胶质瘤中TERT启动子区突变与端粒酶抑制剂治疗敏感性相互关系的研究

Glioma is the most common primary tumor in the center nervous system with the worst prognosis. Telomerase overexpression in glioma made it an ideal therapeutic target. As a telomerase inhibitor, Imetelstat can inhibit cancer cell proliferation and has been approaved to enter the Phase II clinical trials. Besides, it can pass the blood-brain barrier, which made it very useful in glioma treatment. Before using the telomerase inhibitor, it is best to detect the telomerase activity, and the most commonly used detection method is TRAP method. This method tests the RNA component of telomerase which is easy to decompose and difficult to extract and preserve. For this reason, this method can not be widely used in clinical diagnosis. TERT promoter mutation was first identified in melanomas and reported on 《Science》 in 2013. This research indicated that TERT promoter mutations up-regulated the activity of telomerase. We found that the TERT promoter mutations occurred in glioma tissues in the previous study. Based on it, we are going to explore the relationship between TERT promoter mutations and the telomerase inhibitor therapy sensitivity. Moreover, the possible mechanism of how could TERT promoter mutations up-regulate telomerase activity will be deeply discussed. TERT promoter mutations are expected to be a simple, sensitive and special molecular marker in predicting the sensitivity of telomerase inhibitor therapy. The evidence for individualizing target therapy of glioma will be provided.

胶质瘤是中枢神经系统最常见、预后最差的原发性肿瘤。端粒酶在胶质瘤中高表达，在脑组织中无表达，是理想的治疗靶点。端粒酶抑制剂Imetelstat能抑制肿瘤细胞生长并已进入二期临床试验；它能通过血脑屏障，适合治疗胶质瘤。针对端粒酶的靶向治疗必须检测端粒酶活性，然而目前普遍采用的、基于端粒酶RNA组分的各种检测方法均因RNA极易降解、提取和保存困难不易在临床上推广应用。2013年《Science》首次报道黑色素瘤存在端粒酶逆转录酶（TERT）启动子区突变并和端粒酶活性密切相关。我们在发现胶质瘤组织中存在TERT启动子区突变的基础上，通过观察TERT启动子区突变与胶质瘤细胞恶性表型及端粒酶抑制剂抑瘤效果之间的关系，探讨TERT启动子区突变引起端粒酶活性改变的可能机制，明确TERT启动子区突变能否作为一个便于检测、稳定可靠的分子标志物来预测端粒酶抑制剂治疗的敏感性，为胶质瘤个体化靶向治疗提供依据。

胶质瘤是中枢神经系统最常见的原发性肿瘤，即使积极采用手术和放化疗手段，胶质母细胞瘤的中位生存期仅有15个月左右。肿瘤细胞端粒的延长对肿瘤的发生发展至关重要，其中端粒酶为最主要的端粒延长机制。胶质瘤中端粒酶高表达，而在脑组织中无表达，是理想的治疗靶点。针对端粒酶的靶向治疗必须检测端粒酶活性，然而目前普遍采用的、基于端粒酶RNA组分的各种检测方法均因RNA极易降解、提取和保存困难不易在临床上推广应用。因此我们探索端粒其它相关分子改变能否预测端粒酶活性及端粒酶抑制剂敏感性。我们首先检测胶质瘤中TERT启动子区突变的发生情况，结果发现TERT启动子区总发生率为43.9%，WHO级别越高突变率越高。同时TERT 启动子区突变的患者术后生存期短于TERT 野生型的患者，因此对胶质瘤分型及预后评估有着很重要的意义。然后通过原位杂交方法（ISH）检测石蜡包埋的胶质母细胞瘤标本，采用半定量法对标本TERT mRNA的表达进行评分。此外通过TRAP-PCR 法相对定量地检测冰冻高级别胶质瘤组织端粒酶活性。观察TERT启动子区突变与TERT mRNA的表达及端粒酶活性的关系，结果发现TERT启动子区突变导致 TERT mRNA表达增加，增加端粒酶活性。最后我们比较TERT启动子区野生型和突变型胶质瘤细胞系对端粒酶抑制剂的敏感程度，结果初步提示TERT启动子区突变的胶质瘤系对端粒酶抑制剂更敏感。对耐药的胶质瘤细胞系采用端粒酶抑制剂和PI3K通路抑制剂联用发现抑制效果整体更佳，为胶质瘤个体化靶向治疗提供依据。我们的结果证实TERT启动子区突变是胶质瘤诊断、分型及预后评估等方面的重要标志物，同时揭示了TERT启动子区突变导致TERT mRNA表达增加和端粒酶活性增加，初步观察到TERT启动子区突变的胶质瘤对端粒酶抑制剂更敏感。因此达到了任务书要求的目标。

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