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15.12.2018 | Original Article | Ausgabe 3/2019

Virchows Archiv 3/2019

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

Zeitschrift:
Virchows Archiv > Ausgabe 3/2019
Autoren:
Noboru Yatagai, Tsuyoshi Saito, Yoichi Akazawa, Takuo Hayashi, Yuka Yanai, Sho Tsuyama, Hiroya Ueyama, Takashi Murakami, Sumio Watanabe, Akihito Nagahara, Takashi Yao
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The online version of this article (https://​doi.​org/​10.​1007/​s00428-018-2508-9) contains supplementary material, which is available to authorized users.

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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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Zusatzmaterial
ESM 1 (DOCX 28 kb)
428_2018_2508_MOESM1_ESM.docx
Supplementary Table 3 (XLSX 9 kb)
428_2018_2508_MOESM2_ESM.xlsx
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