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  • Review Article
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How to stomach an epigenetic insult: the gastric cancer epigenome

Nature Reviews Gastroenterology & Hepatology volume 14, pages 467–478 (2017)Cite this article

Subjects

Key Points

  • Epigenetic alterations are pervasive in gastric malignancies

  • Tumour epigenetic changes are multifaceted, comprising several mechanisms including aberrant DNA methylation, histone modifications, noncoding RNAs and RNA editing

  • A proportion of tumour-specific DNA methylation events have been causally linked to infectious agents

  • Different epigenetic marks co-occur in end-stage disease making it complex to tease apart causality in promoting cellular transformation

  • Aberrant DNA methylation is found in pre-malignant lesions of gastric cancer, indicative of its role in driving carcinogenesis

  • Unbiased whole-genome technologies might uncover novel epimutations and molecular features in gastric cancer, leading to a better understanding of disease heterogeneity

Abstract

Gastric cancer is a deadly malignancy afflicting close to a million people worldwide. Patient survival is poor and largely due to late diagnosis and suboptimal therapies. Disease heterogeneity is a substantial obstacle, underscoring the need for precision treatment strategies. Studies have identified different subgroups of gastric cancer displaying not just genetic, but also distinct epigenetic hallmarks. Accumulating evidence suggests that epigenetic abnormalities in gastric cancer are not mere bystander events, but rather promote carcinogenesis through active mechanisms. Epigenetic aberrations, induced by pathogens such as Helicobacter pylori, are an early component of gastric carcinogenesis, probably preceding genetic abnormalities. This Review summarizes our current understanding of the gastric cancer epigenome, highlighting key advances in recent years in both tumours and pre-malignant lesions, made possible through targeted and genome-wide technologies. We focus on studies related to DNA methylation and histone modifications, linking these findings to potential therapeutic opportunities. Lessons learned from the gastric cancer epigenome might also prove relevant for other gastrointestinal cancers.

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Figure 1: Epigenetic marks in gastric cancer.
Figure 2: Determinants of the gastric cancer methylome.
Figure 3: Examples of gene expression heterogeneity in epigenome regulators among the TCGA gastric cancer subtypes.

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Acknowledgements

P.T. and N.P. are supported by the National Medical Research Council (Singapore) grants TCR/009-NUHS/2013 and NMRC/STaR/0026/2015, and the Khoo Teck Puat Postdoctoral Fellowship award (Duke-NUS-KPFA/2016/0012). T.U. is supported by the Practical Research for Innovative Cancer Control grant from the Agency for Medical Research and Development, Japan.

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Authors and Affiliations

  1. Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, 8 College Road, 169857, Singapore

    Nisha Padmanabhan & Patrick Tan

  2. Division of Epigenomics, National Cancer Centre Research Institute, 5-1-1 Tsukiji, Chuo-ku, 104–0045, Tokyo, Japan

    Toshikazu Ushijima

  3. Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, 60 Biopolis Street, 138672, Singapore

    Patrick Tan

  4. SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre, 5 Hospital Drive, 169609, Singapore

    Patrick Tan

  5. Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, #12-01, 117599, Singapore

    Patrick Tan

  6. Cellular and Molecular Research, National Cancer Centre, 11 Hospital Drive, 169610, Singapore

    Patrick Tan

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  1. Nisha Padmanabhan
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N.P. researched the data for the article, all authors contributed equally to writing, discussing content and to reviewing and/or editing the article before submission.

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Padmanabhan, N., Ushijima, T. & Tan, P. How to stomach an epigenetic insult: the gastric cancer epigenome. Nat Rev Gastroenterol Hepatol 14, 467–478 (2017). https://doi.org/10.1038/nrgastro.2017.53

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