TP53 inactivation and expression of methylation-associated proteins in gastric adenocarcinoma with enteroblastic differentiation
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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.
KeywordsGastric adenocarcinoma Enteroblastic differentiation TP53 LOH Methylation TET1
We thank Isao Kurahayashi and Noriko Sasahara for their excellent technical assistances.
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.
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.
Compliance with ethical standards
This study was reviewed and approved by the Juntendo University School of Medicine Institutional Review Board (#2016107).
Conflict of interest
The authors declare that they have no conflicts of interest.
- 4.Murakami T, Yao T, Mitomi H, Morimoto T, Ueyama H, Matsumoto K, Saito T, Osada T, Nagahara A, Watanabe S (2016) Clinicopathologic and immunohistochemical characteristics of gastric adenocarcinoma with enteroblastic differentiation: a study of 29 cases. Gastric Cancer 19:498–507. https://doi.org/10.1007/s10120-015-0497-9 CrossRefPubMedGoogle Scholar
- 5.Matsumoto K, Ueyama H, Matsumoto K, Akazawa Y, Komori H, Takeda T, Murakami T, Asaoka D, Hojo M, Tomita N, Nagahara A, Kajiyama Y, Yao T, Watanabe S (2016) Clinicopathological features of alpha-fetoprotein producing early gastric cancer with enteroblastic differentiation. World J Gastroenterol 22:8203–8210. https://doi.org/10.3748/wjg.v22.i36.8203 CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Kinjo T, Taniguchi H, Kushima R, Sekine S, Oda I, Saka M, Gotoda T, Kinjo F, Fujita J, Shimoda T (2012) Histologic and immunohistochemical analyses of alpha-fetoprotein--producing cancer of the stomach. Am J Surg Pathol 36:56–65. https://doi.org/10.1097/PAS.0b013e31823aafec CrossRefPubMedGoogle Scholar
- 8.Ushiku T, Shinozaki A, Shibahara J, Iwasaki Y, Tateishi Y, Funata N, Fukayama M (2010) SALL4 represents fetal gut differentiation of gastric cancer, and is diagnostically useful in distinguishing hepatoid gastric carcinoma from hepatocellular carcinoma. Am J Surg Pathol 34:533–540. https://doi.org/10.1097/PAS.0b013e3181d1dcdd CrossRefPubMedGoogle Scholar
- 9.Ushiku T, Uozaki H, Shinozaki A, Ota S, Matsuzaka K, Nomura S, Kaminishi M, Aburatani H, Kodama T, Fukayama M (2009) Glypican 3-expressing gastric carcinoma: distinct subgroup unifying hepatoid, clear-cell, and alpha-fetoprotein-producing gastric carcinomas. Cancer Sci 100:626–632. https://doi.org/10.1111/j.1349-7006.2009.01108.x CrossRefPubMedGoogle Scholar
- 10.Akazawa Y, Saito T, Hayashi T, Yanai Y, Tsuyama S, Akaike K, Suehara Y, Takahashi F, Takamochi K, Ueyama H, Murakami T, Watanabe S, Nagahara A, Yao T (2018) Next-generation sequencing analysis for gastric adenocarcinoma with enteroblastic differentiation: emphasis on the relationship with hepatoid adenocarcinoma. Hum Pathol. https://doi.org/10.1016/j.humpath.2018.04.022
- 11.Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, Tagle DA, Smith S, Uziel T, Sfez S, Ashkenazi M, Pecker I, Frydman M, Harnik R, Patanjali SR, Simmons A, Clines GA, Sartiel A, Gatti RA, Chessa L, Sanal O, Lavin MF, Jaspers NG, Taylor AM, Arlett CF, Miki T, Weissman SM, Lovett M, Collins FS, Shiloh Y (1995) A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268:1749–1753CrossRefGoogle Scholar
- 13.Li L, Li C, Mao H, Du Z, Chan WY, Murray P, Luo B, Chan AT, Mok TS, Chan FK, Ambinder RF, Tao Q (2016) Epigenetic inactivation of the CpG demethylase TET1 as a DNA methylation feedback loop in human cancers. Sci Rep 6:26591. https://doi.org/10.1038/srep26591 CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Maya R, Balass M, Kim ST, Shkedy D, Leal JF, Shifman O, Moas M, Buschmann T, Ronai Z, Shiloh Y, Kastan MB, Katzir E, Oren M (2001) ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes Dev 15:1067–1077. https://doi.org/10.1101/gad.886901 CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Yemelyanova A, Vang R, Kshirsagar M, Lu D, Marks MA, Shih Ie M, Kurman RJ (2011) Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: an immunohistochemical and nucleotide sequencing analysis. Mod Pathol 24:1248–1253. https://doi.org/10.1038/modpathol.2011.85 CrossRefPubMedGoogle Scholar
- 29.Ciesielski P, Jozwiak P, Wojcik-Krowiranda K, Forma E, Cwonda L, Szczepaniec S, Bienkiewicz A, Brys M, Krzeslak A (2017) Differential expression of ten-eleven translocation genes in endometrial cancers. Tumour Biol 39:1010428317695017. https://doi.org/10.1177/1010428317695017 CrossRefPubMedGoogle Scholar
- 30.Ichimura N, Shinjo K, An B, Shimizu Y, Yamao K, Ohka F, Katsushima K, Hatanaka A, Tojo M, Yamamoto E, Suzuki H, Ueda M, Kondo Y (2015) Aberrant TET1 methylation closely associated with CpG island methylator phenotype in colorectal cancer. Cancer Prev Res (Phila) 8:702–711. https://doi.org/10.1158/1940-6207.Capr-14-0306 CrossRefGoogle Scholar