Epigenetic upregulation of TET2 is an independent poor prognostic factor for intrahepatic cholangiocarcinoma

Author:

Yamashita Hironori,Tourna Aikaterini,Akita Masayuki,Itoh Tomoo,Chokshi Shilpa,Ajiki Tetsuo,Fukumoto Takumi,Youngson Neil A.,Zen YohORCID

Abstract

AbstractMutations in IDH1/2 and the epigenetic silencing of TET2 occur in leukaemia or glioma in a mutually exclusive manner. Although intrahepatic cholangiocarcinoma (iCCA) may harbour IDH1/2 mutations, the contribution of TET2 to carcinogenesis remains unknown. In the present study, the expression and promoter methylation of TET2 were investigated in iCCA. The expression of TET2 was assessed in 52 cases of iCCA (small-duct type, n = 33; large-duct type, n = 19) by quantitative PCR, immunohistochemistry (IHC) and a sequencing-based methylation assay, and its relationships with clinicopathological features and alterations in cancer-related genes (e.g., KRAS and IDH1) were investigated. In contrast to non-neoplastic bile ducts, which were negative for TET2 on IHC, 42 cases (81%) of iCCA showed the nuclear overexpression of TET2. Based on IHC scores (area × intensity), these cases were classified as TET2-high (n = 25) and TET2-low (n = 27). The histological type, tumour size, lymph node metastasis and frequency of mutations in cancer-related genes did not significantly differ between the two groups. Overall and recurrence-free survival were significantly worse in patients with TET2-high iCCA than in those with TET2-low iCCA. A multivariate analysis identified the high expression of TET2 as an independent prognostic factor (HR = 2.94; p = 0.007). The degree of methylation at two promoter CpG sites was significantly less in TET2-high iCCA than in TET2-low iCCA or non-cancer tissue. In conclusion, in contrast to other IDH-related neoplasms, TET2 overexpression is common in iCCA of both subtypes, and its high expression, potentially induced by promoter hypomethylation, is an independent poor prognostic factor.

Funder

Ministry of Education, Culture, Sports, Science and Technology in Japan

Foundation for Liver Research

Publisher

Springer Science and Business Media LLC

Subject

Cell Biology,Molecular Biology,General Medicine,Pathology and Forensic Medicine

Cited by 4 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. The effect of genetics and biochemistry on the pathogenesis of cholangiocarcinoma;International Journal of Hepatobiliary and Pancreatic Diseases;2024-07-25

2. The role of TET2 in solid tumors and its therapeutic potential: a comprehensive review;Clinical and Translational Oncology;2024-04-10

3. The roles of epigenetic regulation in cholangiocarcinogenesis;Biomedicine & Pharmacotherapy;2023-10

4. The clinical value of identifying genetic abnormalities that can be targeted in cholangiocarcinomas;Expert Review of Anticancer Therapy;2023-01-30

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