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Gastric Cancer Risk Prediction Using Epigenetic Alterations Accumulated in Noncancerous Gastric Tissues

  • Masahiro Maeda
  • Harumi Yamada
  • Hiroshi Moro
  • Toshikazu UshijimaEmail author
Chapter
  • 636 Downloads

Abstract

Risk prediction for gastric cancer (GC) is important, especially for H. pylori-eradicated individuals whose number is rapidly increasing in Japan. For accurate cancer risk prediction, analysis of epigenetic changes, particularly aberrant DNA methylations, has a great potential. It is induced in the gastric mucosa by H. pylori infection, persists for life, and is causally involved in gastric carcinogenesis. The DNA methylation levels in individuals without current H. pylori infection correlate with GC risk and have a greater impact than that of accumulated point mutations. A methylation marker is necessary to assess the overall epigenomic damage accumulated in the genome of gastric epithelial cells. Initially, CpG islands methylated in GC cells were used. More informative markers were then isolated by an analysis of the gastric mucosa of gastric cancer patients and healthy individuals. Finally, highly informative markers unaffected by contaminating blood cells have been developed using an advanced technology and a screening algorithm. With an aim of bringing epigenetic cancer risk diagnosis into practice, we first conducted a multicenter prospective cohort study for risk prediction of metachronous GC among GC patients who had undergone endoscopic treatment and achieved the first proof of concept. We are currently conducting a new, nationwide study for risk prediction of primary GC among healthy H. pylori-eradicated individuals. Epigenetic cancer risk diagnosis, which was initially developed for GC and potentially applicable to other inflammation-associated cancers, has a great potential to contribute to precision medicine.

Keywords

Epigenetics Cancer risk DNA methylation Inflammation Field cancerization 

Notes

Acknowledgments

The authors are grateful to Dr. S. Yamashita and H. Takeshima for their advices.

Grant Support: This research was supported by the National Cancer Center Research and Development Fund (H29-E-7), Japan, and by the fund (17ck0106267h0001) for the Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development, AMED.

Compliance with Ethical Standards

Conflict of Interest: The authors (MM and TU) made a joint patent application with Sysmex Corporation for identified epigenetic markers.

Ethical Standards: This article does not contain any studies with human or animal subjects performed by any of the authors.

References

  1. 1.
    Asaka M, Kato M, Sakamoto N. Roadmap to eliminate gastric cancer with Helicobacter pylori eradication and consecutive surveillance in Japan. J Gastroenterol. 2014;49:1–8.CrossRefGoogle Scholar
  2. 2.
    Lee YC, Chiang TH, Chou CK, Tu YK, Liao WC, Wu MS, et al. Association between Helicobacter pylori eradication and gastric cancer incidence: a systematic review and meta-analysis. Gastroenterology. 2016;150:1113–24.e5.CrossRefGoogle Scholar
  3. 3.
    El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000;404:398–402.CrossRefGoogle Scholar
  4. 4.
    Sakamoto H, Yoshimura K, Saeki N, Katai H, Shimoda T, Matsuno Y, et al. Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer. Nat Genet. 2008;40:730–40.CrossRefGoogle Scholar
  5. 5.
    Take S, Mizuno M, Ishiki K, Nagahara Y, Yoshida T, Yokota K, et al. Baseline gastric mucosal atrophy is a risk factor associated with the development of gastric cancer after Helicobacter pylori eradication therapy in patients with peptic ulcer diseases. J Gastroenterol. 2007;42(Suppl 17):21–7.CrossRefGoogle Scholar
  6. 6.
    Maekita T, Nakazawa K, Mihara M, Nakajima T, Yanaoka K, Iguchi M, et al. High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk. Clin Cancer Res. 2006;12:989–95.CrossRefGoogle Scholar
  7. 7.
    Nakajima T, Maekita T, Oda I, Gotoda T, Yamamoto S, Umemura S, et al. Higher methylation levels in gastric mucosae significantly correlate with higher risk of gastric cancers. Cancer Epidemiol Biomarkers Prev. 2006;15:2317–21.CrossRefGoogle Scholar
  8. 8.
    Ushijima T, Hattori N. Molecular pathways: involvement of Helicobacter pylori-triggered inflammation in the formation of an epigenetic field defect, and its usefulness as cancer risk and exposure markers. Clin Cancer Res. 2012;18:923–9.CrossRefGoogle Scholar
  9. 9.
    Nanjo S, Asada K, Yamashita S, Nakajima T, Nakazawa K, Maekita T, et al. Identification of gastric cancer risk markers that are informative in individuals with past H. pylori infection. Gastric Cancer. 2012;15:382–8.CrossRefGoogle Scholar
  10. 10.
    Ando T, Yoshida T, Enomoto S, Asada K, Tatematsu M, Ichinose M, et al. DNA methylation of microRNA genes in gastric mucosae of gastric cancer patients: its possible involvement in the formation of epigenetic field defect. Int J Cancer. 2009;124:2367–74.CrossRefGoogle Scholar
  11. 11.
    Asada K, Nakajima T, Shimazu T, Yamamichi N, Maekita T, Yokoi C, et al. Demonstration of the usefulness of epigenetic cancer risk prediction by a multicentre prospective cohort study. Gut. 2015;64:388–96.CrossRefGoogle Scholar
  12. 12.
    Maeda M, Nakajima T, Oda I, Shimazu T, Yamamichi N, Maekita T, et al. High impact of methylation accumulation on metachronous gastric cancer: 5-year follow-up of a multicentre prospective cohort study. Gut. 2017;66:1721–3.CrossRefGoogle Scholar
  13. 13.
    Maeda M, Yamashita S, Shimazu T, Iida N, Takeshima H, Nakajima T, et al. Novel epigenetic markers for gastric cancer risk stratification in individuals after Helicobacter pylori eradication. Gastric Cancer. 2018.  https://doi.org/10.1007/s10120-018-0803-4.CrossRefGoogle Scholar
  14. 14.
    Bernstein BE, Meissner A, Lander ES. The mammalian epigenome. Cell. 2007;128:669–81.CrossRefGoogle Scholar
  15. 15.
    Padmanabhan N, Ushijima T, Tan P. How to stomach an epigenetic insult: the gastric cancer epigenome. Nat Rev Gastroenterol Hepatol. 2017;14:467–78.PubMedGoogle Scholar
  16. 16.
    Ushijima T, Sasako M. Focus on gastric cancer. Cancer Cell. 2004;5:121–5.CrossRefGoogle Scholar
  17. 17.
    Yoda Y, Takeshima H, Niwa T, Kim JG, Ando T, Kushima R, et al. Integrated analysis of cancer-related pathways affected by genetic and epigenetic alterations in gastric cancer. Gastric Cancer. 2015;18:65–76.CrossRefGoogle Scholar
  18. 18.
    Network TCGATR. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202–9.CrossRefGoogle Scholar
  19. 19.
    Wang K, Kan J, Yuen ST, Shi ST, Chu KM, Law S, et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat Genet. 2011;43:1219–23.CrossRefGoogle Scholar
  20. 20.
    Niwa T, Tsukamoto T, Toyoda T, Mori A, Tanaka H, Maekita T, et al. Inflammatory processes triggered by Helicobacter pylori infection cause aberrant DNA methylation in gastric epithelial cells. Cancer Res. 2010;70:1430–40.CrossRefGoogle Scholar
  21. 21.
    Hur K, Niwa T, Toyoda T, Tsukamoto T, Tatematsu M, Yang HK, et al. Insufficient role of cell proliferation in aberrant DNA methylation induction and involvement of specific types of inflammation. Carcinogenesis. 2011;32:35–41.CrossRefGoogle Scholar
  22. 22.
    Niwa T, Toyoda T, Tsukamoto T, Mori A, Tatematsu M, Ushijima T. Prevention of Helicobacter pylori-induced gastric cancers in gerbils by a DNA demethylating agent. Cancer Prev Res. 2013;6:263–70.CrossRefGoogle Scholar
  23. 23.
    Shin CM, Kim N, Park JH, Kang GH, Kim JS, Jung HC, et al. Prediction of the risk for gastric cancer using candidate methylation markers in the non-neoplastic gastric mucosae. J Pathol. 2012;226:654–65.CrossRefGoogle Scholar
  24. 24.
    Shin CM, Kim N, Jung Y, Park JH, Kang GH, Kim JS, et al. Role of Helicobacter pylori infection in aberrant DNA methylation along multistep gastric carcinogenesis. Cancer Sci. 2010;101:1337–46.CrossRefGoogle Scholar
  25. 25.
    Takeshima H, Niwa T, Toyoda T, Wakabayashi M, Yamashita S, Ushijima T. Degree of methylation burden is determined by the exposure period to carcinogenic factors. Cancer Sci. 2017;108:316–21.CrossRefGoogle Scholar
  26. 26.
    Schneider BG, Peng DF, Camargo MC, Piazuelo MB, Sicinschi LA, Mera R, et al. Promoter DNA hypermethylation in gastric biopsies from subjects at high and low risk for gastric cancer. Int J Cancer. 2010;127:2588–97.CrossRefGoogle Scholar
  27. 27.
    Yoo EJ, Park SY, Cho NY, Kim N, Lee HS, Kim D, et al. Influence of IL1B polymorphism on CpG island hypermethylation in Helicobacter pylori-infected gastric cancer. Virchows Arch. 2010;456:647–52.CrossRefGoogle Scholar
  28. 28.
    Chan AO, Peng JZ, Lam SK, Lai KC, Yuen MF, Cheung HK, et al. Eradication of Helicobacter pylori infection reverses E-cadherin promoter hypermethylation. Gut. 2006;55:463–8.CrossRefGoogle Scholar
  29. 29.
    Nakajima T, Enomoto S, Yamashita S, Ando T, Nakanishi Y, Nakazawa K, et al. Persistence of a component of DNA methylation in gastric mucosae after Helicobacter pylori eradication. J Gastroenterol. 2010;45:37–44.CrossRefGoogle Scholar
  30. 30.
    Shin CM, Kim N, Lee HS, Park JH, Ahn S, Kang GH, et al. Changes in aberrant DNA methylation after Helicobacter pylori eradication: a long-term follow-up study. Int J Cancer. 2013;133:2034–42.CrossRefGoogle Scholar
  31. 31.
    Nakajima T, Oda I, Gotoda T, Hamanaka H, Eguchi T, Yokoi C, et al. Metachronous gastric cancers after endoscopic resection: how effective is annual endoscopic surveillance? Gastric Cancer. 2006;9:93–8.CrossRefGoogle Scholar
  32. 32.
    Mori G, Nakajima T, Asada K, Shimazu T, Yamamichi N, Maekita T, et al. Incidence of and risk factors for metachronous gastric cancer after endoscopic resection and successful Helicobacter pylori eradication: results of a large-scale, multicenter cohort study in Japan. Gastric Cancer. 2016;19:911–8.CrossRefGoogle Scholar
  33. 33.
    Ushijima T. Epigenetic field for cancerization. J Biochem Mol Biol. 2007;40:142–50.PubMedGoogle Scholar
  34. 34.
    Yamashita S, Kishino T, Takahashi T, Shimazu T, Charvat H, Kakugawa Y, et al. Genetic and epigenetic alterations in normal tissues have differential impacts on cancer risk among tissues. Proc Natl Acad Sci U S A. 2018;115(6):1328–33.  https://doi.org/10.1073/pnas.1717340115.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Yamashita S, Iida N, Takeshima H, Hattori N, Maeda M, Kishino T, et al. A novel method to quantify base substitution mutations at the 10−6 per bp level in DNA samples. Cancer Lett. 2017;403:152–8.CrossRefGoogle Scholar
  36. 36.
    Matsumoto Y, Marusawa H, Kinoshita K, Endo Y, Kou T, Morisawa T, et al. Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. Nat Med. 2007;13:470–6.CrossRefGoogle Scholar
  37. 37.
    Kaneda A, Kaminishi M, Yanagihara K, Sugimura T, Ushijima T. Identification of silencing of nine genes in human gastric cancers. Cancer Res. 2002;62:6645–50.PubMedGoogle Scholar
  38. 38.
    Teschendorff AE, Gao Y, Jones A, Ruebner M, Beckmann MW, Wachter DL, et al. DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer. Nat Commun. 2016;7:10478.CrossRefGoogle Scholar
  39. 39.
    Teschendorff AE, Jones A, Fiegl H, Sargent A, Zhuang JJ, Kitchener HC, et al. Epigenetic variability in cells of normal cytology is associated with the risk of future morphological transformation. Genome Med. 2012;4:24.CrossRefGoogle Scholar
  40. 40.
    Takeshima H, Yamashita S, Shimazu T, Niwa T, Ushijima T. The presence of RNA polymerase II, active or stalled, predicts epigenetic fate of promoter CpG islands. Genome Res. 2009;19:1974–82.CrossRefGoogle Scholar
  41. 41.
    Takeshima H, Ushijima T. Methylation destiny: Moira takes account of histones and RNA polymerase II. Epigenetics. 2010;5:89–95.CrossRefGoogle Scholar
  42. 42.
    Keshet I, Schlesinger Y, Farkash S, Rand E, Hecht M, Segal E, et al. Evidence for an instructive mechanism of de novo methylation in cancer cells. Nat Genet. 2006;38:149–53.CrossRefGoogle Scholar
  43. 43.
    Maeda M, Moro H, Ushijima T. Mechanisms for the induction of gastric cancer by Helicobacter pylori infection: aberrant DNA methylation pathway. Gastric Cancer. 2017;20(S1):8–15.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Masahiro Maeda
    • 1
    • 2
  • Harumi Yamada
    • 1
    • 2
  • Hiroshi Moro
    • 1
  • Toshikazu Ushijima
    • 1
    Email author
  1. 1.Division of EpigenomicsNational Cancer Center Research InstituteTokyoJapan
  2. 2.Department of Gastrointestinal SurgeryKyoto University Graduate School of MedicineKyotoJapan

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