Loss of 5-Hydroxymethylcytosine is an Epigenetic Hallmark of Thyroid Carcinomas with TERT Promoter Mutations
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Loss of 5‑Hydroxymethylcytosine is an Epigenetic Hallmark of Thyroid Carcinomas with TERT Promoter Mutations Naoki Oishi1 · Huy Gia Vuong1 · Kunio Mochizuki1 · Tetsuo Kondo1 Accepted: 25 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Epigenetic dysregulation is a hallmark of cancer, and aberrant methylation of cytosine residues plays a crucial role in abnormal gene expression in cancer cells. Recent studies demonstrate that 5-hydroxymethylcytosine (5-hmC) generated through 5-methylcytosine (5-mC) oxidation is significantly depleted in various cancers. However, whether 5-hmC levels change during the stepwise progression of thyroid carcinoma and the mechanisms underlying this effect remain unknown. The aims of this study were (i) to assess 5-hmC levels in normal and cancerous thyroid tissues, and (ii) identify clinicopathologic and genetic factors associated with the dysregulated hydroxymethylation of cytosine. Enzyme-linked immunosorbent assay (ELISA) showed that 5-hmC was significantly reduced in TERT promoter-mutated papillary thyroid carcinomas (PTCs) and anaplastic thyroid carcinomas (ATCs), while there was no significant difference in 5-hmC levels between TERT promoterwild-type PTCs and normal thyroid tissues. Results of semi-quantitative analysis of 5-hmC through immunohistochemistry correlated well with those of ELISA and confirmed the loss of 5-hmC in tumor cells. Immunohistochemistry confirmed lower 5-hmC positivity in TERT promoter-mutated PTCs (n = 10) and ATCs (n = 4) than in normal thyroid tissues (n = 8) and TERT promoter-wild-type PTCs (n = 63). Tumor size (> 1 cm) and advanced stage were associated with decreased global 5-hmC in PTCs, while age, gross extrathyroidal invasion, node metastasis, and BRAF mutation were not. Collectively, these findings demonstrated that loss of 5-hmC is an epigenetic hallmark of thyroid carcinomas with TERT promoter mutation, indicating that TERT promoter-mutated thyroid carcinoma has a distinct molecular profile. Keywords Thyroid cancer · Epigenetics · 5-Hydroxymethylcytosine · TERT promoter mutation · BRAF V600E · Immunohistochemistry
Introduction Thyroid carcinomas consist of various histological types with a wide spectrum of functional and morphologic differentiation: papillary (PTC), follicular (FTC), poorly differentiated (PDTC), and anaplastic (ATC) thyroid carcinomas. PTC, a well-differentiated neoplasm accounting for approximately 90% of all thyroid carcinomas, shows frequent lymph node (LN) metastasis and exhibits considerably favorable clinical outcomes with approximately 90% overall survival [1]. However, subsets of PTCs undergo histologic
* Naoki Oishi [email protected] 1
Faculty of Medicine, Department of Pathology, University of Yamanashi, 1110 Shimokato, 409‑3898 Chuo, Yamanashi, Japan
transformation into anaplastic thyroid carcinoma (ATC), which is a lethal malignancy with the most aggressive clinical course. One of the recent advances in the molecular genetics of thyroid cancer is the identifi
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