Chen Chen, Han Sheng, Meng Lingxuan, Li Zhonghua, Zhang Xue, Wu Anhua
Research Center for Medical Genomics, Key Laboratory of Medical Cell Biology, Ministry of Education, College of Basic Medical Science, China Medical University, Shenyang, Liaoning, China.
Department of Neurosurgery, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
PLoS One. 2014 Jun 17;9(6):e100297. doi: 10.1371/journal.pone.0100297. eCollection 2014.
This study explored the effects of telomerase reverse transcriptase (TERT) promoter mutations on transcriptional activity of the TERT gene under hypoxic and temozolomide (TMZ) treatment conditions, and investigated the status and prognostic value of these mutations in gliomas.
The effect of TERT promoter mutations on the transcriptional activity of the TERT gene under hypoxic and TMZ treatment conditions was investigated in glioma cells using the luciferase assay. TERT promoter mutations were detected in 101 glioma samples (grades I-IV) and 49 other brain tumors by sequencing. TERT mRNA expression in gliomas was examined by real-time PCR. Hazard ratios from survival analysis of glioma patients were determined relative to the presence of TERT promoter mutations.
Mutations in the TERT promoter enhanced gene transcription even under hypoxic and TMZ treatment conditions, inducing upregulation of TERT mRNA expression. Mutations were detected in gliomas, but not in meningiomas, pituitary adenomas, cavernomas, intracranial metastases, normal brain tissues, or peripheral blood of glioma patients. Patients with TERT promoter mutations had lower survival rates, even after adjusting for other known or potential risk factors, and the incidence of mutation was correlated with patient age.
TERT promoter mutations were specific to gliomas. TERT promoter mutations maintained its ability of inducing high transcriptional activity even under hypoxic and TMZ treatment conditions, and the presence of mutations was associated with poor prognosis in glioma patients. These findings demonstrate that TERT promoter mutations are novel prognostic markers for gliomas that can inform prospective therapeutic strategies.
本研究探讨端粒酶逆转录酶（TERT）启动子突变在缺氧和替莫唑胺（TMZ）治疗条件下对TERT基因转录活性的影响，并研究这些突变在胶质瘤中的状态及预后价值。
采用荧光素酶报告基因检测法，在胶质瘤细胞中研究TERT启动子突变在缺氧和TMZ治疗条件下对TERT基因转录活性的影响。通过测序检测101例胶质瘤样本（I-IV级）和49例其他脑肿瘤中的TERT启动子突变。采用实时PCR检测胶质瘤中TERT mRNA的表达。根据TERT启动子突变的存在情况，确定胶质瘤患者生存分析的风险比。
即使在缺氧和TMZ治疗条件下，TERT启动子突变也能增强基因转录，导致TERT mRNA表达上调。在胶质瘤中检测到突变，但在脑膜瘤、垂体腺瘤、海绵状血管瘤、颅内转移瘤、正常脑组织或胶质瘤患者的外周血中未检测到突变。即使在调整了其他已知或潜在的危险因素后，TERT启动子突变的患者生存率仍较低，且突变发生率与患者年龄相关。
TERT启动子突变是胶质瘤特有的。即使在缺氧和TMZ治疗条件下，TERT启动子突变仍保持其诱导高转录活性的能力，且突变的存在与胶质瘤患者的不良预后相关。这些发现表明，TERT启动子突变是胶质瘤新的预后标志物，可为前瞻性治疗策略提供依据。
