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TP53 inactivation and expression of methylation-associated proteins in gastric adenocarcinoma with enteroblastic differentiation

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Abstract

Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare variant of aggressive adenocarcinoma. We demonstrated previously that GAED is genetically characterized by frequent TP53 mutation. In this study, we aimed to further clarify the mechanism of inactivation of TP53 in GAED in the light of promoter methylation of TP53, and expression of methylation-associated proteins such as Ten-eleven translocation (TET) 1 and 5-hydroxymethylcytosine (5-hmc) in addition to ATM mutations. We analyzed 51 cases of GAED. The ATM mutation was detected in only one case. Promoter methylation of TP53 was detected in 18% and frequency of loss of heterozygosity (LOH) at TP53 locus was 37.2%. Reduced TET1 expression was found in 29 cases (56.9%) and was significantly associated with advanced stage (p = 0.01), lymph node metastasis (p = 0.04), and macroscopic type (p = 0.01). Reduced 5-hmc expression was found in 28 cases (54.9%) and was significantly associated with advanced stage (p = 0.01), gender (p = 0.01), tumor location (p = 0.03), tumor size (p = 0.01), and lymph node metastasis (p = 0.01). Among 9 cases with TP53 promoter methylation, reduced expression of TET1 was observed in 6 cases, and reduced expression of 5-hmc was observed in 5 cases. Reduced expression of both TET1 and 5-hmc was significantly associated with adverse clinical outcomes. In summary, promoter methylation of TP53 is partly involved in loss of p53 expression. Aberrant methylation by reduced TET1 and 5-hmc may be involved in the development of aggressive GAED.

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Acknowledgements

We thank Isao Kurahayashi and Noriko Sasahara for their excellent technical assistances.

Funding

This work was financially supported in part by a Grant-in-Aid for General Scientific Research from the Ministry of Education, Science, Sports, and Culture (#17 K08704 to T. Yao), Tokyo, Japan.

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Authors and Affiliations

  1. Department of Human Pathology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan

    Noboru Yatagai, Tsuyoshi Saito, Yoichi Akazawa, Takuo Hayashi, Yuka Yanai, Sho Tsuyama & Takashi Yao

  2. Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Tokyo, 113-8421, Japan

    Noboru Yatagai, Yoichi Akazawa, Hiroya Ueyama, Takashi Murakami, Sumio Watanabe & Akihito Nagahara

  3. Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, 113-8421, Japan

    Tsuyoshi Saito

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Contributions

Noboru Yatagai, Tsuyoshi Saito, Yoichi Akazawa, Takuo Hayashi, Takashi Murakami, and Takashi Yao designed the research project and evaluated the histological and immunohistochemical findings. Noboru Yatagai, Takuo Hayashi, and Tsuyoshi Saito analyzed the obtained data and wrote the main part of the manuscript and Sumio Watanabe, Akihito Nagahara, and Takashi Yao reviewed the draft with critical comments and wrote the manuscript. Noboru Yatagai, Yuya Yanai, Sho Tsuyama, Hiroya Ueyama, and Takashi Murakami performed molecular pathological part of the experiments.

Corresponding author

Correspondence to Tsuyoshi Saito.

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This study was reviewed and approved by the Juntendo University School of Medicine Institutional Review Board (#2016107).

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Yatagai, N., Saito, T., Akazawa, Y. et al. TP53 inactivation and expression of methylation-associated proteins in gastric adenocarcinoma with enteroblastic differentiation. Virchows Arch 474, 315–324 (2019). https://doi.org/10.1007/s00428-018-2508-9

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