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

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Gastric Cancer

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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.

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References

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  14. Bernstein BE, Meissner A, Lander ES. The mammalian epigenome. Cell. 2007;128:669–81.

    Article  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  16. Ushijima T, Sasako M. Focus on gastric cancer. Cancer Cell. 2004;5:121–5.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  18. Network TCGATR. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202–9.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  33. Ushijima T. Epigenetic field for cancerization. J Biochem Mol Biol. 2007;40:142–50.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  41. Takeshima H, Ushijima T. Methylation destiny: Moira takes account of histones and RNA polymerase II. Epigenetics. 2010;5:89–95.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

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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.

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Authors and Affiliations

  1. Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan

    Masahiro Maeda, Harumi Yamada, Hiroshi Moro & Toshikazu Ushijima

  2. Department of Gastrointestinal Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Masahiro Maeda & Harumi Yamada

Authors
  1. Masahiro Maeda
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  2. Harumi Yamada
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  3. Hiroshi Moro
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  4. Toshikazu Ushijima
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Correspondence to Toshikazu Ushijima .

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Editors and Affiliations

  1. Department of Internal Medicine, Kawasaki Medical School Kurashiki, Okayama, Japan

    Akiko Shiotani

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Maeda, M., Yamada, H., Moro, H., Ushijima, T. (2019). Gastric Cancer Risk Prediction Using Epigenetic Alterations Accumulated in Noncancerous Gastric Tissues. In: Shiotani, A. (eds) Gastric Cancer. Springer, Singapore. https://doi.org/10.1007/978-981-13-1120-8_7

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  • DOI: https://doi.org/10.1007/978-981-13-1120-8_7

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  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-13-1119-2

  • Online ISBN: 978-981-13-1120-8

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