TERT promoter methylation is significantly associated with TERT upregulation and disease progression in pituitary adenomas
TERT promoter methylation is significantly associated with TERT upregulation and disease progression in pituitary adenomas
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DOI：
10.1007/s11060-018-03016-8
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发表时间：
2019-01-01
影响因子：
3.9
通讯作者：
Nishikawa, Ryo
中科院分区：
文献类型：
--
作者：
Miyake, Yohei;Adachi, Jun-ichi;Nishikawa, Ryo
目的 端粒酶逆转录酶 (TERT) 基因启动子的改变是上调端粒酶的主要机制，端粒酶在肿瘤发展中起着至关重要的作用。在一部分脑肿瘤中观察到了 TERT 启动子的突变，包括成人神经胶质瘤和高级别脑膜瘤。然而，在垂体腺瘤 (PA) 中，TERT 异常尚不完全清楚。本研究旨在研究 PA 中 TERT 启动子的突变和甲基化变化，并分析它们与临床变量的相关性。方法我们回顾性研究了 70 个 PA，其中包括 53 个原发样本和 17 个复发样本。从医疗记录中获得临床数据，包括手术年龄、性别、最大肿瘤尺寸、肿瘤亚型、切除率和无进展生存期（PFS）。我们通过桑格测序研究了 TERT 启动子热点突变，并使用甲基化敏感的高分辨率熔解分析 (MS-HRM) 定量了 TERT 启动子的甲基化状态。此外，我们使用实时定量 PCR 研究了 TERT mRNA 表达。结果在任何 PA 样本中均未观察到 TERT 启动子热点突变，而 16% 的 PA 表现出 TERT 启动子甲基化。与具有未甲基化启动子的 PA 相比，具有甲基化 TERT 启动子的 PA 明显更有可能表现出疾病进展、较短的 PFS 和较高的 TERT 表达水平。 结论 这是第一项研究表明 TERT 启动子甲基化与疾病进展和较短的 PFS 以及 PA 中 TERT 表达上调相关。我们的结果表明，TERT 启动子甲基化可能是预测 PA 肿瘤复发的潜在生物标志物。
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.