Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
Neuro Oncol. 2013 Apr;15(4):423-32. doi: 10.1093/neuonc/nos329. Epub 2013 Feb 7.
Glioblastoma multiforme (GBM) is a heterogeneous, highly aggressive primary brain tumor with strongly variable patient survival. Because reliable prognostic biomarkers are lacking, we investigated the relation between telomerase-associated parameters and the disease course.
Telomerase-associated parameters were determined in 100 GBM tissues and associated with clinical characteristics and overall survival. Expressions of telomere length, telomerase activity (TA), and human telomerase reverse transcriptase (hTERT) were analyzed by quantitative PCR, telomeric repeat amplification protocol assay, and reverse transcriptase-PCR, respectively. Mutation status of isocitrate dehydrogenase (IDH)1 was determined by direct sequencing, and O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation by methylation-specific PCR.
Of 100 GBM tissues, 61 were positive for both hTERT mRNA and TA, with a highly significant correlation between both parameters (linear regression, P < .0001). Telomere length determination revealed a significant difference between the hTERT/TA-positive and -negative subgroups, with markedly longer telomeres in the hTERT/TA-negative cohort (unpaired Student's t-test, P = .0001). Accordingly, significantly shorter telomeres were detected in GBM tissues derived from older patients (>60 y at diagnosis, P < .0001). While no association of telomere parameters with MGMT promoter status was found, all tumors with IDH1 mutation (6/100) were negative for both hTERT expression and TA and harbored significantly longer telomeres. Patients with tumors lacking hTERT expression/TA showed a significant survival benefit (Kaplan-Meier test, both P < .01), which, however, was based exclusively on the younger patient subgroup (≤60 y, both P < .005; >60 y, both ns).
Telomerase activation is not an independent prognostic parameter in GBM but predicts aggressive tumor behavior solely in a younger patient cohort.
多形性胶质母细胞瘤（GBM）是一种异质性、高度侵袭性的原发性脑肿瘤，患者的生存情况差异较大。由于缺乏可靠的预后生物标志物，我们研究了端粒酶相关参数与疾病进程的关系。
我们检测了 100 例 GBM 组织中的端粒酶相关参数，并将其与临床特征和总生存期相关联。通过定量 PCR、端粒重复扩增协议检测和逆转录酶-PCR 分别分析端粒长度、端粒酶活性（TA）和人类端粒酶逆转录酶（hTERT）的表达。通过直接测序确定异柠檬酸脱氢酶（IDH）1 的突变状态，通过甲基化特异性 PCR 确定 O(6)-甲基鸟嘌呤 DNA 甲基转移酶（MGMT）启动子甲基化状态。
在 100 例 GBM 组织中，有 61 例 hTERT mRNA 和 TA 均为阳性，两者之间存在高度显著的相关性（线性回归，P<0.0001）。端粒长度测定显示 hTERT/TA 阳性和阴性亚组之间存在显著差异，hTERT/TA 阴性亚组的端粒明显更长（未配对学生 t 检验，P=0.0001）。因此，在诊断时年龄较大（>60 岁，P<0.0001）的患者的 GBM 组织中检测到明显较短的端粒。虽然未发现端粒参数与 MGMT 启动子状态有关，但所有 IDH1 突变的肿瘤（100 例中的 6 例）均为 hTERT 表达和 TA 阴性，且端粒明显更长。缺乏 hTERT 表达/TA 的肿瘤患者的生存获益具有显著意义（Kaplan-Meier 检验，两者均 P<0.01），但这种获益仅基于年龄较小的患者亚组（≤60 岁，两者均 P<0.005；>60 岁，两者均无统计学差异）。
端粒酶激活不是 GBM 的独立预后参数，但仅在年轻患者亚组中预测侵袭性肿瘤行为。
