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DNA and Histone Methylation in Colon Cancer

Its Biological Impact and Clinical Implications

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DNA and Histone Methylation as Cancer Targets

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

Colorectal cancers (CRCs) are thought to arise through accumulation of genetic and epigenetic alterations. CRC genomes exhibit dual-faceted DNA methylation abnormality, global hypomethylation with CpG island hypermethylation, and CRCs are classified into two groups based on whether their genomes exhibit microsatellite instability (MSI) or chromosomal instability (CIN). In addition, a subset of CRCs is characterized by concurrent hypermethylation of multiple CpG islands, known as the CpG island methylator phenotype (CIMP). Genomic instability and epigenetic alterations are tightly linked, and CRCs with MSI largely overlap CIMP-positive tumors, while CIN is associated with global DNA hypomethylation. Dysregulation of histone methylation and altered expression of histone modifying enzymes are also commonly observed in CRC, indicating their critical roles in CRC development. Evidence now suggests that DNA and histone methylation could potentially serve as biomarkers useful for CRC diagnosis, risk assessment and prediction of therapeutic effects and prognosis. Although many studies examining clinical applications are still at an early phase, it is anticipated that further investigation will lead to improved prevention and management of CRC.

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References

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136:E359–E386

    Article  CAS  PubMed  Google Scholar 

  2. Jasperson KW, Tuohy TM, Neklason DW, Burt RW (2010) Hereditary and familial colon cancer. Gastroenterology 138:2044–2058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Carethers JM, Jung BH (2015) Genetics and genetic biomarkers in sporadic colorectal cancer. Gastroenterology 149:1177–1190. e3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fodde R, Smits R, Clevers H (2001) APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer 1:55–67

    Article  CAS  PubMed  Google Scholar 

  5. Lynch HT, Snyder CL, Shaw TG, Heinen CD, Hitchins MP (2015) Milestones of Lynch syndrome: 1895–2015. Nat Rev Cancer 15:181–194

    Article  CAS  PubMed  Google Scholar 

  6. Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H 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 57:808–811

    CAS  PubMed  Google Scholar 

  7. Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP et al (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A 95:6870–6875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Okugawa Y, Grady WM, Goel A (2015) Epigenetic alterations in colorectal cancer: emerging biomarkers. Gastroenterology 149:1204–1225. e12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lao VV, Grady WM (2011) Epigenetics and colorectal cancer. Nat Rev Gastroenterol Hepatol 8:686–700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Goel A, Boland CR (2012) Epigenetics of colorectal cancer. Gastroenterology 143:1442–1460. e1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Vaiopoulos AG, Athanasoula K, Papavassiliou AG (1842) Epigenetic modifications in colorectal cancer: molecular insights and therapeutic challenges. Biochim Biophys Acta 2014:971–980

    Google Scholar 

  12. Nakagawa H, Chadwick RB, Peltomaki P, Plass C, Nakamura Y, de La Chapelle A (2001) Loss of imprinting of the insulin-like growth factor II gene occurs by biallelic methylation in a core region of H19-associated CTCF-binding sites in colorectal cancer. Proc Natl Acad Sci U S A 98:591–596

    Article  CAS  PubMed  Google Scholar 

  13. Sakatani T, Kaneda A, Iacobuzio-Donahue CA, Carter MG, de Boom WS, Okano H et al (2005) Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice. Science 307:1976–1978

    Article  CAS  PubMed  Google Scholar 

  14. Suzuki H, Tokino T, Shinomura Y, Imai K, Toyota M (2008) DNA methylation and cancer pathways in gastrointestinal tumors. Pharmacogenomics 9:1917–1928

    Article  CAS  PubMed  Google Scholar 

  15. Schnekenburger M, Diederich M (2012) Epigenetics offer new horizons for colorectal cancer prevention. Curr Colorectal Cancer Rep 8:66–81

    Article  PubMed  PubMed Central  Google Scholar 

  16. Suzuki H, Maruyama R, Yamamoto E, Kai M (2012) DNA methylation and microRNA dysregulation in cancer. Mol Oncol 6:567–578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kumegawa K, Maruyama R, Yamamoto E, Ashida M, Kitajima H, Tsuyada A et al (2016) A genomic screen for long noncoding RNA genes epigenetically silenced by aberrant DNA methylation in colorectal cancer. Sci Rep 6:26699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Irizarry RA, Ladd-Acosta C, Wen B, Wu Z, Montano C, Onyango P et al (2009) The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 41:178–186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Matsuzaki K, Deng G, Tanaka H, Kakar S, Miura S, Kim YS (2005) The relationship between global methylation level, loss of heterozygosity, and microsatellite instability in sporadic colorectal cancer. Clin Cancer Res 11:8564–8569

    Article  CAS  PubMed  Google Scholar 

  20. Estecio MR, Gharibyan V, Shen L, Ibrahim AE, Doshi K, He R et al (2007) LINE-1 hypomethylation in cancer is highly variable and inversely correlated with microsatellite instability. PLoS One 2:e399

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Ogino S, Kawasaki T, Nosho K, Ohnishi M, Suemoto Y, Kirkner GJ et al (2008) LINE-1 hypomethylation is inversely associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer. Int J Cancer 122:2767–2773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cancer Genome Atlas Network (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487:330–337

    Article  CAS  Google Scholar 

  23. Suzuki H, Yamamoto E, Maruyama R, Niinuma T, Kai M (2014) Biological significance of the CpG island methylator phenotype. Biochem Biophys Res Commun 455:35–42

    Article  CAS  PubMed  Google Scholar 

  24. Toyota M, Ho C, Ahuja N, Jair KW, Li Q, Ohe-Toyota M et al (1999) Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification. Cancer Res 59:2307–2312

    CAS  PubMed  Google Scholar 

  25. Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP (1999) CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A 96:8681–8686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Toyota M, Ohe-Toyota M, Ahuja N, Issa JP (2000) Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype. Proc Natl Acad Sci U S A 97:710–715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. van Rijnsoever M, Grieu F, Elsaleh H, Joseph D, Iacopetta B (2002) Characterisation of colorectal cancers showing hypermethylation at multiple CpG islands. Gut 51:797–802

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hawkins N, Norrie M, Cheong K, Mokany E, Ku SL, Meagher A et al (2002) CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability. Gastroenterology 122:1376–1387

    Article  CAS  PubMed  Google Scholar 

  29. Samowitz WS, Albertsen H, Herrick J, Levin TR, Sweeney C, Murtaugh MA et al (2005) Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology 129:837–845

    Article  CAS  PubMed  Google Scholar 

  30. Goel A, Nagasaka T, Arnold CN, Inoue T, Hamilton C, Niedzwiecki D et al (2007) The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer. Gastroenterology 132:127–138

    Article  CAS  PubMed  Google Scholar 

  31. Cheng YW, Pincas H, Bacolod MD, Schemmann G, Giardina SF, Huang J et al (2008) CpG island methylator phenotype associates with low-degree chromosomal abnormalities in colorectal cancer. Clin Cancer Res 14:6005–6013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ogino S, Kawasaki T, Kirkner GJ, Ohnishi M, Fuchs CS (2007) 18q loss of heterozygosity in microsatellite stable colorectal cancer is correlated with CpG island methylator phenotype-negative (CIMP-0) and inversely with CIMP-low and CIMP-high. BMC Cancer 7:72

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Yamashita K, Dai T, Dai Y, Yamamoto F, Perucho M (2003) Genetics supersedes epigenetics in colon cancer phenotype. Cancer Cell 4:121–131

    Article  CAS  PubMed  Google Scholar 

  34. Anacleto C, Leopoldino AM, Rossi B, Soares FA, Lopes A, Rocha JC et al (2005) Colorectal cancer “methylator phenotype”: fact or artifact? Neoplasia 7:331–335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Issa JP (2004) CpG island methylator phenotype in cancer. Nat Rev Cancer 4:988–993

    Article  CAS  PubMed  Google Scholar 

  36. Ogino S, Cantor M, Kawasaki T, Brahmandam M, Kirkner GJ, Weisenberger DJ et al (2006) CpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies. Gut 55:1000–1006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA et al (2006) CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38:787–793

    Article  CAS  PubMed  Google Scholar 

  38. Ogino S, Kawasaki T, Kirkner GJ, Loda M, Fuchs CS (2006) CpG island methylator phenotype-low (CIMP-low) in colorectal cancer: possible associations with male sex and KRAS mutations. J Mol Diagn 8:582–588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Shen L, Toyota M, Kondo Y, Lin E, Zhang L, Guo Y et al (2007) Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proc Natl Acad Sci U S A 104:18654–18659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yagi K, Akagi K, Hayashi H, Nagae G, Tsuji S, Isagawa T et al (2010) Three DNA methylation epigenotypes in human colorectal cancer. Clin Cancer Res 16:21–33

    Article  CAS  PubMed  Google Scholar 

  41. Hinoue T, Weisenberger DJ, Lange CP, Shen H, Byun HM, Van Den Berg D et al (2012) Genome-scale analysis of aberrant DNA methylation in colorectal cancer. Genome Res 22:271–282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hinoue T, Weisenberger DJ, Pan F, Campan M, Kim M, Young J et al (2009) Analysis of the association between CIMP and BRAF in colorectal cancer by DNA methylation profiling. PLoS One 4:e8357

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Suzuki H, Igarashi S, Nojima M, Maruyama R, Yamamoto E, Kai M et al (2010) IGFBP7 is a p53-responsive gene specifically silenced in colorectal cancer with CpG island methylator phenotype. Carcinogenesis 31:342–349

    Article  CAS  PubMed  Google Scholar 

  44. Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR (2008) Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 132:363–374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 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 9:305–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Karpinski P, Walter M, Szmida E, Ramsey D, Misiak B, Kozlowska J et al (2013) Intermediate- and low-methylation epigenotypes do not correspond to CpG island methylator phenotype (low and -zero) in colorectal cancer. Cancer Epidemiol Biomark Prev 22:201–208

    Article  CAS  Google Scholar 

  47. Guinney J, Dienstmann R, Wang X, de Reynies A, Schlicker A, Soneson C et al (2015) The consensus molecular subtypes of colorectal cancer. Nat Med 21:1350–1356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Rashid A, Shen L, Morris JS, Issa JP, Hamilton SR (2001) CpG island methylation in colorectal adenomas. Am J Pathol 159:1129–1135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Chan AO, Broaddus RR, Houlihan PS, Issa JP, Hamilton SR, Rashid A (2002) CpG island methylation in aberrant crypt foci of the colorectum. Am J Pathol 160:1823–1830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Suzuki H, Watkins DN, Jair KW, Schuebel KE, Markowitz SD, Chen WD et al (2004) Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet 36:417–422

    Article  CAS  PubMed  Google Scholar 

  51. Kim YH, Petko Z, Dzieciatkowski S, Lin L, Ghiassi M, Stain S et al (2006) CpG island methylation of genes accumulates during the adenoma progression step of the multistep pathogenesis of colorectal cancer. Genes Chromosomes Cancer 45:781–789

    Article  CAS  PubMed  Google Scholar 

  52. Yamamoto E, Suzuki H, Yamano HO, Maruyama R, Nojima M, Kamimae S et al (2012) Molecular dissection of premalignant colorectal lesions reveals early onset of the CpG island methylator phenotype. Am J Pathol 181:1847–1861

    Article  CAS  PubMed  Google Scholar 

  53. Chan AO, Issa JP, Morris JS, Hamilton SR, Rashid A (2002) Concordant CpG island methylation in hyperplastic polyposis. Am J Pathol 160:529–536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yagi K, Takahashi H, Akagi K, Matsusaka K, Seto Y, Aburatani H et al (2012) Intermediate methylation epigenotype and its correlation to KRAS mutation in conventional colorectal adenoma. Am J Pathol 180:616–625

    Article  CAS  PubMed  Google Scholar 

  55. Rex DK, Ahnen DJ, Baron JA, Batts KP, Burke CA, Burt RW et al (2012) Serrated lesions of the colorectum: review and recommendations from an expert panel. Am J Gastroenterol 107:1315–1329. quiz 4, 30

    Article  PubMed  PubMed Central  Google Scholar 

  56. IJspeert JE, Vermeulen L, Meijer GA, Dekker E (2015) Serrated neoplasia-role in colorectal carcinogenesis and clinical implications. Nat Rev Gastroenterol Hepatol 12:401–409

    Article  CAS  PubMed  Google Scholar 

  57. Kambara T, Simms LA, Whitehall VL, Spring KJ, Wynter CV, Walsh MD et al (2004) BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut 53:1137–1144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yamauchi M, Morikawa T, Kuchiba A, Imamura Y, Qian ZR, Nishihara R et al (2012) Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Gut 61:847–854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Burnett-Hartman AN, Newcomb PA, Potter JD, Passarelli MN, Phipps AI, Wurscher MA et al (2013) Genomic aberrations occurring in subsets of serrated colorectal lesions but not conventional adenomas. Cancer Res 73:2863–2872

    Article  CAS  PubMed  Google Scholar 

  60. Sawada T, Yamamoto E, Yamano HO, Nojima M, Harada T, Maruyama R et al (2016) Assessment of epigenetic alterations in early colorectal lesions containing BRAF mutations. Oncotarget 7:35106–35118

    Article  PubMed  PubMed Central  Google Scholar 

  61. Nishihara R, Wu K, Lochhead P, Morikawa T, Liao X, Qian ZR et al (2013) Long-term colorectal-cancer incidence and mortality after lower endoscopy. N Engl J Med 369:1095–1105

    Article  CAS  PubMed  Google Scholar 

  62. Kimura T, Yamamoto E, Yamano HO, Suzuki H, Kamimae S, Nojima M et al (2012) A novel pit pattern identifies the precursor of colorectal cancer derived from sessile serrated adenoma. Am J Gastroenterol 107:460–469

    Article  CAS  PubMed  Google Scholar 

  63. Nosho K, Shima K, Irahara N, Kure S, Baba Y, Kirkner GJ et al (2009) DNMT3B expression might contribute to CpG island methylator phenotype in colorectal cancer. Clin Cancer Res 15:3663–3671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ibrahim AE, Arends MJ, Silva AL, Wyllie AH, Greger L, Ito Y et al (2011) Sequential DNA methylation changes are associated with DNMT3B overexpression in colorectal neoplastic progression. Gut 60:499–508

    Article  CAS  PubMed  Google Scholar 

  65. Croce CM (2009) Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet 10:704–714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Esquela-Kerscher A, Slack FJ (2006) Oncomirs – microRNAs with a role in cancer. Nat Rev Cancer 6:259–269

    Article  CAS  PubMed  Google Scholar 

  67. Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E et al (2007) MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci U S A 104:15805–15810

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Huang J, Wang Y, Guo Y, Sun S (2010) Down-regulated microRNA-152 induces aberrant DNA methylation in hepatitis B virus-related hepatocellular carcinoma by targeting DNA methyltransferase 1. Hepatology 52:60–70

    Article  CAS  PubMed  Google Scholar 

  69. Zhang Z, Tang H, Wang Z, Zhang B, Liu W, Lu H et al (2011) MiR-185 targets the DNA methyltransferases 1 and regulates global DNA methylation in human glioma. Mol Cancer 10:124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Liu R, Gu J, Jiang P, Zheng Y, Liu X, Jiang X et al (2015) DNMT1-microRNA126 epigenetic circuit contributes to esophageal squamous cell carcinoma growth via ADAM9-EGFR-AKT signaling. Clin Cancer Res 21:854–863

    Article  CAS  PubMed  Google Scholar 

  71. Wang H, Wu J, Meng X, Ying X, Zuo Y, Liu R et al (2011) MicroRNA-342 inhibits colorectal cancer cell proliferation and invasion by directly targeting DNA methyltransferase 1. Carcinogenesis 32:1033–1042

    Article  CAS  PubMed  Google Scholar 

  72. Branco MR, Ficz G, Reik W (2012) Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nat Rev Genet 13:7–13

    CAS  Google Scholar 

  73. Kudo Y, Tateishi K, Yamamoto K, Yamamoto S, Asaoka Y, Ijichi H et al (2012) Loss of 5-hydroxymethylcytosine is accompanied with malignant cellular transformation. Cancer Sci 103:670–676

    Article  CAS  PubMed  Google Scholar 

  74. Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A et al (2009) Mutation in TET2 in myeloid cancers. N Engl J Med 360:2289–2301

    Article  PubMed  Google Scholar 

  75. Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS et al (2010) Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 468:839–843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH et al (2011) Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 19:17–30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP et al (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17:510–522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A et al (2010) Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18:553–567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E et al (2012) IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483:479–483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Ichimura N, Shinjo K, An B, Shimizu Y, Yamao K, Ohka F et al (2015) Aberrant TET1 methylation closely associated with CpG island methylator phenotype in colorectal cancer. Cancer Prev Res (Phila) 8:702–711

    Article  CAS  Google Scholar 

  81. Raptis S, Mrkonjic M, Green RC, Pethe VV, Monga N, Chan YM et al (2007) MLH1 -93G>A promoter polymorphism and the risk of microsatellite-unstable colorectal cancer. J Natl Cancer Inst 99:463–474

    Article  CAS  PubMed  Google Scholar 

  82. Samowitz WS, Curtin K, Wolff RK, Albertsen H, Sweeney C, Caan BJ et al (2008) The MLH1 -93 G>A promoter polymorphism and genetic and epigenetic alterations in colon cancer. Genes Chromosomes Cancer 47:835–844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Miyakura Y, Tahara M, Lefor AT, Yasuda Y, Sugano K (2014) Haplotype defined by the MLH1-93G/A polymorphism is associated with MLH1 promoter hypermethylation in sporadic colorectal cancers. BMC Res Notes 7:835

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Wong JJ, Hawkins NJ, Ward RL, Hitchins MP (2011) Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer. Mod Pathol 24:396–411

    Article  CAS  PubMed  Google Scholar 

  85. Fang M, Ou J, Hutchinson L, Green MR (2014) The BRAF oncoprotein functions through the transcriptional repressor MAFG to mediate the CpG island methylator phenotype. Mol Cell 55:904–915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Tahara T, Yamamoto E, Madireddi P, Suzuki H, Maruyama R, Chung W et al (2014) Colorectal carcinomas with CpG island methylator phenotype 1 frequently contain mutations in chromatin regulators. Gastroenterology 146:530–538. e5

    Article  CAS  PubMed  Google Scholar 

  87. Samowitz WS, Albertsen H, Sweeney C, Herrick J, Caan BJ, Anderson KE et al (2006) Association of smoking, CpG island methylator phenotype, and V600E BRAF mutations in colon cancer. J Natl Cancer Inst 98:1731–1738

    Article  CAS  PubMed  Google Scholar 

  88. Limsui D, Vierkant RA, Tillmans LS, Wang AH, Weisenberger DJ, Laird PW et al (2010) Cigarette smoking and colorectal cancer risk by molecularly defined subtypes. J Natl Cancer Inst 102:1012–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Song M, Garrett WS, Chan AT (2015) Nutrients, foods, and colorectal cancer prevention. Gastroenterology 148:1244–1260. e16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Khosraviani K, Weir HP, Hamilton P, Moorehead J, Williamson K (2002) Effect of folate supplementation on mucosal cell proliferation in high risk patients for colon cancer. Gut 51:195–199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Pufulete M, Al-Ghnaniem R, Leather AJ, Appleby P, Gout S, Terry C et al (2003) Folate status, genomic DNA hypomethylation, and risk of colorectal adenoma and cancer: a case control study. Gastroenterology 124:1240–1248

    Article  CAS  PubMed  Google Scholar 

  92. Pufulete M, Al-Ghnaniem R, Khushal A, Appleby P, Harris N, Gout S et al (2005) Effect of folic acid supplementation on genomic DNA methylation in patients with colorectal adenoma. Gut 54:648–653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. van Engeland M, Weijenberg MP, Roemen GM, Brink M, de Bruine AP, Goldbohm RA et al (2003) Effects of dietary folate and alcohol intake on promoter methylation in sporadic colorectal cancer: the Netherlands cohort study on diet and cancer. Cancer Res 63:3133–3137

    PubMed  Google Scholar 

  94. de Vogel S, Wouters KA, Gottschalk RW, van Schooten FJ, de Goeij AF, de Bruine AP et al (2009) Genetic variants of methyl metabolizing enzymes and epigenetic regulators: associations with promoter CpG island hypermethylation in colorectal cancer. Cancer Epidemiol Biomark Prev 18:3086–3096

    Article  CAS  Google Scholar 

  95. Hazra A, Fuchs CS, Kawasaki T, Kirkner GJ, Hunter DJ, Ogino S (2010) Germline polymorphisms in the one-carbon metabolism pathway and DNA methylation in colorectal cancer. Cancer Causes Control 21:331–345

    Article  PubMed  PubMed Central  Google Scholar 

  96. Curtin K, Slattery ML, Ulrich CM, Bigler J, Levin TR, Wolff RK et al (2007) Genetic polymorphisms in one-carbon metabolism: associations with CpG island methylator phenotype (CIMP) in colon cancer and the modifying effects of diet. Carcinogenesis 28:1672–1679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Slattery ML, Curtin K, Sweeney C, Levin TR, Potter J, Wolff RK et al (2007) Diet and lifestyle factor associations with CpG island methylator phenotype and BRAF mutations in colon cancer. Int J Cancer 120:656–663

    Article  CAS  PubMed  Google Scholar 

  98. Schernhammer ES, Giovannucci E, Baba Y, Fuchs CS, Ogino S (2011) B vitamins, methionine and alcohol intake and risk of colon cancer in relation to BRAF mutation and CpG island methylator phenotype (CIMP). PLoS One 6:e21102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Gazzoli I, Loda M, Garber J, Syngal S, Kolodner RD (2002) A hereditary nonpolyposis colorectal carcinoma case associated with hypermethylation of the MLH1 gene in normal tissue and loss of heterozygosity of the unmethylated allele in the resulting microsatellite instability-high tumor. Cancer Res 62:3925–3928

    CAS  PubMed  Google Scholar 

  100. Hitchins M, Williams R, Cheong K, Halani N, Lin VA, Packham D et al (2005) MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer. Gastroenterology 129:1392–1399

    Article  CAS  PubMed  Google Scholar 

  101. Hitchins MP (2015) Constitutional epimutation as a mechanism for cancer causality and heritability? Nat Rev Cancer 15:625–634

    Article  CAS  PubMed  Google Scholar 

  102. Hitchins MP, Wong JJ, Suthers G, Suter CM, Martin DI, Hawkins NJ et al (2007) Inheritance of a cancer-associated MLH1 germ-line epimutation. N Engl J Med 356:697–705

    Article  CAS  PubMed  Google Scholar 

  103. Hitchins MP, Rapkins RW, Kwok CT, Srivastava S, Wong JJ, Khachigian LM et al (2011) Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 5'UTR. Cancer Cell 20:200–213

    Article  CAS  PubMed  Google Scholar 

  104. Kwok CT, Vogelaar IP, van Zelst-Stams WA, Mensenkamp AR, Ligtenberg MJ, Rapkins RW et al (2014) The MLH1 c.-27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype. Eur J Hum Genet 22:617–624

    Article  CAS  PubMed  Google Scholar 

  105. Chan TL, Yuen ST, Kong CK, Chan YW, Chan AS, Ng WF et al (2006) Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer. Nat Genet 38:1178–1183

    Article  CAS  PubMed  Google Scholar 

  106. Ligtenberg MJ, Kuiper RP, Chan TL, Goossens M, Hebeda KM, Voorendt M et al (2009) Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1. Nat Genet 41:112–117

    Article  CAS  PubMed  Google Scholar 

  107. Mandel JS, Church TR, Bond JH, Ederer F, Geisser MS, Mongin SJ et al (2000) The effect of fecal occult-blood screening on the incidence of colorectal cancer. N Engl J Med 343:1603–1607

    Article  CAS  PubMed  Google Scholar 

  108. van Rossum LG, van Rijn AF, Laheij RJ, van Oijen MG, Fockens P, van Krieken HH et al (2008) Random comparison of guaiac and immunochemical fecal occult blood tests for colorectal cancer in a screening population. Gastroenterology 135:82–90

    Article  PubMed  Google Scholar 

  109. Leung WK, To KF, Man EP, Chan MW, Hui AJ, Ng SS et al (2007) Detection of hypermethylated DNA or cyclooxygenase-2 messenger RNA in fecal samples of patients with colorectal cancer or polyps. Am J Gastroenterol 102:1070–1076

    Article  CAS  PubMed  Google Scholar 

  110. Petko Z, Ghiassi M, Shuber A, Gorham J, Smalley W, Washington MK et al (2005) Aberrantly methylated CDKN2A, MGMT, and MLH1 in colon polyps and in fecal DNA from patients with colorectal polyps. Clin Cancer Res 11:1203–1209

    CAS  PubMed  Google Scholar 

  111. Hellebrekers DM, Lentjes MH, van den Bosch SM, Melotte V, Wouters KA, Daenen KL et al (2009) GATA4 and GATA5 are potential tumor suppressors and biomarkers in colorectal cancer. Clin Cancer Res 15:3990–3997

    Article  CAS  PubMed  Google Scholar 

  112. Ausch C, Kim YH, Tsuchiya KD, Dzieciatkowski S, Washington MK, Paraskeva C et al (2009) Comparative analysis of PCR-based biomarker assay methods for colorectal polyp detection from fecal DNA. Clin Chem 55:1559–1563

    Article  CAS  PubMed  Google Scholar 

  113. Kalimutho M, Di Cecilia S, Del Vecchio BG, Roviello F, Sileri P, Cretella M et al (2011) Epigenetically silenced miR-34b/c as a novel faecal-based screening marker for colorectal cancer. Br J Cancer 104:1770–1778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Melotte V, Lentjes MH, van den Bosch SM, Hellebrekers DM, de Hoon JP, Wouters KA et al (2009) N-Myc downstream-regulated gene 4 (NDRG4): a candidate tumor suppressor gene and potential biomarker for colorectal cancer. J Natl Cancer Inst 101:916–927

    Article  CAS  PubMed  Google Scholar 

  115. Nagasaka T, Tanaka N, Cullings HM, Sun DS, Sasamoto H, Uchida T et al (2009) Analysis of fecal DNA methylation to detect gastrointestinal neoplasia. J Natl Cancer Inst 101:1244–1258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Muller HM, Oberwalder M, Fiegl H, Morandell M, Goebel G, Zitt M et al (2004) Methylation changes in faecal DNA: a marker for colorectal cancer screening? Lancet 363:1283–1285

    Article  PubMed  CAS  Google Scholar 

  117. Glockner SC, Dhir M, Yi JM, McGarvey KE, Van Neste L, Louwagie J et al (2009) Methylation of TFPI2 in stool DNA: a potential novel biomarker for the detection of colorectal cancer. Cancer Res 69:4691–4699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Chen WD, Han ZJ, Skoletsky J, Olson J, Sah J, Myeroff L et al (2005) Detection in fecal DNA of colon cancer-specific methylation of the nonexpressed vimentin gene. J Natl Cancer Inst 97:1124–1132

    Article  CAS  PubMed  Google Scholar 

  119. Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP et al (2014) Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med 370:1287–1297

    Article  CAS  PubMed  Google Scholar 

  120. Ebert MP, Model F, Mooney S, Hale K, Lograsso J, Tonnes-Priddy L et al (2006) Aristaless-like homeobox-4 gene methylation is a potential marker for colorectal adenocarcinomas. Gastroenterology 131:1418–1430

    Article  CAS  PubMed  Google Scholar 

  121. Lee BB, Lee EJ, Jung EH, Chun HK, Chang DK, Song SY et al (2009) Aberrant methylation of APC, MGMT, RASSF2A, and Wif-1 genes in plasma as a biomarker for early detection of colorectal cancer. Clin Cancer Res 15:6185–6191

    Article  CAS  PubMed  Google Scholar 

  122. Melotte V, Yi JM, Lentjes MH, Smits KM, Van Neste L, Niessen HE et al (2015) Spectrin repeat containing nuclear envelope 1 and forkhead box protein E1 are promising markers for the detection of colorectal cancer in blood. Cancer Prev Res (Phila) 8:157–164

    Article  CAS  Google Scholar 

  123. Herbst A, Rahmig K, Stieber P, Philipp A, Jung A, Ofner A et al (2011) Methylation of NEUROG1 in serum is a sensitive marker for the detection of early colorectal cancer. Am J Gastroenterol 106:1110–1118

    Article  CAS  PubMed  Google Scholar 

  124. Lofton-Day C, Model F, Devos T, Tetzner R, Distler J, Schuster M et al (2008) DNA methylation biomarkers for blood-based colorectal cancer screening. Clin Chem 54:414–423

    Article  CAS  PubMed  Google Scholar 

  125. Li M, Chen WD, Papadopoulos N, Goodman SN, Bjerregaard NC, Laurberg S et al (2009) Sensitive digital quantification of DNA methylation in clinical samples. Nat Biotechnol 27:858–863

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Ward RL, Cheong K, Ku SL, Meagher A, O'Connor T, Hawkins NJ (2003) Adverse prognostic effect of methylation in colorectal cancer is reversed by microsatellite instability. J Clin Oncol 21:3729–3736

    Article  CAS  PubMed  Google Scholar 

  127. Barault L, Charon-Barra C, Jooste V, de la Vega MF, Martin L, Roignot P et al (2008) Hypermethylator phenotype in sporadic colon cancer: study on a population-based series of 582 cases. Cancer Res 68:8541–8546

    Article  CAS  PubMed  Google Scholar 

  128. Kim JH, Shin SH, Kwon HJ, Cho NY, Kang GH (2009) Prognostic implications of CpG island hypermethylator phenotype in colorectal cancers. Virchows Arch 455:485–494

    Article  CAS  PubMed  Google Scholar 

  129. Dahlin AM, Palmqvist R, Henriksson ML, Jacobsson M, Eklof V, Rutegard J et al (2010) The role of the CpG island methylator phenotype in colorectal cancer prognosis depends on microsatellite instability screening status. Clin Cancer Res 16:1845–1855

    Article  CAS  PubMed  Google Scholar 

  130. Ahn JB, Chung WB, Maeda O, Shin SJ, Kim HS, Chung HC et al (2011) DNA methylation predicts recurrence from resected stage III proximal colon cancer. Cancer 117:1847–1854

    Article  CAS  PubMed  Google Scholar 

  131. Simons CC, Hughes LA, Smits KM, Khalid-de Bakker CA, de Bruine AP, Carvalho B et al (2013) A novel classification of colorectal tumors based on microsatellite instability, the CpG island methylator phenotype and chromosomal instability: implications for prognosis. Ann Oncol 24:2048–2056

    Article  CAS  PubMed  Google Scholar 

  132. Bae JM, Kim JH, Cho NY, Kim TY, Kang GH (2013) Prognostic implication of the CpG island methylator phenotype in colorectal cancers depends on tumour location. Br J Cancer 109:1004–1012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Juo YY, Johnston FM, Zhang DY, Juo HH, Wang H, Pappou EP et al (2014) Prognostic value of CpG island methylator phenotype among colorectal cancer patients: a systematic review and meta-analysis. Ann Oncol 25:2314–2327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ogino S, Nosho K, Kirkner GJ, Kawasaki T, Meyerhardt JA, Loda M et al (2009) CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut 58:90–96

    Article  PubMed  Google Scholar 

  135. Lee S, Cho NY, Choi M, Yoo EJ, Kim JH, Kang GH (2008) Clinicopathological features of CpG island methylator phenotype-positive colorectal cancer and its adverse prognosis in relation to KRAS/BRAF mutation. Pathol Int 58:104–113

    Article  CAS  PubMed  Google Scholar 

  136. Pai RK, Jayachandran P, Koong AC, Chang DT, Kwok S, Ma L et al (2012) BRAF-mutated, microsatellite-stable adenocarcinoma of the proximal colon: an aggressive adenocarcinoma with poor survival, mucinous differentiation, and adverse morphologic features. Am J Surg Pathol 36:744–752

    Article  PubMed  Google Scholar 

  137. Van Rijnsoever M, Elsaleh H, Joseph D, McCaul K, Iacopetta B (2003) CpG island methylator phenotype is an independent predictor of survival benefit from 5-fluorouracil in stage III colorectal cancer. Clin Cancer Res 9:2898–2903

    PubMed  Google Scholar 

  138. Shen L, Catalano PJ, Benson AB 3rd, O'Dwyer P, Hamilton SR, Issa JP (2007) Association between DNA methylation and shortened survival in patients with advanced colorectal cancer treated with 5-fluorouracil based chemotherapy. Clin Cancer Res 13:6093–6098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Jover R, Nguyen TP, Perez-Carbonell L, Zapater P, Paya A, Alenda C et al (2011) 5-Fluorouracil adjuvant chemotherapy does not increase survival in patients with CpG island methylator phenotype colorectal cancer. Gastroenterology 140:1174–1181

    Article  CAS  PubMed  Google Scholar 

  140. Min BH, Bae JM, Lee EJ, Yu HS, Kim YH, Chang DK et al (2011) The CpG island methylator phenotype may confer a survival benefit in patients with stage II or III colorectal carcinomas receiving fluoropyrimidine-based adjuvant chemotherapy. BMC Cancer 11:344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Shiovitz S, Bertagnolli MM, Renfro LA, Nam E, Foster NR, Dzieciatkowski S et al (2014) CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer. Gastroenterology 147:637–645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003

    Article  CAS  PubMed  Google Scholar 

  143. Amatu A, Sartore-Bianchi A, Moutinho C, Belotti A, Bencardino K, Chirico G et al (2013) Promoter CpG island hypermethylation of the DNA repair enzyme MGMT predicts clinical response to dacarbazine in a phase II study for metastatic colorectal cancer. Clin Cancer Res 19:2265–2272

    Article  CAS  PubMed  Google Scholar 

  144. Hochhauser D, Glynne-Jones R, Potter V, Gravalos C, Doyle TJ, Pathiraja K et al (2013) A phase II study of temozolomide in patients with advanced aerodigestive tract and colorectal cancers and methylation of the O6-methylguanine-DNA methyltransferase promoter. Mol Cancer Ther 12:809–818

    Article  CAS  PubMed  Google Scholar 

  145. Ebert MP, Tanzer M, Balluff B, Burgermeister E, Kretzschmar AK, Hughes DJ et al (2012) TFAP2E-DKK4 and chemoresistance in colorectal cancer. N Engl J Med 366:44–53

    Article  CAS  PubMed  Google Scholar 

  146. Moutinho C, Martinez-Cardus A, Santos C, Navarro-Perez V, Martinez-Balibrea E, Musulen E et al (2014) Epigenetic inactivation of the BRCA1 interactor SRBC and resistance to oxaliplatin in colorectal cancer. J Natl Cancer Inst 106:djt322

    Article  PubMed  CAS  Google Scholar 

  147. Ogino S, Nosho K, Kirkner GJ, Kawasaki T, Chan AT, Schernhammer ES et al (2008) A cohort study of tumoral LINE-1 hypomethylation and prognosis in colon cancer. J Natl Cancer Inst 100:1734–1738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Antelo M, Balaguer F, Shia J, Shen Y, Hur K, Moreira L et al (2012) A high degree of LINE-1 hypomethylation is a unique feature of early-onset colorectal cancer. PLoS One 7:e45357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Rhee YY, Kim MJ, Bae JM, Koh JM, Cho NY, Juhnn YS et al (2012) Clinical outcomes of patients with microsatellite-unstable colorectal carcinomas depend on L1 methylation level. Ann Surg Oncol 19:3441–3448

    Article  PubMed  Google Scholar 

  150. Shen L, Kondo Y, Rosner GL, Xiao L, Hernandez NS, Vilaythong J et al (2005) MGMT promoter methylation and field defect in sporadic colorectal cancer. J Natl Cancer Inst 97:1330–1338

    Article  CAS  PubMed  Google Scholar 

  151. Kamiyama H, Suzuki K, Maeda T, Koizumi K, Miyaki Y, Okada S et al (2012) DNA demethylation in normal colon tissue predicts predisposition to multiple cancers. Oncogene 31:5029–5037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Baylin SB, Jones PA (2011) A decade of exploring the cancer epigenome – biological and translational implications. Nat Rev Cancer 11:726–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Fahrner JA, Eguchi S, Herman JG, Baylin SB (2002) Dependence of histone modifications and gene expression on DNA hypermethylation in cancer. Cancer Res 62:7213–7218

    CAS  PubMed  Google Scholar 

  154. Nguyen CT, Weisenberger DJ, Velicescu M, Gonzales FA, Lin JC, Liang G et al (2002) Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2′-deoxycytidine. Cancer Res 62:6456–6461

    CAS  PubMed  Google Scholar 

  155. Rhee I, Jair KW, Yen RW, Lengauer C, Herman JG, Kinzler KW et al (2000) CpG methylation is maintained in human cancer cells lacking DNMT1. Nature 404:1003–1007

    Article  CAS  PubMed  Google Scholar 

  156. Bachman KE, Park BH, Rhee I, Rajagopalan H, Herman JG, Baylin SB et al (2003) Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell 3:89–95

    Article  CAS  PubMed  Google Scholar 

  157. Si J, Boumber YA, Shu J, Qin T, Ahmed S, He R et al (2010) Chromatin remodeling is required for gene reactivation after decitabine-mediated DNA hypomethylation. Cancer Res 70:6968–6977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Nakazawa T, Kondo T, Ma D, Niu D, Mochizuki K, Kawasaki T et al (2012) Global histone modification of histone H3 in colorectal cancer and its precursor lesions. Hum Pathol 43:834–842

    Article  CAS  PubMed  Google Scholar 

  159. Tamagawa H, Oshima T, Shiozawa M, Morinaga S, Nakamura Y, Yoshihara M et al (2012) The global histone modification pattern correlates with overall survival in metachronous liver metastasis of colorectal cancer. Oncol Rep 27:637–642

    CAS  PubMed  Google Scholar 

  160. Tamagawa H, Oshima T, Numata M, Yamamoto N, Shiozawa M, Morinaga S et al (2013) Global histone modification of H3K27 correlates with the outcomes in patients with metachronous liver metastasis of colorectal cancer. Eur J Surg Oncol 39:655–661

    Article  CAS  PubMed  Google Scholar 

  161. Benard A, Goossens-Beumer IJ, van Hoesel AQ, de Graaf W, Horati H, Putter H et al (2014) Histone trimethylation at H3K4, H3K9 and H4K20 correlates with patient survival and tumor recurrence in early-stage colon cancer. BMC Cancer 14:531

    Article  PubMed  PubMed Central  Google Scholar 

  162. Ding J, Zhang ZM, Xia Y, Liao GQ, Pan Y, Liu S et al (2013) LSD1-mediated epigenetic modification contributes to proliferation and metastasis of colon cancer. Br J Cancer 109:994–1003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Jie D, Zhongmin Z, Guoqing L, Sheng L, Yi Z, Jing W et al (2013) Positive expression of LSD1 and negative expression of E-cadherin correlate with metastasis and poor prognosis of colon cancer. Dig Dis Sci 58:1581–1589

    Article  PubMed  CAS  Google Scholar 

  164. Kang MY, Lee BB, Kim YH, Chang DK, Kyu Park S, Chun HK et al (2007) Association of the SUV39H1 histone methyltransferase with the DNA methyltransferase 1 at mRNA expression level in primary colorectal cancer. Int J Cancer 121:2192–2197

    Article  CAS  PubMed  Google Scholar 

  165. Yokoyama Y, Hieda M, Nishioka Y, Matsumoto A, Higashi S, Kimura H et al (2013) Cancer-associated upregulation of histone H3 lysine 9 trimethylation promotes cell motility in vitro and drives tumor formation in vivo. Cancer Sci 104:889–895

    Article  CAS  PubMed  Google Scholar 

  166. Yadav S, Singhal J, Singhal SS, Awasthi S (2009) hSET1: a novel approach for colon cancer therapy. Biochem Pharmacol 77:1635–1641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Hamamoto R, Furukawa Y, Morita M, Iimura Y, Silva FP, Li M et al (2004) SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat Cell Biol 6:731–740

    Article  CAS  PubMed  Google Scholar 

  168. Pelaez IM, Kalogeropoulou M, Ferraro A, Voulgari A, Pankotai T, Boros I et al (2010) Oncogenic RAS alters the global and gene-specific histone modification pattern during epithelial-mesenchymal transition in colorectal carcinoma cells. Int J Biochem Cell Biol 42:911–920

    Article  PubMed  CAS  Google Scholar 

  169. Gaedcke J, Grade M, Jung K, Camps J, Jo P, Emons G et al (2010) Mutated KRAS results in overexpression of DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase, in rectal carcinomas. Genes Chromosomes Cancer 49:1024–1034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Watanabe T, Kobunai T, Yamamoto Y, Matsuda K, Ishihara S, Nozawa K et al (2011) Differential gene expression signatures between colorectal cancers with and without KRAS mutations: crosstalk between the KRAS pathway and other signalling pathways. Eur J Cancer 47:1946–1954

    Article  CAS  PubMed  Google Scholar 

  171. Hudlebusch HR, Santoni-Rugiu E, Simon R, Ralfkiaer E, Rossing HH, Johansen JV et al (2011) The histone methyltransferase and putative oncoprotein MMSET is overexpressed in a large variety of human tumors. Clin Cancer Res 17:2919–2933

    Article  CAS  PubMed  Google Scholar 

  172. Uemura M, Yamamoto H, Takemasa I, Mimori K, Hemmi H, Mizushima T et al (2010) Jumonji domain containing 1A is a novel prognostic marker for colorectal cancer: in vivo identification from hypoxic tumor cells. Clin Cancer Res 16:4636–4646

    Article  CAS  PubMed  Google Scholar 

  173. Fluge O, Gravdal K, Carlsen E, Vonen B, Kjellevold K, Refsum S et al (2009) Expression of EZH2 and Ki-67 in colorectal cancer and associations with treatment response and prognosis. Br J Cancer 101:1282–1289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Wang CG, Ye YJ, Yuan J, Liu FF, Zhang H, Wang S (2010) EZH2 and STAT6 expression profiles are correlated with colorectal cancer stage and prognosis. World J Gastroenterol 16:2421–2427

    Article  PubMed  PubMed Central  Google Scholar 

  175. Takawa M, Masuda K, Kunizaki M, Daigo Y, Takagi K, Iwai Y et al (2011) Validation of the histone methyltransferase EZH2 as a therapeutic target for various types of human cancer and as a prognostic marker. Cancer Sci 102:1298–1305

    Article  CAS  PubMed  Google Scholar 

  176. Fussbroich B, Wagener N, Macher-Goeppinger S, Benner A, Falth M, Sultmann H et al (2011) EZH2 depletion blocks the proliferation of colon cancer cells. PLoS One 6:e21651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Du J, Li Y, Li J, Zheng J (2010) Polycomb group protein Bmi1 expression in colon cancers predicts the survival. Med Oncol 27:1273–1276

    Article  CAS  PubMed  Google Scholar 

  178. Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C et al (2006) The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439:871–874

    Article  CAS  PubMed  Google Scholar 

  179. Mohammad HP, Cai Y, McGarvey KM, Easwaran H, Van Neste L, Ohm JE et al (2009) Polycomb CBX7 promotes initiation of heritable repression of genes frequently silenced with cancer-specific DNA hypermethylation. Cancer Res 69:6322–6330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Jin B, Yao B, Li JL, Fields CR, Delmas AL, Liu C et al (2009) DNMT1 and DNMT3B modulate distinct polycomb-mediated histone modifications in colon cancer. Cancer Res 69:7412–7421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Schlesinger Y, Straussman R, Keshet I, Farkash S, Hecht M, Zimmerman J et al (2007) Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet 39:232–236

    Article  CAS  PubMed  Google Scholar 

  182. Ohm JE, McGarvey KM, Yu X, Cheng L, Schuebel KE, Cope L et al (2007) A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet 39:237–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Widschwendter M, Fiegl H, Egle D, Mueller-Holzner E, Spizzo G, Marth C et al (2007) Epigenetic stem cell signature in cancer. Nat Genet 39:157–158

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr. William Goldman for editing the manuscript. This study was supported in part by Grants-in-Aid for Scientific Research (B) from the Japan Society for Promotion of Science (JSPS KAKENHI 15H04299, H. Suzuki).

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Authors and Affiliations

  1. Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan

    Hiromu Suzuki & Eiichiro Yamamoto

  2. Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan

    Eiichiro Yamamoto & Hiroshi Nakase

  3. Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan

    Tamotsu Sugai

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  1. Hiromu Suzuki
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  2. Eiichiro Yamamoto
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  4. Tamotsu Sugai
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Correspondence to Hiromu Suzuki .

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  1. Graduate School of Medicine, Chiba University, Chiba, Chiba, Japan

    Atsushi Kaneda

  2. Advanced Biological Information Research Division, INAMORI Frontier Research Center, Kyushu University, Fukuoka, Fukuoka, Japan

    Yu-ichi Tsukada

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Suzuki, H., Yamamoto, E., Nakase, H., Sugai, T. (2017). DNA and Histone Methylation in Colon Cancer. In: Kaneda, A., Tsukada, Yi. (eds) DNA and Histone Methylation as Cancer Targets. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-319-59786-7_17

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