The role of epigenetic alterations in pancreatic cancer

  • Norihiro Sato
  • Michael Goggins
Article

Abstract

The past several years have witnessed an explosive increase in our knowledge about epigenetic features in human cancers. It has become apparent that pancreatic cancer is an epigenetic disease, as it is a genetic disease, characterized by widespread and profound alterations in DNA methylation. The introduction of genome-wide screening techniques has accelerated the discovery of a growing list of genes with abnormal methylation patterns in pancreatic cancer, and some of these epigenetic events play a role in the neoplastic process. The detection and quantification of DNA methylation alterations in pancreatic juice is likely a promising tool for the diagnosis of pancreatic cancer. The potential reversibility of epigenetic changes in genes involved in tumor progression makes them attractive therapeutic targets, but the efficacy of epigenetic therapies in pancreatic cancer, such as the use of DNA methylation inhibitors, remains undetermined. In this review, we briefly summarize recent research findings in the field of pancreatic cancer epigenetics and discuss their biological and clinical implications.

Key words

Epigenetics Hypermethylation Hypomethylation Pancreatic cancer 

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References

  1. 1.
    Jemal, A, Murray, T, Ward, E, Samuels, A, Tiwari, RC, Ghafoor, A,  et al. 2005Cancer statistics, 2005CA Cancer J Clin551030PubMedCrossRefGoogle Scholar
  2. 2.
    Goggins, M, Kern, SE, Offerhaus, JA, Hruban, RH 1999Progress in cancer genetics: lessons from pancreatic cancerAnn Oncol1048PubMedCrossRefGoogle Scholar
  3. 3.
    Bardeesy, N, DePinho, RA 2002Pancreatic cancer biology and geneticsNat Rev Cancer2897909PubMedCrossRefGoogle Scholar
  4. 4.
    Kern, S, Hruban, R, Hollingsworth, MA, Brand, R, Adrian, TE, Jaffee, E,  et al. 2001A white paper: the product of a pancreas cancer think tankCancer Res61492332PubMedGoogle Scholar
  5. 5.
    Hansel, DE, Kern, SE, Hruban, RH 2003Molecular pathogenesis of pancreatic cancerAnnu Rev Genomics Hum Genet423756PubMedCrossRefGoogle Scholar
  6. 6.
    Crnogorac-Jurcevic, T, Efthimiou, E, Capelli, P, Blaveri, E, Baron, A, Terris, B,  et al. 2001Gene expression profiles of pancreatic cancer and stromal desmoplasiaOncogene20743746PubMedCrossRefGoogle Scholar
  7. 7.
    Crnogorac-Jurcevic, T, Efthimiou, E, Nielsen, T, Loader, J, Terris, B, Stamp, G,  et al. 2002Expression profiling of microdissected pancreatic adenocarcinomasOncogene21458794PubMedCrossRefGoogle Scholar
  8. 8.
    Argani, P, Iacobuzio-Donahue, C, Ryu, B, Rosty, C, Goggins, M, Wilentz, RE,  et al. 2001Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE)Clin Cancer Res738628PubMedGoogle Scholar
  9. 9.
    Argani, P, Rosty, C, Reiter, RE, Wilentz, RE, Murugesan, SR, Leach, SD,  et al. 2001Discovery of new markers of cancer through serial analysis of gene expression: prostate stem cell antigen is overexpressed in pancreatic adenocarcinomaCancer Res6143204PubMedGoogle Scholar
  10. 10.
    Iacobuzio-Donahue, CA, Maitra, A, Shen-Ong, GL, van Heek, T, Ashfaq, R, Meyer, R,  et al. 2002Discovery of novel tumor markers of pancreatic cancer using global gene expression technologyAm J Pathol160123949PubMedGoogle Scholar
  11. 11.
    Iacobuzio-Donahue, CA, Maitra, A, Olsen, M, Lowe, AW, van Heek, NT, Rosty, C,  et al. 2003Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarraysAm J Pathol162115162PubMedGoogle Scholar
  12. 12.
    Ryu, B, Jones, J, Blades, NJ, Parmigiani, G, Hollingsworth, MA, Hruban, RH,  et al. 2002Relationships and differentially expressed genes among pancreatic cancers examined by large-scale serial analysis of gene expressionCancer Res6281926PubMedGoogle Scholar
  13. 13.
    Han, H, Bearss, DJ, Browne, LW, Calaluce, R, Nagle, RB, Von Hoff, DD 2002Identification of differentially expressed genes in pancreatic cancer cells using cDNA microarrayCancer Res6228906PubMedGoogle Scholar
  14. 14.
    Logsdon, CD, Simeone, DM, Binkley, C, Arumugam, T, Greenson, JK, Giordano, TJ,  et al. 2003Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancerCancer Res63264957PubMedGoogle Scholar
  15. 15.
    Sato, N, Fukushima, N, Maitra, A, Iacobuzio-Donahue, CA, van Heek, NT, Cameron, JL,  et al. 2004Gene expression profiling identifies genes associated with invasive intraductal papillary mucinous neoplasms of the pancreasAm J Pathol16490314PubMedGoogle Scholar
  16. 16.
    Miyamoto, Y, Maitra, A, Ghosh, B, Zechner, U, Argani, P, Iacobuzio-Donahue, CA,  et al. 2003Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesisCancer Cell356576PubMedCrossRefGoogle Scholar
  17. 17.
    Berman, DM, Karhadkar, SS, Maitra, A, Montes De Oca, R, Gerstenblith, MR, Briggs, K,  et al. 2003Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumoursNature42584651Epub 2003 Sep 2014PubMedCrossRefGoogle Scholar
  18. 18.
    Thayer, SP, di Magliano, MP, Heiser, PW, Nielsen, CM, Roberts, DJ, Lauwers, GY,  et al. 2003Hedgehog is an early and late modiator of pancreatic cancer tumorigenesisNature4258516Epub 2003 Sep 2014PubMedCrossRefGoogle Scholar
  19. 19.
    Prasad, NB, Biankin, AV, Fukushima, N, Maitra, A, Dhara, S, Elkahloun, AG,  et al. 2005Gene expression profiles in pancreatic intraepithelial neoplasia reflect the effects of Hedgehog signaling on pancreatic ductal epithelial cellsCancer Res65161926PubMedCrossRefGoogle Scholar
  20. 20.
    Jones, PA, Baylin, SB 2002The fundamental role of epigenetic events in cancerNat Rev Genet341528PubMedCrossRefGoogle Scholar
  21. 21.
    Laird, PW 2003The power and the promise of DNA methylation markersNat Rev Cancer325366PubMedCrossRefGoogle Scholar
  22. 22.
    Issa, JP 2003Methylation and prognosis: of molecular clocks and hypermethylator phenotypesClin Cancer Res9287981PubMedGoogle Scholar
  23. 23.
    Cp, Issa JP. 2004G island methylator phenotype in cancerNat Rev Cancer498893CrossRefGoogle Scholar
  24. 24.
    Egger, G, Liang, G, Aparicio, A, Jones, PA 2004Epigenetics in human disease and prospects for epigenetic therapyNature42945763PubMedCrossRefGoogle Scholar
  25. 25.
    Esteller, M 2005DNA methylation and cancer therapy: new developments and expectationsCurr Opin Oncol175560PubMedCrossRefGoogle Scholar
  26. 26.
    Schutte, M, Hruban, RH, Geradts, J, Maynard, R, Hilgers, W, Rabindran, SK,  et al. 1997Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomasCancer Res57312630PubMedGoogle Scholar
  27. 27.
    Ueki, T, Toyota, M, Sohn, T, Yeo, CJ, Issa, JP, Hruban, RH,  et al. 2000Hypermethylation of multiple genes in pancreatic adenocarcinomaCancer Res6018359PubMedGoogle Scholar
  28. 28.
    Ueki, T, Toyota, M, Skinner, H, Walter, KM, Yeo, CJ, Issa, JP,  et al. 2001Identification and characterization of differentially methylated CpG islands in pancreatic carcinomaCancer Res6185406PubMedGoogle Scholar
  29. 29.
    Esteller, M, Sparks, A, Toyota, M, Sanchez-Cespedes, M, Capella, G, Peinado, MA,  et al. 2000Analysis of adenomatous polyposis coli promoter hypermethylation in human cancerCancer Res60436671PubMedGoogle Scholar
  30. 30.
    Jansen, M, Fukushima, N, Rosty, C, Walter, K, Altink, R, Heek, TV,  et al. 2002Aberrant methylation of the 5′ CpG island of TSLC1 is common in pancreatic ductal adenocarcinoma and is first manifest in high-grade PanlNsCancer Biol Ther12936PubMedGoogle Scholar
  31. 31.
    Fukushima, N, Sato, N, Sahin, F, Su, GH, Hruban, RH, Goggins, M 2003Aberrant methylation of suppressor of cytokine signalling-1 (SOCS-1) gene in pancreatic ductal neoplasmsBr J Cancer8933843PubMedCrossRefGoogle Scholar
  32. 32.
    Matsubayashi, H, Sato, N, Fukushima, N, Yeo, CJ, Walter, KM, Brune, K,  et al. 2003Methylation of cycline D2 is observed frequently in pancreatic cancer but is also an age-related phenomenon in gastrointestinal tissuesClin Cancer Res9144652PubMedGoogle Scholar
  33. 33.
    Dammann, R, Schagdarsurengin, U, Liu, L, Otto, N, Gimm, O, Dralle, H,  et al. 2003Frequent RASSF1A promoter hypermethylation and K-ras mutations in pancreatic carcinomaOncogene22380612PubMedCrossRefGoogle Scholar
  34. 34.
    Kuroki, T, Yendamuri, S, Trapasso, F, Matsuyama, A, Aqeilan, RI, Alder, H,  et al. 2004The tumor suppressor gene WWOX at FRA16D is involved in pancreatic carcinogenesisClin Cancer Res10245965PubMedCrossRefGoogle Scholar
  35. 35.
    Wada, M, Yazumi, S, Takaishi, S, Hasegawa, K, Sawada, M, Tanaka, H,  et al. 2004Frequent loss of RUNX3 gene expression in human bile duct and pancreatic cancer cell linesOncogene2324017PubMedCrossRefGoogle Scholar
  36. 36.
    Sakai, M, Hibi, K, Koshikawa, K, Inoue, S, Takeda, S, Kaneko, T,  et al. 2004Frequent promoter methylation and gene silencing of CDH13 in pancreatic cancerCancer Sci9558891PubMedCrossRefGoogle Scholar
  37. 37.
    Xu, S, Furukawa, T, Kanai, N, Sunamura, M, Horii, A 2005Abrogation of DUSP6 by hypermethylation in human pancreatic cancerJ Hum Genet5015967Epub 2005 Apr 2012PubMedCrossRefGoogle Scholar
  38. 38.
    Martin, ST, Sato, N, Dhara, S, Chang, R, Hustinx, SR, Abe, T,  et al. 2005Aberrant methylation of the human hedgehog interacting protein (HHIP) gene in pancreatic neoplasmsCancer Biol Ther472833PubMedCrossRefGoogle Scholar
  39. 39.
    Zagon, IS, Smith, JP, McLaughlin, PJ 1999Human pancreatic cancer cell proliferation in tissue culture is tonically inhibited by opioid growth factorInt J Oncol1457784PubMedGoogle Scholar
  40. 40.
    Zagon, IS, Hytrek, SD, Smith, JP, McLaughlin, PJ 1997Opioid growth factor (OGF) inhibits human pancreatic cancer transplanted into nude miceCancer Lett11216775PubMedCrossRefGoogle Scholar
  41. 41.
    Fukushima, N, Sato, N, Ueki, T, Rosty, C, Walter, KM, Wilentz, RE,  et al. 2002Aberrant methylation of preproenkephalin and p16 genes in pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinomaAm J Pathol160157381PubMedGoogle Scholar
  42. 42.
    Hruban, RH, Adsay, NV, Albores-Saavedra, J, Compton, C, Garrett, ES, Goodman, SN,  et al. 2001Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesionsAm J Surg Pathol2557986PubMedCrossRefGoogle Scholar
  43. 43.
    Hruban, RH, Takaori, K, Klimstra, DS, Adsay, NV, Albores-Saavedra, J, Biankin, AV,  et al. 2004An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasmsAm J Surg Pathol2897787PubMedGoogle Scholar
  44. 44.
    Sato, N, Ueki, T, Fukushima, N, Iacobuzio-Donahue, CA, Yeo, CJ, Cameron, JL,  et al. 2002Aberrant methylation of CpG islands in intraductal papillary mucinous neoplasms of the pancreasGastroenterology12336572PubMedCrossRefGoogle Scholar
  45. 45.
    Sato, N, Fukushima, N, Maitra, A, Matsubayashi, H, Yeo, CJ, Cameron, JL,  et al. 2003Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarraysCancer Res63373542PubMedGoogle Scholar
  46. 46.
    Tokumaru, Y, Yamashita, K, Osada, M, Nomoto, S, Sun, DI, Xiao, Y,  et al. 2004Inverse correlation between cyclin A1 hypermethylation and p53 mutation in head and neck cancer identified by reversal of epigenetic silencingCancer Res6459827PubMedCrossRefGoogle Scholar
  47. 47.
    Mandelker, DL, Yamashita, K, Tokumaru, Y, Mimori, K, Howard, DL, Tanaka, Y,  et al. 2005PGP9.5 Promoter methylation is an independent prognostic factor for esophageal squamous cell carcinomaCancer Res6549638PubMedCrossRefGoogle Scholar
  48. 48.
    Ohki, R, Nemoto, J, Murasawa, H, Oda, E, Inazawa, J, Tanaka, N,  et al. 2000Reprimo, a new candidate mediator of the p53-mediated cell cycle arrest at the G2 phaseJ Biol Chem27522 62730Google Scholar
  49. 49.
    Sato, N, Maitra, A, Fukushima, N, van Heek, NT, Matsubayashi, H, Iacobuzio-Donahue, CA,  et al. 2003Frequent hypomethylation of multiple genes overexpressed in pancreatic ductal adenocarcinomaCancer Res63415866PubMedGoogle Scholar
  50. 50.
    Takahashi, T, Suzuki, M, Shigematsu, H, Shivapurkar, N, Echebiri, C, Nomura, M,  et al. 2005Aberrant methylation of Reprimo in human malignanciesInt J Cancer11550310PubMedCrossRefGoogle Scholar
  51. 51.
    Sato, N, Fukushima, N, Maehara, N, Matsubayashi, H, Koopmann, J, Su, GH,  et al. 2003SPARC/osteonectin is a frequent target for aberrant methylation in pancreatic adenocarcinoma and a mediator of tumor-stromal interactionsOncogene22502130PubMedCrossRefGoogle Scholar
  52. 52.
    Sato, N, Parker, AR, Fukushima, N, Miyagi, Y, Iacobuzio-Donahue, CA, Eshleman, JR,  et al. 2005Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinomaOncogene248508PubMedCrossRefGoogle Scholar
  53. 53.
    Hagihara, A, Miyamoto, K, Furuta, J, Hiraoka, N, Wakazono, K, Seki, S,  et al. 2004Identification of 27 5′ CpG islands aberrantly methylated and 13 genes silenced in human pancreatic cancersOncogene23870510PubMedCrossRefGoogle Scholar
  54. 54.
    Sato, N, Matsubayashi, H, Abe, T, Fukushima, N, Goggins, M 2005Epigenetic down-regulation of CDKN1C/p57KIP2 in pancreatic ductal neoplasms identified by gene expression profilingClin Cancer Res1146818PubMedCrossRefGoogle Scholar
  55. 55.
    Rhee, I, Bachman, KE, Park, BH, Jair, KW, Yen, RW, Schuebel, KE,  et al. 2002DNMT1 and DNMT3b cooperate to silence genes in human cancer cellsNature4165526PubMedCrossRefGoogle Scholar
  56. 56.
    Robert, MF, Morin, S, Beaulieu, N, Gauthier, F, Chute, IC, Barsalou, A,  et al. 2003DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cellsNat Genet33615PubMedCrossRefGoogle Scholar
  57. 57.
    Turker, MS 2002Gene silencing in mammalian cells and the spread of DNA methylationOncogene21538893PubMedCrossRefGoogle Scholar
  58. 58.
    Song, JZ, Stirzaker, C, Harrison, J, Melki, JR, Clark, SJ 2002Hypermethylation trigger of the glutathione-S-transferase gene (GSTP1) in prostate cancer cellsOncogene21104861PubMedCrossRefGoogle Scholar
  59. 59.
    Di Croce, L, Raker, VA, Corsaro, M, Fazi, F, Fanelli, M, Faretta, M,  et al. 2002Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factorScience295107982PubMedCrossRefGoogle Scholar
  60. 60.
    Bachman, KE, Park, BH, Rhee, I, Rajagopalan, H, Herman, JG, Baylin, SB,  et al. 2003Histone modifications and silencing prior to DNA methylation of a tumor suppressor geneCancer Cell38995PubMedCrossRefGoogle Scholar
  61. 61.
    Leu, YW, Yan, PS, Fan, M, Jin, VX, Liu, JC, Curran, EM,  et al. 2004Loss of estrogen receptor signaling triggers epigenetic silencing of downstream targets in breast cancerCancer Res64818492PubMedCrossRefGoogle Scholar
  62. 62.
    Kawasaki, H, Taira, K 2004Induction of DNA methylation and gene silencing by short interfering RNAs in human cellsNature4312117Epub 2004 Aug 2015PubMedCrossRefGoogle Scholar
  63. 63.
    Morris, KV, Chan, SW, Jacobsen, SE, Looney, DJ 2004Small interfering RNA-induced transcriptional gene silencing in human cellsScience305128992Epub 2004 Aug 1285PubMedCrossRefGoogle Scholar
  64. 64.
    Lu, J, Getz, G, Miska, EA, Alvarez-Saavedra, E, Lamb, J, Peck, D,  et al. 2005MicroRNA expression profiles classify human cancersNature4358348PubMedCrossRefGoogle Scholar
  65. 65.
    Puolakkainen, PA, Brekken, RA, Muneer, S, Sage, EH 2004Enhanced growth of pancreatic tumors in SPARC-null mice is associated with decreased deposition of extracellular matrix and reduced tumor cell apoptosisMol Cancer Res221524PubMedGoogle Scholar
  66. 66.
    Tai, IT, Dai, M, Owen, DA, Chen, LB 2005Genome-wide expression analysis of therapy-resistant tumors reveals SPARC as a novel target for caner therapyJ Clin Invest1151492502PubMedCrossRefGoogle Scholar
  67. 67.
    Okami, J, Simeone, DM, Logsdon, CD 2004Silencing of the hypoxia-inducible cell death protein BNIP3 in pancreatic cancerCancer Res64533846PubMedCrossRefGoogle Scholar
  68. 68.
    Erkan, M, Kleeff, J, Esposito, I, Giese, T, Ketterer, K, Buchler, MW,  et al. 2005Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosisOncogene24442132PubMedCrossRefGoogle Scholar
  69. 69.
    Akada, M, Crnogorac-Jurcevic, T, Lattimore, S, Mahon, P, Lopes, R, Sunamura, M,  et al. 2005Intrinsic chemoresistance to gemcitabine is associated with decreased expression of BNIP3 in pancreatic cancerClin Cancer Res113094101PubMedCrossRefGoogle Scholar
  70. 70.
    Sato, N, Maehara, N, Goggins, M 2004Gene expression profiling of tumor-stromal interactions between pancreatic cancer cells and stromal fibroblastsCancer Res6469506PubMedCrossRefGoogle Scholar
  71. 71.
    Sato, N, Matsubayashi, H, Fukushima, N, Goggins, M 2005The chemokine receptor CXCR4 is regulated by DNA methylation in pancreatic cancerCancer Biol Ther4706PubMedCrossRefGoogle Scholar
  72. 72.
    Feinberg, AP, Tycko, B 2004The history of cancer epigeneticsNat Rev Cancer414353PubMedCrossRefGoogle Scholar
  73. 73.
    Ehrlich, M 2002DNA methylation in cancer: too much, but also too littleOncogene21540013PubMedCrossRefGoogle Scholar
  74. 74.
    Chen, RZ, Pettersson, U, Beard, C, Jackson-Grusby, L, Jaenisch, R 1998DNA hypomethylation leads to elevated mutation ratesNature3958993PubMedCrossRefGoogle Scholar
  75. 75.
    Gaudet, F, Hodgson, JG, Eden, A, Jackson-Grusby, L, Dausman, J, Gray, JW,  et al. 2003Induction of tumors in mice by genomic hypomethylationScience30048992PubMedCrossRefGoogle Scholar
  76. 76.
    Kim, YI 2004Folate and DNA methylation: a mechanistic link between folate deficiency and colorectal cancer?Cancer Epidemiol Biomarkers Prev135119PubMedGoogle Scholar
  77. 77.
    Stolzenberg-Solomon, RZ, Albanes, D, Nieto, FJ, Hartman, TJ, Tangrea, JA, Rautalahti, M,  et al. 1999Pancreatic cancer risk and nutrition-related methyl-group availability indicators in male smokersJ Natl Cancer Inst9153541PubMedCrossRefGoogle Scholar
  78. 78.
    Matsubayashi, H, Skinner, HG, Iacobuzio-Donahue, C, Abe, T, Sato, N, Sohn, TA,  et al. 2005Chromosomal loss in pancreaticobiliary cancers with deficient methylenetetrahydrofolate reductase genotypesClin Gastroenterol Hepatol375260PubMedCrossRefGoogle Scholar
  79. 79.
    Rosty, C, Ueki, T, Argani, P, Jansen, M, Yeo, CJ, Cameron, JL,  et al. 2002Overexpression of S100A4 in pancreatic ductal adenocarcinomas is associated with poor differentiation and DNA hypomethylationAm J Pathol1604550PubMedGoogle Scholar
  80. 80.
    Sato, N, Fukushima, N, Matsubayashi, H, Goggins, M 2004Identification of maspin and S100P as novel hypomethylation targets in pancreatic cancer using global gene expression profilingOncogene2315318PubMedCrossRefGoogle Scholar
  81. 81.
    Futscher, BW, Oshiro, MM, Wozniak, RJ, Holtan, N, Hanigan, CL, Duan, H,  et al. 2002Role for DNA methylation in the control of cell type specific maspin expressionNat Genet311759PubMedCrossRefGoogle Scholar
  82. 82.
    Ohike, N, Maass, N, Mundhenke, C, Biallek, M, Zhang, M, Jonat, W,  et al. 2003Clinicopathological significance and molecular regulation of maspin expression in ductal adenocarcinoma of the pancreasCancer Lett199193200PubMedCrossRefGoogle Scholar
  83. 83.
    Fitzgerald, M, Oshiro, M, Holtan, N, Krager, K, Cullen, JJ, Futscher, BW,  et al. 2003Human pancreatic carcinoma cells activate maspin expression through loss of epigenetic controlNeoplasia542736PubMedGoogle Scholar
  84. 84.
    Baylin, S, Bestor, TH 2002Altered methylation patterns in cancer cell genomes: cause or consequence?Cancer Cell1299305PubMedCrossRefGoogle Scholar
  85. 85.
    De Smet, C, Loriot, A, Boon, T 2004Promoter-dependent mechanism leading to selective hypomethylation within the 5′ region of gene MAGE-A1 in tumor cellsMol Cell Biol24478190PubMedCrossRefGoogle Scholar
  86. 86.
    Goggins, M, Canto, M, Hruban, R 2000Can we screen high-risk individuals to detect early pancreatic carcinoma?J Surg Oncol742438PubMedCrossRefGoogle Scholar
  87. 87.
    Rosty, C, Goggins, M 2002Early detection of pancreatic carcinomaHematol Oncol Clin North Am163752PubMedCrossRefGoogle Scholar
  88. 88.
    Klein, AP, Brune, KA, Petersen, GM, Goggins, M, Tersmette, AC, Offerhaus, GJ,  et al. 2004Prospective risk of pancreatic cancer in familial pancreatic cancer kindredsCancer Res6426348PubMedCrossRefGoogle Scholar
  89. 89.
    Canto, MI, Goggins, M, Yeo, CJ, Griffin, C, Axilbund, JE, Brune, K,  et al. 2004Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approachClin Gastroenterol Hepatol260621PubMedCrossRefGoogle Scholar
  90. 90.
    Fukushima, N, Walter, KM, Uek, T, Sato, N, Matsubayashi, H, Cameron, JL,  et al. 2003Diagnosing pancreatic cancer using methylation specific PCR analysis of pancreatic juiceCancer Biol Ther27883PubMedGoogle Scholar
  91. 91.
    Klump, B, Hsieh, CJ, Nehls, O, Dette, S, Holzmann, K, Kiesslich, R,  et al. 2003Methylation status of p14ARF and p16INK4a as detected in pancreatic secretionsBr J Cancer8821722PubMedCrossRefGoogle Scholar
  92. 92.
    Herman, JG, Graff, JR, Myohanen, S, Nelkin, BD, Baylin, SB 1996Methylation-specific PCR: a novel PCR assay for methylation status of CpG islandsProc Natl Acad Sci USA9398216PubMedCrossRefGoogle Scholar
  93. 93.
    Yan, L, McFaul, C, Howes, N, Leslie, J, Lancaster, G, Wong, T,  et al. 2005Molecular analysis to detect pancreatic ductal adenocarcinoma in high-risk groupsGastroenterology128212430PubMedCrossRefGoogle Scholar
  94. 94.
    Matsubayashi, H, Canto, M, Sato, N, Klein, A, Abe, T, Yamashita, K,  et al. 2006DNA methylation alterations in the pancreatic juice of patients with suspected pancreatic diseaseCancer Res66120817PubMedCrossRefGoogle Scholar
  95. 95.
    Matsubayashi, H, Sato, N, Brune, K, Blackford, AL, Hruban, RH, Canto, M,  et al. 2005Age- and disease-related methylation of multiple genes in nonneoplastic duodenum and in duodenal juiceClin Cancer Res1157383PubMedGoogle Scholar
  96. 96.
    Yao, X, Hu, JF, Daniels, M, Shiran, H, Zhou, X, Yan, H,  et al. 2003A methylated oligonucleotide inhibits IGF2 expression and enhances survival in a model of hepatocellular carcinomaJ Clin Invest11126573PubMedCrossRefGoogle Scholar
  97. 97.
    Karpf, AR, Jones, DA 2002Reactivating the expression of methylation silenced genes in human cancerOncogene215496503PubMedCrossRefGoogle Scholar
  98. 98.
    Kelly, WK, Richon, VM, O'Connor, O, Curley, T, MacGregor-Curtelli, B, Tong, W,  et al. 2003Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenouslyClin Cancer Res9357888PubMedGoogle Scholar
  99. 99.
    Issa, JP, Gharibyan, V, Cortes, J, Jelinek, J, Morris, G, Verstovsek, S,  et al. 2005Phase II study of Low-dose Decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylateJ Clin Oncol23394856PubMedCrossRefGoogle Scholar
  100. 100.
    Issa, JP 2003DecitabineCurr Opin Oncol1544651PubMedCrossRefGoogle Scholar
  101. 101.
    Bender, CM, Pao, MM, Jones, PA 1998Inhibition of DNA methylation by 5-aza-2′-deoxycytidine suppresses the growth of human tumor cell linesCancer Res5895101PubMedGoogle Scholar
  102. 102.
    Belinsky, SA, Klinge, DM, Stidley, CA, Issa, JP, Herman, JG, March, TH,  et al. 2003Inhibition of DNA methylation and histone deacetylation prevents murine lung cancerCancer Res63708993PubMedGoogle Scholar
  103. 103.
    Juttermann, R, Li, E, Jaenisch, R 1994Toxicity of 5-aza-2′-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylationProc Natl Acad Sci U S A9111 797801CrossRefGoogle Scholar
  104. 104.
    Jackson-Grusby, L, Laird, PW, Magge, SN, Moeller, BJ, Jaenisch, R 1997Mutagenicity of 5-aza-2′-deoxycytidine is mediated by the mammalian DNA methyltransferaseProc Natl Acad Sci U S A9446815PubMedCrossRefGoogle Scholar
  105. 105.
    Cheng, JC, Matsen, CB, Gonzales, FA, Ye, W, Greer, S, Marquez, VE,  et al. 2003Inhibition of DNA methylation and reactivation of silenced genes by zebularineJ Natl Cancer Inst95399409PubMedGoogle Scholar
  106. 106.
    Missiaglia, E, Donadelli, M, Palmieri, M, Crnogorac-Jurcevic, T, Scarpa, A, Lemoine, NR 2005Growth delay of human pancreatic cancer cells by methylase inhibitor 5-aza-2′-deoxycytidine treatment is associated with activation of the interferon signalling pathwayOncogene24199211PubMedCrossRefGoogle Scholar
  107. 107.
    Bert, T, Lubomierski, N, Gangsauge, S, Munch, K, Printz, H, Prasnikar, N,  et al. 2002Expression spectrum and methylation-dependent regulation of melanoma antigen-encoding gene family members in pancreatic cancer cellsPancreatology214654PubMedCrossRefGoogle Scholar
  108. 108.
    Donadelli, M, Costanzo, C, Faggioli, L, Scupoli, MT, Moore, PS, Bassi, C,  et al. 2003Trichostatin A, an inhibitor of histone deacetylases, strongly suppresses growth of pancreatic adenocarcinoma cellsMol Carcinog385969PubMedCrossRefGoogle Scholar
  109. 109.
    Sato, N, Ohta, T, Kitagawa, H, Kayahara, M, Ninomiya, I, Fushida, S,  et al. 2004FR901228, a novel histone deacetylase inhibitor, induces cell cycle arrest and subsequent apoptosis in refractory human pancreatic cancer cellsInt J Oncol2467985PubMedGoogle Scholar
  110. 110.
    Moore, PS, Barbi, S, Donadelli, M, Costanzo, C, Bassi, C, Palmieri, M,  et al. 2004Gene expression profiling after treatment with the histone deacetylase inhibitor trichostatin A reveals altered expression of both pro- and anti-apoptotic genes in pancreatic adenocarcinoma cellsBiochim Biophys Acta169316776PubMedCrossRefGoogle Scholar
  111. 111.
    Guo, Y, Pakneshan, P, Gladu, J, Slack, A, Szyf, M, Rabbani, SA 2002Regulation of DNA methylation in human breast cancer. Effect on the urokinase-type plasminogen activator gene production and tumor invasionJ Biol Chem27741 5719Google Scholar
  112. 112.
    Pakneshan, P, Xing, RH, Rabbani, SA 2003Methylation status of uPA promoter as a molecular mechanism regulating prostate cancer invasion and growth in vitro and in vivoFASEB J1710818PubMedCrossRefGoogle Scholar
  113. 113.
    Sato, N, Maehara, N, Su, GH, Goggins, M 2003Effects of 5-aza-2′-deoxycytidine on matrix metalloproteinase expression and pancreatic cancer cell invasivenessJ Natl Cancer Inst9532730PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 2006

Authors and Affiliations

  • Norihiro Sato
    • 1
    • 4
  • Michael Goggins
    • 1
    • 2
    • 3
  1. 1.Department of Pathology, The Johns Hopkins Medical InstitutionsThe Sol Goldman Center for Pancreatic Cancer ResearchBaltimoreUSA
  2. 2.Department of OncologyThe Johns Hopkins Medical InstitutionsBaltimoreUSA
  3. 3.Department of MedicineThe Johns Hopkins Medical InstitutionsBaltimoreUSA
  4. 4.Department of Surgery and Oncology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan

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