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TERT promoter methylation is significantly associated with TERT upregulation and disease progression in pituitary adenomas

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Abstract

Purpose

Alterations in the promoter of the telomerase reverse transcriptase (TERT) gene are a major mechanism of upregulating telomerase, which plays a crucial role in tumor development. Mutations in the TERT promoter have been observed in a subset of brain tumors, including adult gliomas and high-grade meningiomas. In pituitary adenomas (PAs), however, abnormalities in TERT are not fully understood. The present study aimed to investigate not only mutational but also methylation changes in the TERT promoter in PAs and to analyze their correlations with clinical variables.

Methods

We retrospectively studied 70 PAs consisting of 53 primary and 17 recurrent samples. Clinical data, including age at surgery, sex, largest tumor dimension, tumor subtype, resection rate, and progression-free survival (PFS), were obtained from medical records. We investigated TERT promoter hotspot mutations via Sanger sequencing and quantified the methylation status of the TERT promoter using methylation-sensitive high-resolution melting analysis (MS-HRM). Additionally, we investigated TERT mRNA expression using real-time quantitative PCR.

Results

TERT promoter hotspot mutations were not observed in any PA sample, while 16% of PAs exhibited TERT promoter methylation. PAs with methylated TERT promoters were significantly more likely to show disease progression, shorter PFS, and higher TERT expression levels compared to those with unmethylated promoters.

Conclusions

This is the first study showing that TERT promoter methylation is associated with disease progression and shorter PFS as well as upregulated TERT expression in PAs. Our results suggest that TERT promoter methylation may be a potential biomarker for predicting tumor recurrence in PAs.

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Acknowledgements

This work was supported by a grant from the Hidaka Research Project and a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (JSPS KAKENHI Grant Number 15K10369), 2015–2017. We would like to thank Ms. Kozue Watanabe and Ms. Ayako Kubota for their technical assistance.

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Authors and Affiliations

  1. Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, 1397-1, Yamane, Hidaka, Saitama, 350-1298, Japan

    Yohei Miyake, Jun-ichi Adachi, Tomonari Suzuki, Kazuhiko Mishima, Reina Mizuno & Ryo Nishikawa

  2. Community Health Science Center, Saitama Medical University, Moroyama, Saitama, Japan

    Ryuichiro Araki

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  1. Yohei Miyake
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Correspondence to Jun-ichi Adachi.

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Miyake, Y., Adachi, Ji., Suzuki, T. et al. TERT promoter methylation is significantly associated with TERT upregulation and disease progression in pituitary adenomas. J Neurooncol 141, 131–138 (2019). https://doi.org/10.1007/s11060-018-03016-8

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  • DOI: https://doi.org/10.1007/s11060-018-03016-8

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