Labussière Marianne, Boisselier Blandine, Mokhtari Karima, Di Stefano Anna-Luisa, Rahimian Anais, Rossetto Marta, Ciccarino Pietro, Saulnier Olivier, Paterra Rosina, Marie Yannick, Finocchiaro Gaetano, Sanson Marc
From Sorbonne Universités (M.L., B.B., K.M., A.-L.D.S., A.R., M.R., P.C., O.S., M.S.), UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, Paris; Institut du Cerveau et de la Moelle épinière (ICM) (B.B., Y.M.), Plateforme de Génotypage Séquençage, Paris; Groupe Hospitalier Pitié Salpêtrière, Laboratoire de Neuropathologie R Escourolle (K.M.), Onconeurothèque (K.M., Y.M., M.S.), and Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2 (A.-L.D.S., M.S.), AP-HP, Paris, France; National Neurological Institute C. Mondino (A.-L.D.S.), Pavia; Department of Neuroscience (M.R., P.C.), University of Padova; and Unit of Molecular Neuro-Oncology (R.P., G.F.), Fondazione IRCCS Carlo Besta, Milan, Italy.
Neurology. 2014 Sep 23;83(13):1200-6. doi: 10.1212/WNL.0000000000000814. Epub 2014 Aug 22.
To identify the prognostic significance of TERT promoter mutations (TERTp-mut) and their associations with common molecular alterations in glioblastomas (GBMs).
We sequenced the TERTp-mut in DNA from 395 GBMs and analyzed the results with their respective histology, genetic profile (IDH1 mutation, EGFR amplification, CDKN2A homozygous deletion, loss of chromosome 10, TP53 mutation), and overall survival (OS).
TERTp-mut were found in 299 of 395 GBMs (75.7%) and were associated with an older age (median 59.6 years for TERTp-mut vs 53.6 years for TERT promoter wild type [TERTp-wt], p < 0.0001). TERTp-mut was an independent factor of poor prognosis (OS = 13.8 vs 18.4 months), in both IDH-mutated (OS = 13.8 vs 37.6 months, p = 0.022) and IDH-wt GBMs (OS = 13.7 vs 17.5 months, p = 0.006). TERTp-mut was associated with IDH-wt, EGFR amplification, CDKN2A deletion, and chromosome 10q loss, but not with MGMT promoter methylation. In the TERTp-wt group, OS was twice longer in EGFR-wt than in EGFR amplification GBMs (OS = 26.6 vs 13.3 months; p = 0.005). In the EGFR-wt group, patients with TERTp-wt had a significantly better outcome (OS = 26.3 vs 12.5 months, p < 0.0001), whereas in the EGFR amplification group, patients with TERTp-mut survived longer (OS = 15.8 vs 13.3 months, p = 0.05). Taken together, the absence of both EGFR amplification and TERTp-mut is associated with longer survival in patients with GBM (26.5 months for patients with IDH-wt, 36.7 months for patients with IDH mutation).
The analysis of TERTp-mut, in combination with EGFR amplification and IDH mutation status, refines the prognostic classification of GBMs.
确定端粒酶逆转录酶启动子突变（TERTp-mut）的预后意义及其与胶质母细胞瘤（GBM）常见分子改变的相关性。
我们对395例GBM的DNA进行TERTp-mut测序，并将结果与其各自的组织学、基因谱（异柠檬酸脱氢酶1（IDH1）突变、表皮生长因子受体（EGFR）扩增、细胞周期蛋白依赖性激酶抑制剂2A（CDKN2A）纯合缺失、10号染色体缺失、抑癌基因p53（TP53）突变）及总生存期（OS）进行分析。
395例GBM中有299例（75.7%）检测到TERTp-mut，且与年龄较大相关（TERTp-mut组中位年龄为59.6岁，TERT启动子野生型（TERTp-wt）组为53.6岁，p<0.0001）。TERTp-mut是预后不良的独立因素（OS分别为13.8个月和18.4个月），在IDH突变型GBM（OS分别为13.8个月和37.6个月，p = 0.022）和IDH野生型GBM中均如此（OS分别为13.7个月和17.5个月，p = 0.006）。TERTp-mut与IDH野生型、EGFR扩增、CDKN2A缺失及10号染色体长臂缺失相关，但与O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）启动子甲基化无关。在TERTp-wt组中，EGFR野生型GBM的OS是EGFR扩增GBM的两倍（OS分别为26.6个月和13.3个月；p = 0.005）。在EGFR野生型组中，TERTp-wt患者的预后明显更好（OS分别为26.3个月和12.5个月，p<0.0001），而在EGFR扩增组中，TERTp-mut患者存活时间更长（OS分别为15.8个月和13.3个月，p = 0.05）。综上所述，EGFR扩增和TERTp-mut均不存在与GBM患者更长的生存期相关（IDH野生型患者为26.5个月，IDH突变患者为36.7个月）。
TERTp-mut分析结合EGFR扩增和IDH突变状态可优化GBM的预后分类。
