. Genomics 82(2):230–237PubMedGoogle Scholar
  38. 38.
    Bourc’his D, Bestor TH (2004) Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 431(7004):96–99PubMedGoogle Scholar
  39. 39.
    Webster KE, O’Bryan MK, Fletcher S et al (2005) Meiotic and epigenetic defects in Dnmt3L-knockout mouse spermatogenesis. Proc Natl Acad Sci USA 102(11):4068–4073PubMedGoogle Scholar
  40. 40.
    Kuramochi-Miyagawa S, Watanabe T, Gotoh K et al (2008) DNA methylation of retrotransposon genes is regulated by Piwi family members MILI and MIWI2 in murine fetal testes. Genes Dev 22(7):908–917PubMedGoogle Scholar
  41. 41.
    Clark SJ, Harrison J, Paul CL, Frommer M (1994) High sensitivity mapping of methylated cytosines. Nucleic Acids Res 22(15):2990–2997PubMedGoogle Scholar
  42. 42.
    Brena RM, Huang TH, Plass C (2006) Quantitative assessment of DNA methylation: potential applications for disease diagnosis, classification, and prognosis in clinical settings. J Mol Med 84(5):365–377PubMedGoogle Scholar
  43. 43.
    Kane MF, Loda M, Gaida GM et al (1997) Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 57(5):808–811PubMedGoogle Scholar
  44. 44.
    Herman JG, Umar A, Polyak K et al (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 95(12):6870–6875PubMedGoogle Scholar
  45. 45.
    Dobrovic A, Simpfendorfer D (1997) Methylation of the BRCA1 gene in sporadic breast cancer. Cancer Res 57(16):3347–3350PubMedGoogle Scholar
  46. 46.
    Rice JC, Massey-Brown KS, Futscher BW (1998) Aberrant methylation of the BRCA1 CpG island promoter is associated with decreased BRCA1 mRNA in sporadic breast cancer cells. Oncogene 17(14):1807–1812PubMedGoogle Scholar
  47. 47.
    Raval A, Tanner SM, Byrd JC et al (2007) Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia. Cell 129(5):879–890PubMedGoogle Scholar
  48. 48.
    Merlo A, Herman JG, Mao L et al (1995) 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers [see comments]. Nat Med 1(7):686–692PubMedGoogle Scholar
  49. 49.
    Bartkova J, Lukas J, Muller H, Strauss M, Gusterson B, Bartek J (1995) Abnormal patterns of D-type cyclin expression and G1 regulation in human head and neck cancer. Cancer Res 55(4):949–956PubMedGoogle Scholar
  50. 50.
    Otterson GA, Khleif SN, Chen W, Coxon AB, Kaye FJ (1995) CDKN2 gene silencing in lung cancer by DNA hypermethylation and kinetics of p16INK4 protein induction by 5-aza 2′deoxycytidine. Oncogene 11(6):1211–1216PubMedGoogle Scholar
  51. 51.
    Diala ES, Cheah MS, Rowitch D, Hoffman RM (1983) Extent of DNA methylation in human tumor cells. J Natl Cancer Inst 71(4):755–764PubMedGoogle Scholar
  52. 52.
    Rainier S, Johnson LA, Dobry CJ, Ping AJ, Grundy PE, Feinberg AP (1993) Relaxation of imprinted genes in human cancer. Nature 362(6422):747–749PubMedGoogle Scholar
  53. 53.
    Ogawa O, Becroft DM, Morison IM et al (1993) Constitutional relaxation of insulin-like growth factor II gene imprinting associated with Wilms’ tumour and gigantism. Nat Genet 5(4):408–412PubMedGoogle Scholar
  54. 54.
    Huang TH, Perry MR, Laux DE (1999) Methylation profiling of CpG islands in human breast cancer cells. Hum Mol Genet 8(3):459–470PubMedGoogle Scholar
  55. 55.
    Smiraglia DJ, Plass C (2002) The study of aberrant methylation in cancer via restriction landmark genomic scanning. Oncogene 21(35):5414–5426PubMedGoogle Scholar
  56. 56.
    Toyota M, Ho C, Ahuja N et al (1999) Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification. Cancer Res 59(10):2307–2312PubMedGoogle Scholar
  57. 57.
    Rush LJ, Dai Z, Smiraglia DJ et al (2001) Novel methylation targets in de novo acute myeloid leukemia with prevalence of chromosome 11 loci. Blood 97(10):3226–3233PubMedGoogle Scholar
  58. 58.
    Raval A, Rush LJ, Funchain P et al (2002) Aberrant DNA methylation in chronic lymphocytic leukemia: a role in pathogenesis? Blood 100(11):379aGoogle Scholar
  59. 59.
    Dai Z, Lakshmanan RR, Zhu WG et al (2001) Global methylation profiling of lung cancer identifies novel methylated genes. Neoplasia 3(4):314–323PubMedGoogle Scholar
  60. 60.
    Smiraglia DJ, Smith LT, Lang JC et al (2003) Differential targets of CpG island hypermethylation in primary and metastatic head and neck squamous cell carcinoma (HNSCC). J Med Genet 40(1):25–33PubMedGoogle Scholar
  61. 61.
    Wei SH, Chen CM, Strathdee G et al (2002) Methylation microarray analysis of late-stage ovarian carcinomas distinguishes progression-free survival in patients and identifies candidate epigenetic markers. Clin Cancer Res 8:2246–2252PubMedGoogle Scholar
  62. 62.
    Costello JF, Fruhwald MC, Smiraglia DJ et al (2000) Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nature Genet 24(2):132–138PubMedGoogle Scholar
  63. 63.
    Plass C, Smiraglia DJ (2006) Genome-wide analysis of DNA methylation changes in human malignancies. Curr Top Microbiol Immunol 310:179–198PubMedGoogle Scholar
  64. 64.
    Bialik S, Kimchi A (2006) The death-associated protein kinases: structure, function, and beyond. Annu Rev Biochem 75:189–210PubMedGoogle Scholar
  65. 65.
    Liu TX, Becker MW, Jelinek J et al (2007) Chromosome 5q deletion and epigenetic suppression of the gene encoding alpha-catenin (CTNNA1) in myeloid cell transformation. Nat Med 13(1):78–83PubMedGoogle Scholar
  66. 66.
    Smith LT, Lin M, Brena RM et al (2006) Epigenetic regulation of the tumor suppressor gene TCF21 on 6q23-q24 in lung and head and neck cancer. Proc Natl Acad Sci USA 103(4):982–987PubMedGoogle Scholar
  67. 67.
    Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68(4):820–823PubMedGoogle Scholar
  68. 68.
    Ohm JE, McGarvey KM, Yu X et al (2007) A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet 39(2):237–242PubMedGoogle Scholar
  69. 69.
    Widschwendter M, Fiegl H, Egle D et al (2007) Epigenetic stem cell signature in cancer. Nat Genet 39(2):157–158PubMedGoogle Scholar
  70. 70.
    Schlesinger Y, Straussman R, Keshet I et al (2007) Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet 39(2):232–236PubMedGoogle Scholar
  71. 71.
    Fraga MF, Ballestar E, Villar-Garea A et al (2005) Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37(4):391–400PubMedGoogle Scholar
  72. 72.
    Hatada I, Fukasawa M, Kimura M et al (2006) Genome-wide profiling of promoter methylation in human. Oncogene 25(21):3059–3064PubMedGoogle Scholar
  73. 73.
    Khulan B, Thompson RF, Ye K et al (2006) Comparative isoschizomer profiling of cytosine methylation: the HELP assay. Genome Res 16(8):1046–1055PubMedGoogle Scholar
  74. 74.
    Fazzari MJ, Greally JM (2004) Epigenomics: beyond CpG islands. Nat Rev Genet 5(6):446–455PubMedGoogle Scholar
  75. 75.
    Oda M, Glass JL, Thompson RF et al (2009) High-resolution genome-wide cytosine methylation profiling with simultaneous copy number analysis and optimization for limited cell numbers. Nucleic Acids Res 37(12):3829–3839PubMedGoogle Scholar
  76. 76.
    Meissner A, Mikkelsen TS, Gu H et al (2008) Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454(7205):766–770PubMedGoogle Scholar
  77. 77.
    Weber M, Davies JJ, Wittig D et al (2005) Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat Genet 37(8):853–862PubMedGoogle Scholar
  78. 78.
    Gebhard C, Schwarzfischer L, Pham TH et al (2006) Genome-wide profiling of CpG methylation identifies novel targets of aberrant hypermethylation in myeloid leukemia. Cancer Res 66(12):6118–6128PubMedGoogle Scholar
  79. 79.
    Rauch T, Li H, Wu X, Pfeifer GP (2006) MIRA-assisted microarray analysis, a new technology for the determination of DNA methylation patterns, identifies frequent methylation of homeodomain-containing genes in lung cancer cells. Cancer Res 66(16):7939–7947PubMedGoogle Scholar
  80. 80.
    Ball MP, Li JB, Gao Y et al (2009) Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells. Nat Biotechnol 27(4):361–368PubMedGoogle Scholar
  81. 81.
    Deng J, Shoemaker R, Xie B et al (2009) Targeted bisulfite sequencing reveals changes in DNA methylation associated with nuclear reprogramming. Nat Biotechnol 27(4):353–360PubMedGoogle Scholar
  82. 82.
    Hodges E, Smith A, Kendall J et al (2009) High definition profiling of mammalian DNA methylation by array capture and single molecule bisulfite sequencing. Genome Res 19(9):1593–1605PubMedGoogle Scholar
  83. 83.
    Down TA, Rakyan VK, Turner DJ et al (2008) A Bayesian deconvolution strategy for immunoprecipitation-based DNA methylome analysis. Nat Biotechnol 26(7):779–785PubMedGoogle Scholar
  84. 84.
    Pelizzola M, Koga Y, Urban AE et al (2008) MEDME: an experimental and analytical methodology for the estimation of DNA methylation levels based on microarray derived MeDIP-enrichment. Genome Res 18(10):1652–1659PubMedGoogle Scholar
  85. 85.
    Chan TL, Yuen ST, Kong CK et al (2006) Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer. Nat Genet 38(10):1178–1183PubMedGoogle Scholar
  86. 86.
    Chen SS, Raval A, Johnson A et al (2009) Epigenetic changes during disease progression in a murine model of human chronic lymphocytic leukemia. Proc Natl Acad Sci USA 106(32):13433–13438PubMedGoogle Scholar
  87. 87.
    Judson H, Stewart A, Leslie A et al (2006) Relationship between point gene mutation, chromosomal abnormality, and tumour suppressor gene methylation status in colorectal adenomas. J Pathol 210(3):344–350PubMedGoogle Scholar
  88. 88.
    Schulmann K, Sterian A, Berki A et al (2005) Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett’s-associated neoplastic progression and predicts progression risk. Oncogene 24(25):4138–4148PubMedGoogle Scholar
  89. 89.
    Banno K, Yanokura M, Susumu N et al (2006) Relationship of the aberrant DNA hypermethylation of cancer-related genes with carcinogenesis of endometrial cancer. Oncol Rep 16(6):1189–1196PubMedGoogle Scholar
  90. 90.
    Jeronimo C, Usadel H, Henrique R et al (2001) Quantitation of GSTP1 methylation in non-neoplastic prostatic tissue and organ-confined prostate adenocarcinoma. J Natl Cancer Inst 93(22):1747–1752PubMedGoogle Scholar
  91. 91.
    Palmisano WA, Divine KK, Saccomanno G et al (2000) Predicting lung cancer by detecting aberrant promoter methylation in sputum. Cancer Res 60(21):5954–5958PubMedGoogle Scholar
  92. 92.
    Esteller M, Fraga MF, Guo M et al (2001) DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis. Hum Mol Genet 10(26):3001–3007PubMedGoogle Scholar
  93. 93.
    Moore LE, Pfeiffer RM, Poscablo C et al (2008) Genomic DNA hypomethylation as a biomarker for bladder cancer susceptibility in the Spanish Bladder Cancer Study: a case-control study. Lancet Oncol 9(4):359–366PubMedGoogle Scholar
  94. 94.
    Jurgens B, Schmitz-Drager BJ, Schulz WA (1996) Hypomethylation of L1 LINE sequences prevailing in human urothelial carcinoma. Cancer Res 56(24):5698–5703PubMedGoogle Scholar
  95. 95.
    Righini CA, de Fraipont F, Timsit JF et al (2007) Tumor-specific methylation in saliva: a promising biomarker for early detection of head and neck cancer recurrence. Clin Cancer Res 13(4):1179–1185PubMedGoogle Scholar
  96. 96.
    Esteller M, Gonzalez S, Risques RA et al (2001) K-ras and p16 aberrations confer poor prognosis in human colorectal cancer. J Clin Oncol 19(2):299–304PubMedGoogle Scholar
  97. 97.
    Veeck J, Niederacher D, An H et al (2006) Aberrant methylation of the Wnt antagonist SFRP1 in breast cancer is associated with unfavourable prognosis. Oncogene 25(24):3479–3488PubMedGoogle Scholar
  98. 98.
    Widschwendter A, Muller HM, Fiegl H et al (2004) DNA methylation in serum and tumors of cervical cancer patients. Clin Cancer Res 10(2):565–571PubMedGoogle Scholar
  99. 99.
    Corcoran M, Parker A, Orchard J et al (2005) ZAP-70 methylation status is associated with ZAP-70 expression status in chronic lymphocytic leukemia. Haematologica 90(8):1078–1088PubMedGoogle Scholar
  100. 100.
    Hegi ME, Diserens AC, Gorlia T et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352(10):997–1003PubMedGoogle Scholar
  101. 101.
    Strathdee G, MacKean MJ, Illand M, Brown R (1999) A role for methylation of the hMLH1 promoter in loss of hMLH1 expression and drug resistance in ovarian cancer. Oncogene 18:2335–2341PubMedGoogle Scholar
  102. 102.
    Gifford G, Paul J, Vasey PA, Kaye SB, Brown R (2004) The acquisition of hMLH1 methylation in plasma DNA after chemotherapy predicts poor survival for ovarian cancer patients. Clin Cancer Res 10(13):4420–4426PubMedGoogle Scholar
  103. 103.
    Plumb JA, Strathdee G, Sludden J, Kaye SB, Brown R (2000) Reversal of drug resistance in human tumor xenografts of 2′-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer Res 60:6039–6044PubMedGoogle Scholar
  104. 104.
    Daskalakis M, Nguyen TT, Nguyen C et al (2002) Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2′-deoxycytidine (decitabine) treatment. Blood 100(8):2957–2964PubMedGoogle Scholar
  105. 105.
    Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B et al (2006) Phase I/II study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. Blood 108(10):3271–3279Google Scholar
  106. 106.
    Saunthararajah Y, Hillery CA, Lavelle D et al (2003) Effects of 5-aza-2′-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease. Blood 102(12):3865–3870PubMedGoogle Scholar
  107. 107.
    Laird PW, Jackson-Grusby L, Fazeli A et al (1995) Suppression of intestinal neoplasia by DNA hypomethylation. Cell 81(2):197–205PubMedGoogle Scholar
  108. 108.
    Opavsky R, Wang SH, Trikha P et al (2007) CpG island methylation in a mouse model of lymphoma is driven by the genetic configuration of tumor cells. PLoS Genet 3(9):1757–1769PubMedGoogle Scholar
  109. 109.
    Bailey VJ, Easwaran H, Zhang Y et al (2009) MS-qFRET: a quantum dot-based method for analysis of DNA methylation. Genome Res 19(8):1455–1461PubMedGoogle Scholar
  110. 110.
    Nakayama M, Bennett CJ, Hicks JL et al (2003) Hypermethylation of the human glutathione S-transferase-pi gene (GSTP1) CpG island is present in a subset of proliferative inflammatory atrophy lesions but not in normal or hyperplastic epithelium of the prostate: a detailed study using laser-capture microdissection. Am J Pathol 163(3):923–933PubMedGoogle Scholar
  111. 111.
    Goessl C, Krause H, Muller M et al (2000) Fluorescent methylation-specific polymerase chain reaction for DNA-based detection of prostate cancer in bodily fluids. Cancer Res 60(21):5941–5945PubMedGoogle Scholar
  112. 112.
    Goessl C, Muller M, Miller K (2000) Methylation-specific PCR (MSP) for detection of tumour DNA in the blood plasma and serum of patients with prostate cancer. Prostate Cancer Prostatic Dis 3(S1):S17PubMedGoogle Scholar
  113. 113.
    Ogino S, Kawasaki T, Kirkner GJ, Kraft P, Loda M, Fuchs CS (2007) Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample. J Mol Diagn 9(3):305–314PubMedGoogle Scholar
  114. 114.
    Esteller M, Gaidano G, Goodman SN et al (2002) 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 94(1):26–32PubMedGoogle Scholar
  115. 115.
    Hibi K, Taguchi M, Nakayama H et al (2001) Molecular detection of p16 promoter methylation in the serum of patients with esophageal squamous cell carcinoma. Clin Cancer Res 7(10):3135–3138PubMedGoogle Scholar
  116. 116.
    Feng Q, Balasubramanian A, Hawes SE et al (2005) Detection of hypermethylated genes in women with and without cervical neoplasia. J Natl Cancer Inst 97(4):273–282PubMedGoogle Scholar
  117. 117.
    Brock MV, Hooker CM, Ota-Machida E et al (2008) DNA methylation markers and early recurrence in stage I lung cancer. N Engl J Med 358(11):1118–1128PubMedGoogle Scholar
  118. 118.
    Belinsky SA, Palmisano WA, Gilliland FD et al (2002) Aberrant promoter methylation in bronchial epithelium and sputum from current and former smokers. Cancer Res 62(8):2370–2377PubMedGoogle Scholar
  119. 119.
    Wong IH, Lo YM, Zhang J et al (1999) Detection of aberrant p16 methylation in the plasma and serum of liver cancer patients. Cancer Res 59(1):71–73PubMedGoogle Scholar
  120. 120.
    Esteller M, Garcia-Foncillas J, Andion E et al (2000) Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 343(19):1350–1354PubMedGoogle Scholar
  121. 121.
    Watanabe H, Okada G, Ohtsubo K et al (2006) Aberrant methylation of secreted apoptosis-related protein 2 (SARP2) in pure pancreatic juice in diagnosis of pancreatic neoplasms. Pancreas 32(4):382–389PubMedGoogle Scholar
  122. 122.
    Friedrich MG, Chandrasoma S, Siegmund KD et al (2005) Prognostic relevance of methylation markers in patients with non-muscle invasive bladder carcinoma. Eur J Cancer 41(17):2769–2778PubMedGoogle Scholar
  123. 123.
    Lombaerts M, van Wezel T, Philippo K et al (2006) E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines. Br J Cancer 94(5):661–671PubMedGoogle Scholar
  124. 124.
    Chiles MC, Ai L, Zuo C, Fan CY, Smoller BR (2003) E-cadherin promoter hypermethylation in preneoplastic and neoplastic skin lesions. Mod Pathol 16(10):1014–1018PubMedGoogle Scholar
  125. 125.
    Richiardi L, Fiano V, Vizzini L et al (2009) Promoter methylation in APC, RUNX3, and GSTP1 and mortality in prostate cancer patients. J Clin Oncol 27(19):3161–3168PubMedGoogle Scholar

Copyright information

© Springer Basel AG 2011

Authors and Affiliations

  • Yoon Jung Park
    • 1
  • Rainer Claus
    • 1
  • Dieter Weichenhan
    • 1
  • Christoph Plass
    • 1
  1. 1.Division of Epigenomics and Cancer Risk FactorsGerman Cancer Research CenterHeidelbergGermany

Personalised recommendations