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The methylation level of a single cancer risk marker gene reflects methylation burden in gastric mucosa

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Abstract

Background

Gastric cancer risk can be accurately predicted by measuring the methylation level of a single marker gene in gastric mucosa. However, the mechanism is still uncertain. We hypothesized that the methylation level measured reflects methylation alterations in the entire genome (methylation burden), induced by Helicobacter pylori (H. pylori) infection, and thus cancer risk.

Methods

Gastric mucosa of 15 healthy volunteers without H. pylori infection (G1), 98 people with atrophic gastritis (G2), and 133 patients with gastric cancer (G3) after H. pylori eradication were collected. Methylation burden of an individual was obtained by microarray analysis as an inverse of the correlation coefficient between the methylation levels of 265,552 genomic regions in the person’s gastric mucosa and those in an entirely healthy mucosa.

Results

The methylation burden significantly increased in the order of G1 (n = 4), G2 (n = 18), and G3 (n = 19) and was well correlated with the methylation level of a single marker gene (r = 0.91 for miR124a-3). The average methylation levels of nine driver genes tended to increase according to the risk levels (P = 0.08 between G2 vs G3) and was also correlated with the methylation level of a single marker gene (r = 0.94). Analysis of more samples (14 G1, 97 G2, and 131 G3 samples) yielded significant increases of the average methylation levels between risk groups.

Conclusions

The methylation level of a single marker gene reflects the methylation burden, which includes driver gene methylation, and thus accurately predicts cancer risk.

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Data availability

DNA methylation data are available at the Gene Expression Omnibus (GEO) database with the accession number GSE226818.

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Acknowledgements

The authors are grateful to Ms. Mika Wakabayashi for her technical assistance.

Funding

This study is funded by AMED (grant number 22ck0106552h9903).

Author information

Authors and Affiliations

  1. Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan

    Takahiro Irie, Harumi Yamada, Chihiro Takeuchi, Yu-Yu Liu & Toshikazu Ushijima

  2. Department of Coloproctological Surgery, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Takahiro Irie, Kiichi Sugimoto & Kazuhiro Sakamoto

  3. Department of Surgery, Kyoto University, Kyoto, Japan

    Harumi Yamada

  4. Faculty of International Liberal Arts, Juntendo University, Tokyo, Japan

    Hadrien Charvat

  5. Division of Behavioral Sciences, National Cancer Center Institute for Cancer Control, National Cancer Center, Tokyo, Japan

    Taichi Shimazu

  6. Third Department of Internal Medicine, University of Toyama, Toyama, Japan

    Takayuki Ando

  7. Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan

    Takao Maekita

  8. Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan

    Seiichiro Abe & Hiroyuki Takamaru

  9. Department of Gastroenterology Faculty of Medicine, Oita University, Oita, Japan

    Masaaki Kodama & Kazunari Murakami

Authors
  1. Takahiro Irie
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  2. Harumi Yamada
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Contributions

Conception and design: TI, HY, CT, and TU. Development of methodology: TI, HY, and CT. Acquisition of materials: TS, TA, TM, SA, IO, MK, and KM. Analysis and interpretation of data: TI, HY, CT, YL, HC, TS, and TU. Writing, review, and/or revision of the manuscript: TI, KS (Kiichi Sugimoto), KS (Kazuhiro Sakamoto), and TU.

Corresponding author

Correspondence to Toshikazu Ushijima.

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The authors declare that they have no conflict of interest.

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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions.

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Informed consent was obtained from all patients for being included in the study.

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Irie, T., Yamada, H., Takeuchi, C. et al. The methylation level of a single cancer risk marker gene reflects methylation burden in gastric mucosa. Gastric Cancer 26, 667–676 (2023). https://doi.org/10.1007/s10120-023-01399-w

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