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端粒酶逆转录酶(TERT)启动子突变与rs2853669多态性:对胶质母细胞瘤的预后影响及与常见改变的相互作用

TERT promoter mutations and rs2853669 polymorphism: prognostic impact and interactions with common alterations in glioblastomas.

作者信息

Nencha Umberto, Rahimian Amithys, Giry Marine, Sechi Andrea, Mokhtari Karima, Polivka Marc, Schmitt Yohann, Di Stefano Anna-Luisa, Alentorn Agusti, Labussière Marianne, Sanson Marc

机构信息

Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, 75013, Paris, France.

OncoNeuroTek, 75013, Paris, France.

出版信息

J Neurooncol. 2016 Feb;126(3):441-6. doi: 10.1007/s11060-015-1999-3. Epub 2015 Nov 25.

Abstract

TERT promoter (TERTp) mutation is the most common mutation in glioblastomas. It creates a putative binding site for Ets/TCF transcription factors, enhancing telomerase expression and activity, whereas the rs2853669 variant disrupts another Ets/TCF binding. We explore here the interaction between these two alterations, tumor genomic profile and the impact on prognosis. The TERTp and rs2853669 statuses were determined and confronted with the outcome and molecular profile, i.e., loss of chromosome 10q, CDKN2A deletion, IDH mutation, EGFR amplification, MGMT promoter methylation. 651 glioblastomas were selected (sex ratio = 1.35, median age 60.4 years, median survival 13.5 months). The TERTp mutation found in 481 patients (74 %) was independent from rs2853669 genotypes. TERTp mutation, but not rs2853669 status, was associated with older age (61.4 vs. 52.8 years). rs2853669 status had no impact on overall survival (OS) either in mutated TERTp or wild-type TERTp. Neither rs2736100 (TERT, 5q15.33) nor rs192011116 (TERC, 3q26.2) status had any impact on survival or showed any association with a TERTp mutation. The TERTp mutation was associated with EGFR amplification chromosome 10q loss, CDKN2A deletion and IDH wt. EGFR amplification was associated with a better outcome in TERTp mutated GBM, and a worse outcome in TERTp WT. This study-the largest analyzing the TERTp mutation and the rs2853669 polymorphism-fails to find any prognostic impact of rs2853669. It confirms the dual prognostic impact of EGFR amplification depending on TERTp status.

摘要

端粒酶逆转录酶启动子(TERTp)突变是胶质母细胞瘤中最常见的突变。它为Ets/TCF转录因子创造了一个假定的结合位点,增强了端粒酶的表达和活性,而rs2853669变体则破坏了另一个Ets/TCF结合位点。我们在此探讨这两种改变之间的相互作用、肿瘤基因组特征及其对预后的影响。确定了TERTp和rs2853669的状态,并将其与预后和分子特征(即10号染色体长臂缺失、CDKN2A缺失、异柠檬酸脱氢酶(IDH)突变、表皮生长因子受体(EGFR)扩增、O6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)启动子甲基化)进行对比。选取了651例胶质母细胞瘤(男女比例=1.35,中位年龄60.4岁,中位生存期13.5个月)。在481例患者(74%)中发现的TERTp突变与rs2853669基因型无关。TERTp突变与年龄较大有关(61.4岁对52.8岁),而rs2853669状态则无关。rs2853669状态对TERTp突变型或野生型TERTp的总生存期(OS)均无影响。rs2736100(TERT,5q15.33)和rs192011116(TERC,3q26.2)状态对生存期均无影响,也未显示与TERTp突变有任何关联。TERTp突变与EGFR扩增、10号染色体长臂缺失、CDKN2A缺失和IDH野生型有关。在TERTp突变的胶质母细胞瘤中,EGFR扩增与较好的预后相关,而在TERTp野生型中则与较差的预后相关。这项分析TERTp突变和rs2853669多态性的最大规模研究未发现rs2853669有任何预后影响。它证实了EGFR扩增根据TERTp状态具有双重预后影响。

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