Prognosis of glioblastoma according to different TERT promoter mutations

Clinical and molecular features have been stablished as prognostic factors in glioblastoma (GB) patients (pt). TERT promoter (TERTp) mutations are frequently presented in 60-75% of GB, in particular C228T and C250T mutations. The main function of TERTp mutation is to reactivate telomerase conferring cell immortalization. Previous studies have associated TERTp mutation with poor prognosis, however it could be also related to IDH mutation and MGMT promoter methylation (MGMTp-m) status. This study aims to assess the role of TERTp mutations in a GB cohort. The GLIOCAT project studied a sample of newly diagnosed GB who had received standard first-line treatment from 2004 to 2015. TERTp mutation and MGMTp-m were evaluated by PCR/MS-PCR, respectively, and IDH1 by immunohistochemistry. Survival time was defined from the date of diagnosis to the date of death or last follow-up. Median overall survival (mOS) was estimated using the Kaplan-Meier method and compared between strata through the log-rank test. A multivariate Cox regression model was performed to adjust the effect of C228T mutation by MGMTp methylation, age, and type of surgery. TERTp mutations were studied in 129 GB pts, from which 118 were evaluated. 44 pts (37.6%) were >65y, 72 pts (61%) were men ,and in 27 pts (25%) a complete surgery was performed. MGMTp-m was shown in 56 pt (47.9%) and TERTp mutations were: C228T: 71pt (60.1%), C250T:19pt (16.1%), C229T: 1pt (2%) and wild type (wt): 17pt (14.4%). TERTp C229T mutation was excluded in the survival analyses. The global mOS was 16 months(m) (95%CI: 13.7-19.3), 14.4m (95%CI: 11.3-17. 7) in the C228T group, 24.2m (95%CI 17. 9-30.7) in C250T and 17.6m (95%CI 11.2-24.2) in wt pt, (p=0.034). Multivariate analysis showed that TERTp C228T mutation and age above 65 years were poor prognostic factors with HR 2.0 (95% CI: 1.2-3.6, p=0.013) and HR 1.63 (95% CI: 1.1-2.6; p=0.039), respectively; while methylation of MGMTp was a favorable prognostic factor HR 0.5 (95% CI 0.3-0.8; p=0.003). TERTp mutations were not associated with MGMTp-m status (chi-square test, p= 0.728). The presence of TERTp mutation was not associated with poor prognosis, however TERTp C228T mutation showed poor prognosis in GB regardless of methylation status, age, and type of surgery.