Skip to main content
SpringerLink
Log in

The value of epigenetic markers in esophageal cancer

  • Review
  • Published:
Frontiers of Medicine in China Aims and scope Submit manuscript

Abstract

Developing esophageal cancer is a multi-step process that begins with the accumulation of genetic and epigenetic alterations, and leads to the activation of oncogenes and the inactivation or loss of tumor suppressor genes (TSG). In addition to genetic alteration, epigenetic modifications, and in particular DNA methylation, are recognized as a common molecular alteration in human tumors. In esophageal cancer, aberrant methylation of promoter regions occurs not only in advanced cancer, but also in premalignant lesions. DNA methylation is related to survival time and sensitivity of chemoradiotherapy. This review is mainly focused on epigenetic changes in esophageal cancer and the value of early detection for patient prognosis, treatment choices, and potential targeting therapy.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Parkin D M, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin, 2005, 55(2): 74–108

    Article  PubMed  Google Scholar 

  2. Hu N, Dawsey S M, Wu M, Bonney G E, He L J, Han X Y, Fu M, Taylor P R. Family history of oesophageal cancer in Shanxi Province. Int J Epidemiol, 1992, 21(5): 877–822

    Article  CAS  PubMed  Google Scholar 

  3. Yang C S. Research on esophageal cancer in China: a review. Cancer Res, 1980, 40(8 Pt 1): 2633–2644

    CAS  PubMed  Google Scholar 

  4. Taylor P R, Dawsey S M, Hu N, Albanes D, Wu M. Nutritional intervention to prevent hereditary cancer. J Natl Cancer Inst Monogr, 1995, (17): 43–47

    PubMed  Google Scholar 

  5. Carter C L, Hu N, Wu M, Lin P Z, Murigande C, Bonney G E. Segregation analysis of esophageal cancer in 221 high-risk Chinese families. J Natl Cancer Inst, 1992, 84(10): 771–776

    Article  CAS  PubMed  Google Scholar 

  6. Muñoz N. Epidemiological aspects of oesophageal cancer. Endoscopy, 1993, 25(9): 609–612

    Article  PubMed  Google Scholar 

  7. Nielsen N H, Mikkelsen F, Hansen J P. Oesophageal cancer in Greenland: selected epidemiological and clinical aspects. J Cancer Res Clin Oncol, 1979, 94(1): 69–80

    Article  CAS  PubMed  Google Scholar 

  8. Cameron A J. Epidemiology of columnar-lined esophagus and adenocarcinoma. Gastroenterol Clin North Am, 1997, 26(3): 487–494

    Article  CAS  PubMed  Google Scholar 

  9. Okano J, Snyder L, Rustgi A K. Genetic alterations in esophageal cancer. Methods Mol Biol, 2003, 222: 131–145

    CAS  PubMed  Google Scholar 

  10. Vogelstein B, Kinzler K W. The multistep nature of cancer. Trends Genet, 1993, 9(4): 138–141

    Article  CAS  PubMed  Google Scholar 

  11. Zhang W, Glöckner S C, Guo M, Machida E O, Wang D H, Easwaran H, Van Neste L, Herman J G, Schuebel K E, Watkins D N, Ahuja N, Baylin S B. Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer. Cancer Res, 2008, 68(8): 2764–2772

    Article  CAS  PubMed  Google Scholar 

  12. Wang J S, Guo M, Montgomery E A, Thompson R E, Cosby H, Hicks L, Wang S, Herman J G, Canto M I. DNA promoter hypermethylation of p16 and APC predicts neoplastic progression in Barrett’s esophagus. Am J Gastroenterol, 2009, 104(9): 2153–2160

    Article  CAS  PubMed  Google Scholar 

  13. Carmona F J, Esteller M. Epigenomics of human colon cancer. Mutat Res, 2010, 693(1–2):53–60

    CAS  PubMed  Google Scholar 

  14. Mokrowiecka A, Wierzchniewska-Ławska A, Smolarz B, Romanowicz-Makowska H, Malecka-Panas E. [Polymorphism/loss of heterozygosity of APC gene in GERD-Barrett’s metaplasiadysplasia-adenocarcinoma sequence]. Pol Merkur Lekarski, 2009, 26(155): 385–389

    CAS  PubMed  Google Scholar 

  15. Kohler E M, Brauburger K, Behrens J, Schneikert J. Contribution of the 15 amino acid repeats of truncated APC to beta-catenin degradation and selection of APC mutations in colorectal tumours from FAP patients. Oncogene, 2010, 29(11): 1663–1671

    Article  CAS  PubMed  Google Scholar 

  16. Holliday R. The inheritance of epigenetic defects. Science, 1987, 238(4824): 163–170

    Article  CAS  PubMed  Google Scholar 

  17. Jones P A, Baylin S B. The fundamental role of epigenetic events in cancer. Nat Rev Genet, 2002, 3(6): 415–428

    CAS  PubMed  Google Scholar 

  18. Riggs A D, Pfeifer G P. X-chromosome inactivation and cell memory. Trends Genet, 1992, 8(5): 169–174

    Article  CAS  PubMed  Google Scholar 

  19. Ali A B, Iau P T, Sng J H. Cancer-specific methylation in the BRCA1 promoter in sporadic breast tumours. Med Oncol, 2010 Feb 5.

  20. Merlo A, Herman J G, Mao L, Lee D J, Gabrielson E, Burger P C, Baylin S B, Sidransky D. 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med, 1995, 1(7): 686–692

    Article  CAS  PubMed  Google Scholar 

  21. Guo M, House M G, Suzuki H, Ye Y, Brock M V, Lu F, Liu Z, Rustgi A K, Herman J G. Epigenetic silencing of CDX2 is a feature of squamous esophageal cancer. Int J Cancer, 2007, 121(6): 1219–1226

    Article  CAS  PubMed  Google Scholar 

  22. Guo M, House M G, Akiyama Y, Qi Y, Capagna D, Harmon J, Baylin S B, Brock M V, Herman J G. Hypermethylation of the GATA gene family in esophageal cancer. Int J Cancer, 2006, 119(9): 2078–2083

    Article  CAS  PubMed  Google Scholar 

  23. Aguilera O, Fraga M F, Ballestar E, Paz M F, Herranz M, Espada J, García JM, Muñoz A, Esteller M, González-Sancho JM. Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. Oncogene, 2006, 25(29): 4116–4121

    Article  CAS  PubMed  Google Scholar 

  24. Martinez R, Setien F, Voelter C, Casado S, Quesada M P, Schackert G, Esteller M. CpG island promoter hypermethylation of the proapoptotic gene caspase-8 is a common hallmark of relapsed glioblastoma multiforme. Carcinogenesis, 2007, 28(6): 1264–1268

    Article  CAS  PubMed  Google Scholar 

  25. Blanco D, Vicent S, Fraga M F, Fernandez-Garcia I, Freire J, Lujambio A, Esteller M, Ortiz-de-Solorzano C, Pio R, Lecanda F, Montuenga L M. Molecular analysis of a multistep lung cancer model induced by chronic inflammation reveals epigenetic regulation of p16 and activation of the DNA damage response pathway. Neoplasia, 2007, 9(10): 840–852

    Article  CAS  PubMed  Google Scholar 

  26. Yue W, Sun Q, Dacic S, Landreneau R J, Siegfried JM, Yu J, Zhang L. Downregulation of Dkk3 activates beta-catenin/TCF-4 signaling in lung cancer. Carcinogenesis, 2008, 29(1): 84–92

    Article  CAS  PubMed  Google Scholar 

  27. Lee B B, Lee E J, Jung E H, Chun H K, Chang D K, Song S Y, Park J, Kim D H. Aberrant methylation of APC, MGMT, RASSF2A, and Wif-1 genes in plasma as a biomarker for early detection of colorectal cancer. Clin Cancer Res, 2009, 15(19): 6185–6191

    Article  CAS  PubMed  Google Scholar 

  28. Lofton-Day C, Model F, Devos T, Tetzner R, Distler J, Schuster M, Song X, Lesche R, Liebenberg V, Ebert M, Molnar B, Grützmann R, Pilarsky C, Sledziewski A. DNA methylation biomarkers for blood-based colorectal cancer screening. Clin Chem, 2008, 54(2): 414–423

    Article  CAS  PubMed  Google Scholar 

  29. Atherfold P A, Jankowski J A. Molecular biology of Barrett’s cancer. Best Pract Res Clin Gastroenterol, 2006, 20(5): 813–827

    Article  CAS  PubMed  Google Scholar 

  30. Dulai G S, Guha S, Kahn K L, Gornbein J, Weinstein W M. Preoperative prevalence of Barrett’s esophagus in esophageal adenocarcinoma: a systematic review. Gastroenterology, 2002, 122(1): 26–33

    Article  PubMed  Google Scholar 

  31. Corley D A, Levin T R, Habel L A, Weiss N S, Buffler P A. Surveillance and survival in Barrett’s adenocarcinomas: a population-based study. Gastroenterology, 2002, 122(3): 633–640

    Article  PubMed  Google Scholar 

  32. McManus D T, Olaru A, Meltzer S J. Biomarkers of esophageal adenocarcinoma and Barrett’s esophagus. Cancer Res, 2004, 64(5): 1561–1569

    Article  CAS  PubMed  Google Scholar 

  33. Bian Y S, Osterheld M C, Fontolliet C, Bosman F T, Benhattar J. p16 inactivation by methylation of the CDKN2A promoter occurs early during neoplastic progression in Barrett’s esophagus. Gastroenterology, 2002, 122(4): 1113–1121

    Article  CAS  PubMed  Google Scholar 

  34. Wong D J, Paulson T G, Prevo L J, Galipeau P C, Longton G, Blount P L, Reid B J. p16(INK4a) lesions are common, early abnormalities that undergo clonal expansion in Barrett’s metaplastic epithelium. Cancer Res, 2001, 61(22): 8284–8289

    CAS  PubMed  Google Scholar 

  35. Klump B, Hsieh C J, Holzmann K, Gregor M, Porschen R. Hypermethylation of the CDKN2/p16 promoter during neoplastic progression in Barrett’s esophagus. Gastroenterology, 1998, 115(6): 1381–1386

    Article  CAS  PubMed  Google Scholar 

  36. Wong D J, Barrett M T, Stöger R, Emond M J, Reid B J. p16INK4a promoter is hypermethylated at a high frequency in esophageal adenocarcinomas. Cancer Res, 1997, 57(13): 2619–2622

    CAS  PubMed  Google Scholar 

  37. Eads C A, Lord R V, Wickramasinghe K, Long T I, Kurumboor S K, Bernstein L, Peters J H, DeMeester S R, DeMeester T R, Skinner K A, Laird P W. Epigenetic patterns in the progression of esophageal adenocarcinoma. Cancer Res, 2001, 61(8): 3410–3418

    CAS  PubMed  Google Scholar 

  38. Guo M, Ren J, House M G, Qi Y, Brock M V, Herman J G. Accumulation of promoter methylation suggests epigenetic progression in squamous cell carcinoma of the esophagus. Clin Cancer Res, 2006, 12(15): 4515–4522

    Article  CAS  PubMed  Google Scholar 

  39. Guo M, Ren J, Brock M V, Herman J G, Carraway H E. Promoter methylation of HIN-1 in the progression to esophageal squamous cancer. Epigenetics, 2008, 3(6): 336–341

    Article  PubMed  Google Scholar 

  40. Jin Z, Cheng Y, Olaru A, Kan T, Yang J, Paun B, Ito T, Hamilton J P, David S, Agarwal R, Selaru F M, Sato F, Abraham J M, Beer D G, Mori Y, Shimada Y, Meltzer S J. Promoter hypermethylation of CDH13 is a common, early event in human esophageal adenocarcinogenesis and correlates with clinical risk factors. Int J Cancer, 2008, 123(10): 2331–2336

    Article  CAS  PubMed  Google Scholar 

  41. Jin Z, Hamilton J P, Yang J, Mori Y, Olaru A, Sato F, Ito T, Kan T, Cheng Y, Paun B, David S, Beer D G, Agarwal R, Abraham J M, Meltzer S J. Hypermethylation of the AKAP12 promoter is a biomarker of Barrett’s-associated esophageal neoplastic progression. Cancer Epidemiol Biomarkers Prev, 2008, 17(1): 111–117

    Article  CAS  PubMed  Google Scholar 

  42. Jin Z, Mori Y, Hamilton J P, Olaru A, Sato F, Yang J, Ito T, Kan T, Agarwal R, Meltzer S J. Hypermethylation of the somatostatin promoter is a common, early event in human esophageal carcinogenesis. Cancer, 2008, 112(1): 43–49

    Article  CAS  PubMed  Google Scholar 

  43. Jin Z, Olaru A, Yang J, Sato F, Cheng Y, Kan T, Mori Y, Mantzur C, Paun B, Hamilton J P, Ito T, Wang S, David S, Agarwal R, Beer D G, Abraham JM, Meltzer S J. Hypermethylation of tachykinin-1 is a potential biomarker in human esophageal cancer. Clin Cancer Res, 2007, 13(21): 6293–6300

    Article  CAS  PubMed  Google Scholar 

  44. Jin Z, Mori Y, Yang J, Sato F, Ito T, Cheng Y, Paun B, Hamilton J P, Kan T, Olaru A, David S, Agarwal R, Abraham J M, Beer D, Montgomery E, Meltzer S J. Hypermethylation of the nel-like 1 gene is a common and early event and is associated with poor prognosis in early-stage esophageal adenocarcinoma. Oncogene, 2007, 26(43): 6332–6340

    Article  CAS  PubMed  Google Scholar 

  45. Kuester D, Dar A A, Moskaluk C C, Krueger S, Meyer F, Hartig R, Stolte M, Malfertheiner P, Lippert H, Roessner A, El-Rifai W, Schneider-Stock R. Early involvement of death-associated protein kinase promoter hypermethylation in the carcinogenesis of Barrett’s esophageal adenocarcinoma and its association with clinical progression. Neoplasia, 2007, 9(3): 236–245

    Article  CAS  PubMed  Google Scholar 

  46. Hamilton J P, Sato F, Jin Z, Greenwald B D, Ito T, Mori Y, Paun B C, Kan T, Cheng Y, Wang S, Yang J, Abraham J M, Meltzer S J. Reprimo methylation is a potential biomarker of Barrett’s-Associated esophageal neoplastic progression. Clin Cancer Res, 2006, 12(22): 6637–6642

    Article  CAS  PubMed  Google Scholar 

  47. Anupam K, Tusharkant C, Gupta S D, Ranju R. Loss of disabled-2 expression is an early event in esophageal squamous tumorigenesis. World J Gastroenterol, 2006, 12(37): 6041–6045

    CAS  PubMed  Google Scholar 

  48. Clément G, Braunschweig R, Pasquier N, Bosman F T, Benhattar J. Methylation of APC, TIMP3, and TERT: a new predictive marker to distinguish Barrett’s oesophagus patients at risk for malignant transformation. J Pathol, 2006, 208(1): 100–107

    Article  PubMed  Google Scholar 

  49. Zou H, Osborn N K, Harrington J J, Klatt K K, Molina J R, Burgart L J, Ahlquist D A. Frequent methylation of eyes absent 4 gene in Barrett’s esophagus and esophageal adenocarcinoma. Cancer Epidemiol Biomarkers Prev, 2005, 14(4): 830–834

    Article  CAS  PubMed  Google Scholar 

  50. Campbell N P, Villaflor V M. Neoadjuvant treatment of esophageal cancer. World J Gastroenterol, 2010, 16(30): 3793–3803

    Article  CAS  PubMed  Google Scholar 

  51. Hyngstrom J R, Posner M C. Neoadjuvant strategies for the treatment of locally advanced esophageal cancer. J Surg Oncol, 2010, 101(4): 299–304

    Article  CAS  PubMed  Google Scholar 

  52. Kim M P, Correa A M, Lee J, Rice D C, Roth J A, Mehran R J, Walsh G L, Ajani J A, Maru D M, Chang J Y, Marom E M, Macapinlac H A, Lee J H, Vaporciyan A A, Rice T, Swisher S G, Hofstetter W L. Pathologic T0N1 esophageal cancer after neoadjuvant therapy and surgery: an orphan status. Ann Thorac Surg, 2010, 90(3): 884–890, discussion 890–891

    Article  PubMed  Google Scholar 

  53. Metzger R, Heukamp L, Drebber U, Bollschweiler E, Zander T, Hoelscher A H, Warnecke-Eberz U. CUL2 and STK11 as novel response-predictive genes for neoadjuvant radiochemotherapy in esophageal cancer. Pharmacogenomics, 2010, 11(8): 1105–1113

    Article  CAS  PubMed  Google Scholar 

  54. Esteller M, Garcia-Foncillas J, Andion E, Goodman S N, Hidalgo O F, Vanaclocha V, Baylin S B, Herman J G. Inactivation of the DNArepair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med, 2000, 343(19): 1350–1354

    Article  CAS  PubMed  Google Scholar 

  55. Rivera A L, Pelloski C E, Gilbert M R, Colman H, De La Cruz C, Sulman E P, Bekele B N, Aldape K D. MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neuro Oncol, 2010, 12(2): 116–121

    CAS  PubMed  Google Scholar 

  56. Hamilton J P, Sato F, Jin Z, Greenwald B D, Ito T, Mori Y, Paun B C, Kan T, Cheng Y, Wang S, Yang J, Abraham J M, Meltzer S J. Reprimo methylation is a potential biomarker of Barrett’s-Associated esophageal neoplastic progression. Clin Cancer Res, 2006, 12(22): 6637–6642

    Article  CAS  PubMed  Google Scholar 

  57. Hamilton J P, Sato F, Greenwald B D, Suntharalingam M, Krasna M J, Edelman M J, Doyle A, Berki A T, Abraham J M, Mori Y, Kan T, Mantzur C, Paun B, Wang S, Ito T, Jin Z, Meltzer S J. Promoter methylation and response to chemotherapy and radiation in esophageal cancer. Clin Gastroenterol Hepatol, 2006, 4(6): 701–708

    Article  CAS  PubMed  Google Scholar 

  58. Mandelker D L, Yamashita K, Tokumaru Y, Mimori K, Howard D L, Tanaka Y, Carvalho A L, Jiang WW, Park H L, Kim M S, Osada M, Mori M, Sidransky D. PGP9. 5 promoter methylation is an independent prognostic factor for esophageal squamous cell carcinoma. Cancer Res, 2005, 65(11): 4963–4968

    Article  CAS  PubMed  Google Scholar 

  59. Li L W, Yu X Y, Yang Y, Zhang C P, Guo L P, Lu S H. Expression of esophageal cancer related gene 4 (ECRG4), a novel tumor suppressor gene, in esophageal cancer and its inhibitory effect on the tumor growth in vitro and in vivo. Int J Cancer, 2009, 125(7): 1505–1513

    Article  CAS  PubMed  Google Scholar 

  60. Brock M V, Gou M, Akiyama Y, Muller A, Wu T T, Montgomery E, Deasel M, Germonpr’e P, Rubinson L, Heitmiller R F, Yang S C, Forastiere A A, Baylin S B, Herman J G. Prognostic importance of promoter hypermethylation of multiple genes in esophageal adenocarcinoma. Clin Cancer Res, 2003, 9(8): 2912–2919

    CAS  PubMed  Google Scholar 

  61. Kawakami K, Brabender J, Lord R V, Groshen S, Greenwald B D, Krasna MJ, Yin J, Fleisher A S, Abraham JM, Beer D G, Sidransky D, Huss H T, Demeester T R, Eads C, Laird PW, Ilson D H, Kelsen D P, Harpole D, Moore M B, Danenberg K D, Danenberg P V, Meltzer S J. Hypermethylated APC DNA in plasma and prognosis of patients with esophageal adenocarcinoma. J Natl Cancer Inst, 2000, 92(22): 1805–1811

    Article  CAS  PubMed  Google Scholar 

  62. Lee E J, Lee B B, Kim J W, Shim Y M, Hoseok I, Han J, Cho E Y, Park J, Kim D H. Aberrant methylation of Fragile Histidine Triad gene is associated with poor prognosis in early stage esophageal squamous cell carcinoma. Eur J Cancer, 2006, 42(7): 972–980

    Article  CAS  PubMed  Google Scholar 

  63. Jin Z, Mori Y, Yang J, Sato F, Ito T, Cheng Y, Paun B, Hamilton J P, Kan T, Olaru A, David S, Agarwal R, Abraham J M, Beer D, Montgomery E, Meltzer S J. Hypermethylation of the nel-like 1 gene is a common and early event and is associated with poor prognosis in early-stage esophageal adenocarcinoma. Oncogene, 2007, 26(43): 6332–6340

    Article  CAS  PubMed  Google Scholar 

  64. Ohta M, Mimori K, Fukuyoshi Y, Kita Y, Motoyama K, Yamashita K, Ishii H, Inoue H, Mori M, Olaru A, David S, Agarwal R, Abraham J M, Beer D, Montgomery E, Meltzer S J. Clinical significance of the reduced expression of G protein gamma 7 (GNG7) in oesophageal cancer. Br J Cancer, 2008, 98(2): 410–417

    Article  CAS  PubMed  Google Scholar 

  65. Lee E J, Lee B B, Han J, Cho E Y, Shim YM, Park J, Kim D H. CpG island hypermethylation of E-cadherin (CDH1) and integrin alpha4 is associated with recurrence of early stage esophageal squamous cell carcinoma. Int J Cancer, 2008, 123(9): 2073–2079

    Article  CAS  PubMed  Google Scholar 

  66. Zare M, Jazii F R, Alivand M R, Nasseri N K, Malekzadeh R, Yazdanbod M. Qualitative analysis of Adenomatous Polyposis Coli promoter: hypermethylation, engagement and effects on survival of patients with esophageal cancer in a high risk region of the world, a potential molecular marker. BMC Cancer, 2009, 9: 24

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, Beijing, 100853, China

    Xiao-Mei Zhang & Ming-Zhou Guo

Authors
  1. Xiao-Mei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ming-Zhou Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ming-Zhou Guo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, XM., Guo, MZ. The value of epigenetic markers in esophageal cancer. Front. Med. China 4, 378–384 (2010). https://doi.org/10.1007/s11684-010-0230-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11684-010-0230-3

Keywords

Search

Navigation