title: Human TERT promoter mutation enables survival advantage from MGMT promoter methylation in IDH1 wild-type primary glioblastoma treated by standard chemoradiotherapy.
abstract: Promoter mutation in the human telomerase reverse transcriptase gene (hTERT) occurs in ~75% of primary glioblastoma (GBM). Although the mutation appears to upregulate telomerase expression and contributes to the maintenance of telomere length, its clinical significance remains unclear.
  
  
  
  We performed hTERT promoter genotyping on 303 isocitrate dehydrogenase 1 wild-type GBM tumors treated with standard chemoradiotherapy. We also stratified 190 GBM patients from the database of The Cancer Genome Atlas (TCGA) by hTERT gene expression. We analyzed overall and progression-free survival by Kaplan-Meier and Cox regression.
  
  
  
  We detected hTERT promoter mutation in 75% of the patients. When included as the only biomarker, hTERT mutation was not prognostic in our patient cohort by Cox regression analysis. However, when hTERT and O6-DNA methylguanine-methyltransferase (MGMT) were included together, we observed an interaction between these 2 factors. To further investigate this interaction, we performed pairwise comparison of the 4 patient subcohorts grouped by hTERT-MGMT status (MUT-M, WT-M, MUT-U, and WT-U). MGMT methylated patients showed improved survival only in the presence of hTERT promoter mutation: MUT-M versus MUT-U (overall survival of 28.3 vs 15.9 mos, log-rank P < .0001 and progression-free survival of 15.4 vs 7.86 mo, log-rank P < .0001). These results were confirmed by Cox analyses. Analogously, the cohort from TCGA demonstrated survival benefit of MGMT promoter methylation only in patients with high hTERT expression. In addition, hTERT mutation was negatively prognostic in our MGMT unmethylated patients, while the analogous association with high expression was not observed in the cohort from TCGA.
  
  
  
  The prognostic influence of MGMT promoter methylation depends on hTERT promoter mutation. This interaction warrants further mechanistic investigation.
authors: Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors: HuyTram N
authors: HN
authors: Nguyen
authors: Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors: Amy
authors: A
authors: Lie
authors: Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors: Tie
authors: T
authors: Li
authors: Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors: Reshmi
authors: R
authors: Chowdhury
authors: Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors: Fei
authors: F
authors: Liu
authors: Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors: Byram
authors: B
authors: Ozer
authors: Department of Pathology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors: Bowen
authors: B
authors: Wei
authors: Kaiser Permanente Southern California, Los Angeles, California, USA.
authors: Richard M
authors: RM
authors: Green
authors: Department of Radiological Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors: Benjamin M
authors: BM
authors: Ellingson
authors: Department of Biomathematics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors: He-Jing
authors: HJ
authors: Wang
authors: Department of Biomathematics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors: Robert
authors: R
authors: Elashoff
authors: Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors: Linda M
authors: LM
authors: Liau
authors: Department of Pathology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors: William H
authors: WH
authors: Yong
authors: Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors: Phioanh L
authors: PL
authors: Nghiemphu
authors: Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors: Timothy
authors: T
authors: Cloughesy
authors: Department of Neurology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California, USA.
authors: Albert
authors: A
authors: Lai
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D059248:Chemoradiotherapy / Q000401:mortality*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D015996:Survival Rate; D019098:Telomerase / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C509186:TERT protein, human; D019098:Telomerase; D045643:DNA Repair Enzymes
keywords: MGMT promoter methylation; hTERT promoter mutation; overall survival; primary glioblastoma; progression free survival