Department of Human Pathology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan.
Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Tokyo, 113-8421, Japan.
Virchows Arch. 2019 Mar;474(3):315-324. doi: 10.1007/s00428-018-2508-9. Epub 2018 Dec 15.
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.
胃性腺癌伴肠上皮分化（GAED）是一种侵袭性腺癌的罕见变异型。我们之前曾表明，GAED 的遗传特征是 TP53 频繁突变。在这项研究中，我们旨在进一步阐明 GAED 中 TP53 失活的机制，除了 ATM 突变外，还研究了 TP53 启动子甲基化以及甲基化相关蛋白如 Ten-eleven translocation（TET）1 和 5-羟甲基胞嘧啶（5-hmc）的表达。我们分析了 51 例 GAED 病例。仅在 1 例中检测到 ATM 突变。TP53 启动子甲基化在 18%的病例中检测到，TP53 基因座杂合性缺失（LOH）的频率为 37.2%。29 例（56.9%）发现 TET1 表达降低，与晚期分期（p=0.01）、淋巴结转移（p=0.04）和大体类型（p=0.01）显著相关。28 例（54.9%）发现 5-hmc 表达降低，与晚期分期（p=0.01）、性别（p=0.01）、肿瘤位置（p=0.03）、肿瘤大小（p=0.01）和淋巴结转移（p=0.01）显著相关。在 9 例 TP53 启动子甲基化的病例中，6 例观察到 TET1 表达降低，5 例观察到 5-hmc 表达降低。TET1 和 5-hmc 表达降低均与不良临床结局显著相关。综上所述，TP53 启动子甲基化部分参与了 p53 表达的丧失。TET1 和 5-hmc 的异常甲基化可能参与了侵袭性 GAED 的发生。
