Skip to main content
SpringerLink
Log in

DNA Hypomethylation and Activation of Germline-Specific Genes in Cancer

  • Chapter
  • First Online:
Book cover Epigenetic Alterations in Oncogenesis

Part of the book series: Advances in Experimental Medicine and Biology ((volume 754))

Abstract

DNA methylation, occurring at cytosines in CpG dinucleotides, is a potent mechanism of transcriptional repression. Proper genomic methylation ­patterns become profoundly altered in cancer cells: both gains (hypermethylation) and losses (hypomethylation) of methylated sites are observed. Although DNA hypomethylation is detected in a vast majority of human tumors and affects many genomic regions, its role in tumor biology remains elusive. Surprisingly, DNA hypomethylation in cancer was found to cause the aberrant activation of only a limited group of genes. Most of these are normally expressed exclusively in germline cells and were grouped under the term “cancer-germline” (CG) genes. CG genes represent unique examples of genes that rely primarily on DNA methylation for their tissue-specific expression. They are also being exploited to uncover the mechanisms that lead to DNA hypomethylation in tumors. Moreover, as CG genes encode tumor-specific antigens, their activation in cancer highlights a direct link between epigenetic alterations and tumor immunity. As a result, clinical trials combining epigenetic drugs with anti-CG antigen vaccines are being considered.

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 EPUB and 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

References

  1. Akers SN, Odunsi K, Karpf AR (2010) Regulation of cancer germline antigen gene expression: implications for cancer immunotherapy. Future Oncol 6(5):717–732

    PubMed  CAS  Google Scholar 

  2. Almeida LG, Sakabe NJ, deOliveira AR, Silva MC, Mundstein AS, Cohen T, Chen YT, Chua R, Gurung S, Gnjatic S, Jungbluth AA, Caballero OL, Bairoch A, Kiesler E, White SL, Simpson AJ, Old LJ, Camargo AA, Vasconcelos AT (2009) CTdatabase: a knowledge-base of high-throughput and curated data on cancer-testis antigens. Nucleic Acids Res 37(Database issue):D816–819

    PubMed  CAS  Google Scholar 

  3. Antequera F, Boyes J, Bird A (1990) High levels of de novo methylation and altered chromatin structure at CpG islands in cell lines. Cell 62(3):503–514

    PubMed  CAS  Google Scholar 

  4. Bai S, He B, Wilson EM (2005) Melanoma antigen gene protein MAGE-11 regulates androgen receptor function by modulating the interdomain interaction. Mol Cell Biol 25(4):1238–1257

    PubMed  CAS  Google Scholar 

  5. Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP (1998) Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res 72:141–196

    PubMed  CAS  Google Scholar 

  6. Bestor TH (2000) The DNA methyltransferases of mammals. Hum Mol Genet 9(16):2395–2402

    PubMed  CAS  Google Scholar 

  7. Bird AP (1980) DNA methylation and the frequency of CpG in animal DNA. Nucleic Acids Res 8:1499–1504

    PubMed  CAS  Google Scholar 

  8. Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16(1):6–21

    PubMed  CAS  Google Scholar 

  9. Boël P, Wildmann C, Sensi M-L, Brasseur R, Renauld J-C, Coulie P, Boon T, van der Bruggen P (1995) BAGE, a new gene encoding an antigen recognized on human melanomas by cytolytic T lymphocytes. Immunity 2:167–175

    PubMed  Google Scholar 

  10. Boon T, Cerottini J-C, Van den Eynde B, van der Bruggen P, Van Pel A (1994) Tumor antigens recognized by T lymphocytes. Annu Rev Immunol 12:337–365

    PubMed  CAS  Google Scholar 

  11. Boon T, Coulie PG, Van den Eynde BJ, van der Bruggen P (2006) Human T cell responses against melanoma. Annu Rev Immunol 24:175–208

    PubMed  CAS  Google Scholar 

  12. Boyes J, Bird A (1992) 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(1):327–333

    PubMed  CAS  Google Scholar 

  13. Brandeis M, Frank D, Keshet I, Siegfried Z, Mendelsohn M, Nemes A, Temper V, Razin A, Cedar H (1994) Sp1 elements protect a CpG island from de novo methylation. Nature 371(6496):435–438

    PubMed  CAS  Google Scholar 

  14. Cadieux B, Ching TT, VandenBerg SR, Costello JF (2006) Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation. Cancer Res 66(17):8469–8476

    PubMed  CAS  Google Scholar 

  15. Cedar H, Bergman Y (2009) Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet 10(5):295–304

    PubMed  CAS  Google Scholar 

  16. Chen ZX, Riggs AD (2011) DNA methylation and demethylation in mammals. J Biol Chem 286(21):18347–18353

    PubMed  CAS  Google Scholar 

  17. Cho B, Lee H, Jeong S, Bang YJ, Lee HJ, Hwang KS, Kim HY, Lee YS, Kang GH, Jeoung DI (2003) Promoter hypomethylation of a novel cancer/testis antigen gene CAGE is correlated with its aberrant expression and is seen in premalignant stage of gastric carcinoma. Biochem Biophys Res Commun 307(1):52–63

    PubMed  CAS  Google Scholar 

  18. Cilensek ZM, Yehiely F, Kular RK, Deiss LP (2002) A member of the GAGE family of tumor antigens is an anti-apoptotic gene that confers resistance to Fas/CD95/APO-1, Interferon-gamma, taxol and gamma-irradiation. Cancer Biol Ther 1(4):380–387

    PubMed  CAS  Google Scholar 

  19. Cross SH, Bird AP (1995) CpG islands and genes. Curr Opin Genet Dev 5:309–314

    PubMed  CAS  Google Scholar 

  20. De Plaen E, Arden K, Traversari C, Gaforio JJ, Szikora J-P, De Smet C, Brasseur F, van der Bruggen P, Lethé B, Lurquin C, Brasseur R, Chomez P, De Backer O, Cavenee W, Boon T (1994) Structure, chromosomal localization and expression of twelve genes of the MAGE family. Immunogenetics 40:360–369

    PubMed  CAS  Google Scholar 

  21. De Plaen E, Naerhuyzen B, De Smet C, Szikora J-P, Boon T (1997) Alternative promoters of gene MAGE4a. Genomics 40:305–313

    PubMed  Google Scholar 

  22. De Smet C, Loriot A (2010) DNA hypomethylation in cancer: epigenetic scars of a neoplastic journey. Epigenetics 5(3):206–213

    Google Scholar 

  23. De Smet C, Lurquin C, van der Bruggen P, De Plaen E, Brasseur F, Boon T (1994) Sequence and expression pattern of the human MAGE2 gene. Immunogenetics 39:121–129

    PubMed  Google Scholar 

  24. De Smet C, Courtois SJ, Faraoni I, Lurquin C, Szikora JP, De Backer O, Boon T (1995) Involvement of two Ets binding sites in the transcriptional activation of the MAGE1 gene. Immunogenetics 42(4):282–290

    PubMed  Google Scholar 

  25. De Smet C, De Backer O, Faraoni I, Lurquin C, Brasseur F, Boon T (1996) The activation of human gene MAGE-1 in tumor cells is correlated with genome-wide demethylation. Proc Natl Acad Sci USA 93(14):7149–7153

    PubMed  Google Scholar 

  26. De Smet C, Lurquin C, Lethé B, Martelange V, Boon T (1999) DNA methylation is the primary silencing mechanism for a set of germ line- and tumor-specific genes with a CpG-rich promoter. Mol Cell Biol 19:7327–7335

    PubMed  Google Scholar 

  27. De Smet C, Loriot A, Boon T (2004) Promoter-dependent mechanism leading to selective hypomethylation within the 5′ region of gene MAGE-A1 in tumor cells. Mol Cell Biol 24(11):4781–4790

    PubMed  Google Scholar 

  28. Doyle JM, Gao J, Wang J, Yang M, Potts PR (2010) MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases. Mol Cell 39(6):963–974

    PubMed  CAS  Google Scholar 

  29. Ehrlich M (2002) DNA methylation in cancer: too much, but also too little. Oncogene 21(35):5400–5413

    PubMed  CAS  Google Scholar 

  30. Feinberg AP, Gehrke CW, Kuo KC, Ehrlich M (1988) Reduced genomic 5-methylcytosine content in human colonic neoplasia. Cancer Res 48(5):1159–1161

    PubMed  CAS  Google Scholar 

  31. Felsenfeld G, Groudine M (2003) Controlling the double helix. Nature 421(6921):448–453

    PubMed  Google Scholar 

  32. Flatau E, Gonzales FA, Michalowsky LA, Jones PA (1984) DNA methylation in 5-aza-2′-deoxycytidine-resistant variants of C3H 10T1/2C18 cells. Mol Cell Biol 4(10):2098–2102

    PubMed  CAS  Google Scholar 

  33. Gaudet F, Hodgson JG, Eden A, Jackson-Grusby L, Dausman J, Gray JW, Leonhardt H, Jaenisch R (2003) Induction of tumors in mice by genomic hypomethylation. Science 300(5618):489–492

    PubMed  CAS  Google Scholar 

  34. Gaugler B, Van den Eynde B, van der Bruggen P, Romero P, Gaforio JJ, De Plaen E, Lethé B, Brasseur F, Boon T (1994) Human gene MAGE-3 codes for an antigen recognized on a melanoma by autologous cytolytic T lymphocytes. J Exp Med 179:921–930

    PubMed  CAS  Google Scholar 

  35. Goodyear O, Agathanggelou A, Novitzky-Basso I, Siddique S, McSkeane T, Ryan G, Vyas P, Cavenagh J, Stankovic T, Moss P, Craddock C (2010) Induction of a CD8+ T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and sodium valproate in patients with acute myeloid leukemia and myelodysplasia. Blood 116(11):1908–1918

    PubMed  CAS  Google Scholar 

  36. Grunwald C, Koslowski M, Arsiray T, Dhaene K, Praet M, Victor A, Morresi-Hauf A, Lindner M, Passlick B, Lehr HA, Schafer SC, Seitz G, Huber C, Sahin U, Tureci O (2006) Expression of multiple epigenetically regulated cancer/germline genes in nonsmall cell lung cancer. Int J Cancer 118(10):2522–2528

    PubMed  CAS  Google Scholar 

  37. Haas GG Jr, D’Cruz OJ, De Bault LE (1988) Distribution of human leukocyte antigen-ABC and -D/DR antigens in the unfixed human testis. Am J Reprod Immunol Microbiol 18(2):47–51

    PubMed  Google Scholar 

  38. Hoffmann MJ, Muller M, Engers R, Schulz WA (2006) Epigenetic control of CTCFL/BORIS and OCT4 expression in urogenital malignancies. Biochem Pharmacol 72(11):1577–1588

    PubMed  CAS  Google Scholar 

  39. Holliday R, Pugh JE (1975) DNA modification mechanisms and gene activity during ­development. Science 186:226–232

    Google Scholar 

  40. Hong JA, Kang Y, Abdullaev Z, Flanagan PT, Pack SD, Fischette MR, Adnani MT, Loukinov DI, Vatolin S, Risinger JI, Custer M, Chen GA, Zhao M, Nguyen DM, Barrett JC, Lobanenkov VV, Schrump DS (2005) Reciprocal binding of CTCF and BORIS to the NY-ESO-1 promoter coincides with derepression of this cancer-testis gene in lung cancer cells. Cancer Res 65(17):7763–7774

    PubMed  CAS  Google Scholar 

  41. Jackson K, Yu MC, Arakawa K, Fiala E, Youn B, Fiegl H, Muller-Holzner E, Widschwendter M, Ehrlich M (2004) DNA hypomethylation is prevalent even in low-grade breast cancers. Cancer Biol Ther 3(12):1225–1231

    PubMed  CAS  Google Scholar 

  42. James SR, Link PA, Karpf AR (2006) Epigenetic regulation of X-linked cancer/germline antigen genes by DNMT1 and DNMT3b. Oncogene 25(52):6975–6985

    PubMed  CAS  Google Scholar 

  43. Jones PA, Wolkowicz MJ, Rideout WM III, Gonzales FA, Marziasz CM, Coetzee GA, Tapscott SJ (1990) De novo methylation of the MyoD1 CpG island during the establishment of immortal cell lines. Proc Natl Acad Sci USA 87(16):6117–6121

    PubMed  CAS  Google Scholar 

  44. Jungbluth AA, Chen YT, Stockert E, Busam KJ, Kolb D, Iversen K, Coplan K, Williamson B, Altorki N, Old LJ (2001) Immunohistochemical analysis of NY-ESO-1 antigen expression in normal and malignant human tissues. Int J Cancer 92(6):856–860

    PubMed  CAS  Google Scholar 

  45. Kaneda A, Tsukamoto T, Takamura-Enya T, Watanabe N, Kaminishi M, Sugimura T, Tatematsu M, Ushijima T (2004) Frequent hypomethylation in multiple promoter CpG islands is associated with global hypomethylation, but not with frequent promoter hypermethylation. Cancer Sci 95(1):58–64

    PubMed  CAS  Google Scholar 

  46. Kang Y, Hong JA, Chen GA, Nguyen DM, Schrump DS (2007) Dynamic transcriptional regulatory complexes including BORIS, CTCF and Sp1 modulate NY-ESO-1 expression in lung cancer cells. Oncogene 26(30):4394–4403

    PubMed  CAS  Google Scholar 

  47. Karpf AR, Lasek AW, Ririe TO, Hanks AN, Grossman D, Jones DA (2004) Limited gene activation in tumor and normal epithelial cells treated with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine. Mol Pharmacol 65(1):18–27

    PubMed  CAS  Google Scholar 

  48. Karpf AR, Bai S, James SR, Mohler JL, Wilson EM (2009) Increased expression of androgen receptor coregulator MAGE-11 in prostate cancer by DNA hypomethylation and cyclic AMP. Mol Cancer Res 7(4):523–535

    PubMed  CAS  Google Scholar 

  49. Kholmanskikh O, Loriot A, Brasseur F, De Plaen E, De Smet C (2008) Expression of BORIS in melanoma: lack of association with MAGE-A1 activation. Int J Cancer 122(4):777–784

    PubMed  CAS  Google Scholar 

  50. Khong HT, Wang QJ, Rosenberg SA (2004) Identification of multiple antigens recognized by tumor-infiltrating lymphocytes from a single patient: tumor escape by antigen loss and loss of MHC expression. J Immunother 27(3):184–190

    PubMed  Google Scholar 

  51. Kondo T, Zhu X, Asa SL, Ezzat S (2007) The cancer/testis antigen melanoma-associated antigen-A3/A6 is a novel target of fibroblast growth factor receptor 2-IIIb through histone H3 modifications in thyroid cancer. Clin Cancer Res 13(16):4713–4720

    PubMed  CAS  Google Scholar 

  52. Koslowski M, Bell C, Seitz G, Lehr HA, Roemer K, Muntefering H, Huber C, Sahin U, Tureci O (2004) Frequent nonrandom activation of germ-line genes in human cancer. Cancer Res 64(17):5988–5993

    PubMed  CAS  Google Scholar 

  53. Lin CH, Hsieh SY, Sheen IS, Lee WC, Chen TC, Shyu WC, Liaw YF (2001) Genome-wide hypomethylation in hepatocellular carcinogenesis. Cancer Res 61(10):4238–4243

    PubMed  CAS  Google Scholar 

  54. Link PA, Gangisetty O, James SR, Woloszynska-Read A, Tachibana M, Shinkai Y, Karpf AR (2009) Distinct roles for histone methyltransferases G9a and GLP in cancer germ-line antigen gene regulation in human cancer cells and murine embryonic stem cells. Mol Cancer Res 7(6):851–862

    PubMed  CAS  Google Scholar 

  55. Lorincz MC, Schubeler D, Goeke SC, Walters M, Groudine M, Martin DI (2000) Dynamic analysis of proviral induction and de novo methylation: implications for a histone deacetylase-independent, methylation density-dependent mechanism of transcriptional repression. Mol Cell Biol 20(3):842–850

    PubMed  CAS  Google Scholar 

  56. Loriot A, Boon T, De Smet C (2003) Five new human cancer-germline genes identified among 12 genes expressed in spermatogonia. Int J Cancer 105(3):371–376

    PubMed  CAS  Google Scholar 

  57. Loriot A, De Plaen E, Boon T, De Smet C (2006) Transient down-regulation of DNMT1 methyltransferase leads to activation and stable hypomethylation of MAGE-A1 in melanoma cells. J Biol Chem 281(15):10118–10126

    PubMed  CAS  Google Scholar 

  58. Loriot A, Sterpin C, De Backer O, De Smet C (2008) Mouse embryonic stem cells induce targeted DNA demethylation within human MAGE-A1 transgenes. Epigenetics 3(1):38–42

    PubMed  Google Scholar 

  59. Loukinov DI, Pugacheva E, Vatolin S, Pack SD, Moon H, Chernukhin I, Mannan P, Larsson E, Kanduri C, Vostrov AA, Cui H, Niemitz EL, Rasko JE, Docquier FM, Kistler M, Breen JJ, Zhuang Z, Quitschke WW, Renkawitz R, Klenova EM, Feinberg AP, Ohlsson R, Morse HC III, Lobanenkov VV (2002) BORIS, a novel male germ-line-specific protein associated with epigenetic reprogramming events, shares the same 11-zinc-finger domain with CTCF, the insulator protein involved in reading imprinting marks in the soma. Proc Natl Acad Sci USA 99(10):6806–6811

    PubMed  CAS  Google Scholar 

  60. Lucas S, De Smet C, Arden KC, Viars CS, Lethe B, Lurquin C, Boon T (1998) Identification of a new MAGE gene with tumor-specific expression by representational difference analysis. Cancer Res 58(4):743–752

    PubMed  CAS  Google Scholar 

  61. Lurquin C, De Smet C, Brasseur F, Muscatelli F, Martelange V, De Plaen E, Brasseur R, Monaco AP, Boon T (1997) Two members of the human MAGEB gene family located in Xp21.3 are expressed in tumors of various histological origins. Genomics 46(3):397–408

    PubMed  CAS  Google Scholar 

  62. Macleod D, Charlton J, Mullins J, Bird AP (1994) Sp1 sites in the mouse aprt gene promoter are required to prevent methylation of the CpG island. Genes Dev 8(19):2282–2292

    PubMed  CAS  Google Scholar 

  63. Martelange V, De Smet C, De Plaen E, Lurquin C, Boon T (2000) Identification on a human sarcoma of two new genes with tumor-specific expression. Cancer Res 60(14):3848–3855

    PubMed  CAS  Google Scholar 

  64. Monte M, Simonatto M, Peche LY, Bublik DR, Gobessi S, Pierotti MA, Rodolfo M, Schneider C (2006) MAGE-A tumor antigens target p53 transactivation function through histone deacetylase recruitment and confer resistance to chemotherapeutic agents. Proc Natl Acad Sci USA 103(30):11160–11165

    PubMed  CAS  Google Scholar 

  65. Nagao T, Higashitsuji H, Nonoguchi K, Sakurai T, Dawson S, Mayer RJ, Itoh K, Fujita J (2003) MAGE-A4 interacts with the liver oncoprotein gankyrin and suppresses its tumorigenic activity. J Biol Chem 278(12):10668–10674

    PubMed  CAS  Google Scholar 

  66. Novak P, Jensen T, Oshiro MM, Watts GS, Kim CJ, Futscher BW (2008) Agglomerative epigenetic aberrations are a common event in human breast cancer. Cancer Res 68(20):8616–8625

    PubMed  CAS  Google Scholar 

  67. Novak P, Jensen TJ, Garbe JC, Stampfer MR, Futscher BW (2009) Stepwise DNA methylation changes are linked to escape from defined proliferation barriers and mammary epithelial cell immortalization. Cancer Res 69(12):5251–5258

    PubMed  CAS  Google Scholar 

  68. Oikawa T, Yamada T (2003) Molecular biology of the Ets family of transcription factors. Gene 303:11–34

    PubMed  CAS  Google Scholar 

  69. Peikert T, Specks U, Farver C, Erzurum SC, Comhair SA (2006) Melanoma antigen A4 is expressed in non-small cell lung cancers and promotes apoptosis. Cancer Res 66(9): 4693–4700

    PubMed  CAS  Google Scholar 

  70. Rao M, Chinnasamy N, Hong JA, Zhang Y, Zhang M, Xi S, Liu F, Marquez VE, Morgan RA, Schrump DS (2011) Inhibition of histone lysine methylation enhances cancer-testis antigen expression in lung cancer cells: implications for adoptive immunotherapy of cancer. Cancer Res 71(12):4192–4204

    PubMed  CAS  Google Scholar 

  71. Rauch TA, Zhong X, Wu X, Wang M, Kernstine KH, Wang Z, Riggs AD, Pfeifer GP (2008) High-resolution mapping of DNA hypermethylation and hypomethylation in lung cancer. Proc Natl Acad Sci USA 105(1):252–257

    PubMed  CAS  Google Scholar 

  72. Riggs AD (1989) DNA methylation and cell memory. Cell Biophys 15(1–2):1–13

    PubMed  CAS  Google Scholar 

  73. Sahin U, Tureci O, Schmitt H, Cochlovius B, Johannes T, Schmits R, Stenner F, Luo G, Schobert I, Pfreundschuh M (1995) Human neoplasms elicit multiple specific immune responses in the autologous host. Proc Natl Acad Sci USA 92:11810–11813

    PubMed  CAS  Google Scholar 

  74. Sahin U, Tureci O, Chen YT, Seitz G, Villena-Heinsen C, Old LJ, Pfreundschuh M (1998) Expression of multiple cancer/testis (CT) antigens in breast cancer and melanoma: basis for polyvalent CT vaccine strategies. Int J Cancer 78(3):387–389

    PubMed  CAS  Google Scholar 

  75. Scanlan MJ, Gordon CM, Williamson B, Lee SY, Chen YT, Stockert E, Jungbluth A, Ritter G, Jager D, Jager E, Knuth A, Old LJ (2002) Identification of cancer/testis genes by database mining and mRNA expression analysis. Int J Cancer 98(4):485–492

    PubMed  CAS  Google Scholar 

  76. Scanlan MJ, Simpson AJ, Old LJ (2004) The cancer/testis genes: review, standardization, and commentary. Cancer Immun 4:1

    PubMed  Google Scholar 

  77. Shen L, Kondo Y, Guo Y, Zhang J, Zhang L, Ahmed S, Shu J, Chen X, Waterland RA, Issa JP (2007) Genome-wide profiling of DNA methylation reveals a class of normally methylated CpG island promoters. PLoS Genet 3(10):2023–2036

    PubMed  CAS  Google Scholar 

  78. Sigalotti L, Coral S, Nardi G, Spessotto A, Cortini E, Cattarossi I, Colizzi F, Altomonte M, Maio M (2002) Promoter methylation controls the expression of MAGE2, 3 and 4 genes in human cutaneous melanoma. J Immunother 25(1):16–26

    PubMed  CAS  Google Scholar 

  79. Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ (2005) Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer 5(8):615–625

    PubMed  CAS  Google Scholar 

  80. Suske G (1999) The Sp-family of transcription factors. Gene 238(2):291–300

    PubMed  CAS  Google Scholar 

  81. Swann JB, Smyth MJ (2007) Immune surveillance of tumors. J Clin Invest 117(5):1137–1146

    PubMed  CAS  Google Scholar 

  82. Takahashi K, Shichijo S, Noguchi M, Hirohata M, Itoh K (1995) Identification of MAGE-1 and MAGE-4 proteins in spermatogonia and primary spermatocytes of testis. Cancer Res 55(16):3478–3482

    PubMed  CAS  Google Scholar 

  83. Tilman G, Loriot A, Van Beneden A, Arnoult N, Londono-Vallejo JA, De Smet C, Decottignies A (2009) Subtelomeric DNA hypomethylation is not required for telomeric sister chromatid exchanges in ALT cells. Oncogene 28(14):1682–1693

    PubMed  CAS  Google Scholar 

  84. Van den Eynde B, Peeters O, De Backer O, Gaugler B, Lucas S, Boon T (1995) A new family of genes coding for an antigen recognized by autologous cytolytic T lymphocytes on a human melanoma. J Exp Med 182:689–698

    PubMed  Google Scholar 

  85. van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, Knuth A, Boon T (1991) A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254(5038):1643–1647

    PubMed  Google Scholar 

  86. Van Der Bruggen P, Zhang Y, Chaux P, Stroobant V, Panichelli C, Schultz ES, Chapiro J, Van Den Eynde BJ, Brasseur F, Boon T (2002) Tumor-specific shared antigenic peptides recognized by human T cells. Immunol Rev 188(1):51–64

    Google Scholar 

  87. Vatolin S, Abdullaev Z, Pack SD, Flanagan PT, Custer M, Loukinov DI, Pugacheva E, Hong JA, Morse H III, Schrump DS, Risinger JI, Barrett JC, Lobanenkov VV (2005) Conditional expression of the CTCF-paralogous transcriptional factor BORIS in normal cells results in demethylation and derepression of MAGE-A1 and reactivation of other cancer-testis genes. Cancer Res 65(17):7751–7762

    PubMed  CAS  Google Scholar 

  88. Walsh CP, Bestor TH (1999) Cytosine methylation and mammalian development. Genes Dev 13(1):26–34

    PubMed  CAS  Google Scholar 

  89. Wang Z, Zhang J, Zhang Y, Lim SH (2006) SPAN-Xb expression in myeloma cells is dependent on promoter hypomethylation and can be upregulated pharmacologically. Int J Cancer 118(6):1436–1444

    PubMed  CAS  Google Scholar 

  90. Wang J, Emadali A, Le Bescont A, Callanan M, Rousseaux S, Khochbin S (2011) Induced malignant genome reprogramming in somatic cells by testis-specific factors. Biochim Biophys Acta 1809(4–6):221–225

    PubMed  CAS  Google Scholar 

  91. Weber J, Salgaller M, Samid D, Johnson B, Herlyn M, Lassam N, Treisman J, Rosenberg SA (1994) Expression of the MAGE-1 tumor antigen is up-regulated by the demethylating agent 5-aza-2′-deoxycytidine. Cancer Res 54(7):1766–1771

    PubMed  CAS  Google Scholar 

  92. Weber M, Davies JJ, Wittig D, Oakeley EJ, Haase M, Lam WL, Schubeler D (2005) Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat Genet 37(8):853–862

    PubMed  CAS  Google Scholar 

  93. Weber M, Hellmann I, Stadler MB, Ramos L, Paabo S, Rebhan M, Schubeler D (2007) Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet 39(4):457–466

    PubMed  CAS  Google Scholar 

  94. Wilson VL, Jones PA (1983) DNA methylation decreases in aging but not in immortal cells. Science 220(4601):1055–1057

    PubMed  CAS  Google Scholar 

  95. Woloszynska-Read A, James SR, Link PA, Yu J, Odunsi K, Karpf AR (2007) DNA methylation-dependent regulation of BORIS/CTCFL expression in ovarian cancer. Cancer Immun 7:21

    PubMed  Google Scholar 

  96. Woloszynska-Read A, Mhawech-Fauceglia P, Yu J, Odunsi K, Karpf AR (2008) Intertumor and intratumor NY-ESO-1 expression heterogeneity is associated with promoter-specific and global DNA methylation status in ovarian cancer. Clin Cancer Res 14(11):3283–3290

    PubMed  CAS  Google Scholar 

  97. Woloszynska-Read A, James SR, Song C, Jin B, Odunsi K, Karpf AR (2010) BORIS/CTCFL expression is insufficient for cancer-germline antigen gene expression and DNA hypomethylation in ovarian cell lines. Cancer Immun 10:6

    PubMed  Google Scholar 

  98. Yang B, O’Herrin SM, Wu J, Reagan-Shaw S, Ma Y, Bhat KM, Gravekamp C, Setaluri V, Peters N, Hoffmann FM, Peng H, Ivanov AV, Simpson AJ, Longley BJ (2007) MAGE-A, mMage-b, and MAGE-C proteins form complexes with KAP1 and suppress p53-dependent apoptosis in MAGE-positive cell lines. Cancer Res 67(20):9954–9962

    PubMed  CAS  Google Scholar 

  99. Yang B, Wu J, Maddodi N, Ma Y, Setaluri V, Longley BJ (2007) Epigenetic control of MAGE gene expression by the KIT tyrosine kinase. J Invest Dermatol 127(9):2123–2128

    PubMed  CAS  Google Scholar 

  100. Yegnasubramanian S, Haffner MC, Zhang Y, Gurel B, Cornish TC, Wu Z, Irizarry RA, Morgan J, Hicks J, DeWeese TL, Isaacs WB, Bova GS, De Marzo AM, Nelson WG (2008) DNA hypomethylation arises later in prostate cancer progression than CpG island hypermethylation and contributes to metastatic tumor heterogeneity. Cancer Res 68(21):8954–8967

    PubMed  CAS  Google Scholar 

  101. Yoder JA, Walsh CP, Bestor TH (1997) Cytosine methylation and the ecology of intragenomic parasites. Trends Genet 13(8):335–340

    PubMed  CAS  Google Scholar 

  102. Zhu X, Asa SL, Ezzat S (2008) Fibroblast growth factor 2 and estrogen control the balance of histone 3 modifications targeting MAGE-A3 in pituitary neoplasia. Clin Cancer Res 14(7):1984–1996

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Genetics and Epigenetics, de Duve Institute, Catholic University of Louvain, Brussels, Belgium

    Charles De Smet & Axelle Loriot

Authors
  1. Charles De Smet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Axelle Loriot
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Charles De Smet .

Editor information

Editors and Affiliations

  1. University of Nebraska Medical Center, Eppley Institute for Research in Cancer, 985950 Nebraska Medical Center, Omaha, 68198, Nebraska, USA

    Adam R. Karpf

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

De Smet, C., Loriot, A. (2013). DNA Hypomethylation and Activation of Germline-Specific Genes in Cancer. In: Karpf, A. (eds) Epigenetic Alterations in Oncogenesis. Advances in Experimental Medicine and Biology, vol 754. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9967-2_7

Download citation

Publish with us

Policies and ethics

Search

Navigation