Labussière M, Di Stefano A L, Gleize V, Boisselier B, Giry M, Mangesius S, Bruno A, Paterra R, Marie Y, Rahimian A, Finocchiaro G, Houlston R S, Hoang-Xuan K, Idbaih A, Delattre J-Y, Mokhtari K, Sanson M
1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U 1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France.
1] Sorbonne Universités, UMPC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, Paris 75013, France [2] INSERM U 1127, Paris 75013, France [3] CNRS, UMR 7225, Paris 75013, France [4] National Neurological Institute C. Mondino, University of Pavia, 27100 Pavia, Italy.
Br J Cancer. 2014 Nov 11;111(10):2024-32. doi: 10.1038/bjc.2014.538. Epub 2014 Oct 14.
The role of telomerase reverse transcriptase (TERT) in gliomagenesis has been recently further strengthened by the frequent occurrence of TERT promoter mutations (TERTp-mut) in gliomas and evidence that the TERT SNP genetic rs2736100 influences glioma risk. TERTp-mut creates a binding site for Ets/TCF transcription factors, whereas the common rs2853669 polymorphism disrupts another Ets/TCF site on TERT promoter.
We sequenced for TERTp-mut in 807 glioma DNAs and in 235 blood DNAs and analysed TERT expression by RT-PCR in 151 samples. TERTp-mut status and TERTp polymorphism rs2853669 were correlated with histology, genomic profile, TERT mRNA expression, clinical outcome and rs2736100 genotype.
TERTp-mut identified in 60.8% of gliomas (491 out of 807) was globally associated with poorer outcome (Hazard ratio (HR)=1.50). We defined, based on TERTp-mut and IDH mutation status, four prognostic groups: (1) TERTp-mut and IDH-mut associated with 1p19q codeletion, overall survival (OS)>17 years; (2) TERTp-wt and IDH-mut, associated with TP53 mutation, OS=97.5 months; (3) TERTp-wt and IDH-wt, with no specific association, OS=31.6 months; (4) TERTp-mut and IDH-wt, associated with EGFR amplification, OS=15.4 months. TERTp-mut was associated with higher TERT mRNA expression, whereas the rs2853669 variant was associated with lower TERT mRNA expression. The mutation of CIC (a repressor of ETV1-5 belonging to the Ets/TCF family) was also associated with TERT mRNA upregulation.
In addition to IDH mutation status, defining the TERTp-mut status of glial tumours should afford enhanced prognostic stratification of patients with glioma. We also show that TERTp-mut, rs2853669 variant and CIC mutation influence Tert expression. This effect could be mediated by Ets/TCF transcription factors.
端粒酶逆转录酶（TERT）在胶质瘤发生中的作用最近因胶质瘤中TERT启动子突变（TERTp-mut）的频繁出现以及TERT单核苷酸多态性（SNP）基因rs2736100影响胶质瘤风险的证据而得到进一步强化。TERTp-mut为Ets/TCF转录因子创造了一个结合位点，而常见的rs2853669多态性破坏了TERT启动子上的另一个Ets/TCF位点。
我们对807份胶质瘤DNA和235份血液DNA进行了TERTp-mut测序，并通过逆转录聚合酶链反应（RT-PCR）分析了151份样本中的TERT表达。TERTp-mut状态和TERTp多态性rs2853669与组织学、基因组图谱、TERT mRNA表达、临床结局及rs2736100基因型相关。
在60.8%的胶质瘤（807例中的491例）中检测到的TERTp-mut与总体预后较差相关（风险比（HR）=1.50）。基于TERTp-mut和异柠檬酸脱氢酶（IDH）突变状态，我们定义了四个预后组：（1）TERTp-mut和IDH突变与1p19q共缺失相关，总生存期（OS）>17年；（2）TERTp野生型（TERTp-wt）和IDH突变，与TP53突变相关，OS=97.5个月；（3）TERTp-wt和IDH野生型（IDH-wt），无特定关联，OS=31.6个月；（4）TERTp-mut和IDH-wt，与表皮生长因子受体（EGFR）扩增相关，OS=15.4个月。TERTp-mut与较高的TERT mRNA表达相关，而rs2853669变异与较低的TERT mRNA表达相关。CIC（属于Ets/TCF家族的ETV1-5的一种阻遏物）的突变也与TERT mRNA上调相关。
除了IDH突变状态外，确定胶质肿瘤的TERTp-mut状态应能增强对胶质瘤患者的预后分层。我们还表明，TERTp-mut、rs2853669变异和CIC突变影响Tert表达。这种效应可能由Ets/TCF转录因子介导。
