TERT promoter mutations and long telomere length predict poor survival and radiotherapy resistance in gliomas.
TERT promoter mutations and long telomere length predict poor survival and radiotherapy resistance in gliomas.
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TERT 启动子突变和长端粒长度预测神经胶质瘤的较差生存率和放疗抵抗力
DOI：
10.18632/oncotarget.6007
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发表时间：
2016-02-23
期刊：
影响因子：
--
通讯作者：
Hou P
中科院分区：
文献类型：
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作者：
Gao K;Li G;Qu Y;Wang M;Cui B;Ji M;Shi B;Hou P
越来越多的证据表明，端粒酶逆转录酶（telomerase reverse transcriptase，TERT）启动子的体细胞功能获得性突变是促进TERT转录激活并维持端粒长度的主要机制之一。为了研究这些突变和端粒长度在胶质瘤中的预后价值，我们分析了389例胶质瘤患者的TERT启动子中的两个体细胞突变C228 T和C250 T、相对端粒长度（RTL）、IDH 1突变和MGMT甲基化，并探讨了它们与患者特征和临床结局的相关性。我们的数据显示，C228 T和C250 T突变分别在17.0%（66/389）和11.8%（46/389）的胶质瘤中发现，这两种突变在这种癌症中是相互排斥的。此外，它们与WHO分级显著相关。我们还发现胶质瘤的RTL显著长于脑膜瘤和正常脑组织（中位数，0.89 vs. 0.44和0.50; P < 0.001），并证明RTL与肿瘤复发密切相关。重要的是，与TERT野生型或短RTL相比，TERT启动子突变或长RTL导致显著较差的存活率。同时存在的TERT启动子突变和长RTL与患者生存率差的相关性比单独存在更普遍。值得注意的是，具有TERT启动子突变特别是C228 T或长RTL的患者对放射治疗具有抗性。总的来说，TERT启动子突变和长RTL不仅是不良临床结局的预后因素，而且也是胶质瘤放疗抵抗的预测因子。
Increasing evidences have implicated somatic gain-of-function mutations at the telomerase reverse transcriptase (TERT) promoter as one of the major mechanisms that promote transcriptional activation of TERT and subsequently maintain telomere length in human cancers including glioma. To investigate the prognostic value of these mutations and telomere length, individually and their coexistence, in gliomas, we analyzed two somatic mutations C228T and C250T in the TERT promoter, relative telomere length (RTL), IDH1 mutation and MGMT methylation in 389 glioma patients, and explored their associations with patient characteristics and clinical outcomes. Our data showed that C228T and C250T mutations were found in 17.0% (66 of 389) and 11.8% (46 of 389) of gliomas, respectively, and these two mutations were mutually exclusive in this cancer. Moreover, they were significantly associated with WHO grade. We also found that the RTL was significant longer in gliomas than in meningiomas and normal brain tissues (Median, 0.89 vs. 0.44 and 0.50; P < 0.001), and demonstrated that the RTL was strongly correlated with tumor recurrence. Importantly, TERT promoter mutations or long RTL caused a significantly poorer survival than TERT wild-type or short RTL. Coexisting TERT promoter mutations and long RTL were more commonly associated with poor patient survival than they were individually. Notably, the patients with TERT promoter mutations particularly C228T or long RTL were resistant to radiotherapy. Collectively, TERT promoter mutations and long RTL are not only prognostic factors for poor clinical outcomes, but also the predictors of radiotherapy resistance in gliomas.