TERT promoter mutations in primary and secondary glioblastomas
TERT promoter mutations in primary and secondary glioblastomas
复制标题
DOI：
10.1007/s00401-013-1163-0
复制
发表时间：
2013-12-01
影响因子：
12.7
通讯作者：
Ohgaki, Hiroko
中科院分区：
文献类型：
--
作者：
Nonoguchi, Naosuke;Ohta, Takashi;Ohgaki, Hiroko
端粒酶逆转录酶（TERT）在多种人类肿瘤中上调。在黑色素瘤和包括神经胶质瘤在内的多种人类肿瘤中，已经报道了增加启动子活性的TERT基因核心启动子区的突变。在本研究中，我们通过直接DNA测序在358例胶质母细胞瘤中筛选了TERT启动子突变。在分析的55%的胶质母细胞瘤中检测到TERT启动子突变（C228 T、C250 T）。其中，73%有C228 T突变，27%有C250 T突变;只有一个胶质母细胞瘤同时有C228 T和C250 T突变。原发性（IDH 1野生型）胶质母细胞瘤（187/322; 58%）中TERT启动子突变的频率显著高于继发性（IDH 1突变）胶质母细胞瘤（10/36，28%; P = 0.0056）。它们与IDH 1突变（P = 0.0056）和TP 53突变（P = 0.043）呈显著负相关，与EGFR扩增呈显著正相关（P = 0.048）。在单变量分析（中位数，9.3 vs. 10.5个月; P = 0.015）和校正年龄和性别后的多变量分析（HR 1.38，95% CI 1.01-1.88，P = 0.041）中，有TERT突变的胶质母细胞瘤患者的生存期短于无TERT突变的患者。然而，在多变量分析中，进一步调整其他遗传改变后，或单独分析原发性和继发性胶质母细胞瘤时，TERT突变对患者的生存率没有显著影响。这些结果表明，TERT突变对不良生存期的预后价值主要是由于其与IDH 1突变的负相关性，IDH 1突变是继发性胶质母细胞瘤患者更好生存的重要预后标志。
Telomerase reverse transcriptase (TERT) is up-regulated in a variety of human neoplasms. Mutations in the core promoter region of the TERT gene, which increases promoter activity, have been reported in melanomas and a variety of human neoplasms, including gliomas. In the present study, we screened for TERT promoter mutations by direct DNA sequencing in a population-based collection of 358 glioblastomas. TERT promoter mutations (C228T, C250T) were detected in 55 % glioblastomas analysed. Of these, 73 % had a C228T mutation, and 27 % had a C250T mutation; only one glioblastoma had both C228T and C250T mutations. TERT promoter mutations were significantly more frequent in primary (IDH1 wild-type) glioblastomas (187/322; 58 %) than in secondary (IDH1 mutated) glioblastomas (10/36, 28 %; P = 0.0056). They showed significant inverse correlations with IDH1 mutations (P = 0.0056) and TP53 mutations (P = 0.043), and a significant positive correlation with EGFR amplification (P = 0.048). Glioblastoma patients with TERT mutations showed a shorter survival than those without TERT mutations in univariate analysis (median, 9.3 vs. 10.5 months; P = 0.015) and multivariate analysis after adjusting for age and gender (HR 1.38, 95 % CI 1.01-1.88, P = 0.041). However, TERT mutations had no significant impact on patients' survival in multivariate analysis after further adjusting for other genetic alterations, or when primary and secondary glioblastomas were separately analysed. These results suggest that the prognostic value of TERT mutations for poor survival is largely due to their inverse correlation with IDH1 mutations, which are a significant prognostic marker of better survival in patients with secondary glioblastomas.