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Severe induction of aberrant DNA methylation by nodular gastritis in adults

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Abstract

Background

Nodular gastritis (NG) is characterized by marked antral lymphoid follicle formation, and is a strong risk factor for diffuse-type gastric cancer in adults. However, it is unknown whether aberrant DNA methylation, which is induced by atrophic gastritis (AG) and is a risk for gastric cancer, is induced by NG. Here, we analyzed methylation induction by NG.

Methods

Gastric mucosal samples were obtained from non-cancerous antral tissues of 16 NG and 20 AG patients with gastric cancer and 5 NG and 6 AG patients without, all age- and gender-matched. Genome-wide methylation analysis and expression analysis were conducted by a BeadChip array and RNA-sequencing, respectively.

Results

Clustering analysis of non-cancerous antral tissues of NG and AG patients with gastric cancer was conducted using methylation levels of 585 promoter CpG islands (CGIs) of methylation-resistant genes, and a large fraction of NG samples formed a cluster with strong methylation induction. Promoter CGIs of CDH1 and DAPK1 tumor-suppressor genes were more methylated in NG than in AG. Notably, methylation levels of these genes were also higher in the antrum of NG patients without cancer. Genes related to lymphoid follicle formation, such as CXCL13/CXCR5 and CXCL12/CXCR4, had higher expression in NG, and genes involved in DNA demethylation TET2 and IDH1, had only half the expression in NG.

Conclusions

Severe aberrant methylation, involving multiple tumor-suppressor genes, was induced in the gastric antrum and body of patients with NG, in accordance with their high gastric cancer risk.

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Abbreviations

NG:

Nodular gastritis

H. pylori :

Helicobacter pylori

AG:

Atrophic gastritis

CGIs:

CpG islands

DNMTs:

DNA methyltransferases

NO:

Nitric oxide

FFPE:

Formalin-fixed paraffin-embedded

FF:

Fresh-frozen

NBI:

Narrow Band Imaging

qPCR:

Quantitative PCR

HSD:

Highest standard deviation

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Acknowledgements

TU is a recipient of grants supported by AMED under Grant Nos. JP23ck0106804 and JP20gm1310006. HT is a recipient of a grant supported by JSPS KAKENHI under Grant No. JP21K07928. NY is a recipient of a Research Grant of the Princess Takamatsu Cancer Research Fund (ID: 19-25138) and JSPS KAKENHI under Grant No. JP21H03178.

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Authors and Affiliations

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

    Akiko Sasaki, Hideyuki Takeshima, Satoshi Yamashita, Chihiro Takeuchi, Masahide Fukuda, Yumi Furuichi & Toshikazu Ushijima

  2. Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Kanagawa, Japan

    Akiko Sasaki, Chikamasa Ichita, Chihiro Sumida & Kazuya Koizumi

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

    Hideyuki Takeshima, Yui Ohashi, Chihiro Takeuchi, Yumi Furuichi & Toshikazu Ushijima

  4. Department of General Surgery, Shonan Kamakura General Hospital, Kanagawa, Japan

    Jun Kawachi

  5. Department of Diagnostic Pathology, Shonan Kamakura General Hospital, Kanagawa, Japan

    Wataru Naito

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

    Masahide Fukuda

  7. Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan

    Yumi Furuichi

  8. Center for Epidemiology and Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Nobutake Yamamichi

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

    Takayuki Ando

  10. Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan

    Hideki Kobara

  11. Department of Medical Examination, Uji-Tokushukai Medical Center, Kyoto, Japan

    Tohru Kotera

  12. Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan

    Takao Itoi

  13. Division of Molecular Pharmacology, National Cancer Center Research Institute, Tokyo, Japan

    Akinobu Hamada

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  1. Akiko Sasaki
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Contributions

AS, HT, and TU conceived and designed the study. AS, HT, and YO carried out experiments. AS, HT, SY, and AH conducted data analysis. CI, JK, CT, MF, YF, NY, TA, HK, TK, CS, and KK collected clinical samples and WN supervised the pathological diagnosis and sample processing. AS, HT, TI, and TU wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Toshikazu Ushijima.

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Sasaki, A., Takeshima, H., Yamashita, S. et al. Severe induction of aberrant DNA methylation by nodular gastritis in adults. J Gastroenterol (2024). https://doi.org/10.1007/s00535-024-02094-y

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