TERT promoter mutation associated with multifocal phenotype and poor prognosis in patients with IDH wild-type glioblastoma.

Zensho Kikuchi,Ema Yoshioka,Ryuta Saito,Toshihiro Kumabe,Yukihiko Sonoda,Rintaro Ohe,Masayuki Kanamori,Ken-Ichiro Matsuda,Tomoko Shofuda,Teiji Tominaga,Ichiyo Shibahara,Yonehiro Kanemura,Tetsu Yamaki

doi:10.1093/noajnl/vdaa114

Abstract

BackgroundAlthough mutations in the promoter region of the telomerase reverse transcriptase (TERTp) gene are the most common alterations in glioblastoma (GBM), their clinical significance remains unclear. Therefore, we investigated the impact of TERTp status on patient outcome and clinicopathological features in patients with GBM over a long period of follow-up.MethodsWe retrospectively analyzed 153 cases of GBM. Six patients with isocitrate dehydrogenase 1 (IDH1) or H3F3A gene mutations were excluded from this study. Among the 147 cases of IDH wild-type GBM, 92 (62.6%) had the TERTp mutation. Clinical, immunohistochemical, and genetic factors (BRAF, TP53 gene mutation, CD133, ATRX expression, O6-methylguanine-DNA methyltransferase [MGMT] promoter methylation) and copy number alterations (CNAs) were investigated.ResultsGBM patients with the TERTp mutation were older at first diagnosis versus those with TERTp wild type (66.0 vs. 60.0 years, respectively, P = .034), and had shorter progression-free survival (7 vs. 10 months, respectively, P = .015) and overall survival (16 vs. 24 months, respectively, P = .017). Notably, magnetic resonance imaging performed showed that TERTp-mutant GBM was strongly associated with multifocal/distant lesions (P = .004). According to the CNA analysis, TERTp mutations were positively correlated with EGFR amp/gain, CDKN2A deletion, and PTEN deletion; however, these mutations were negatively correlated with PDGFR amp/gain, CDK4 gain, and TP53 deletion.Conclusions TERTp mutations were strongly correlated with multifocal/distant lesions and poor prognosis in patients with IDH wild-type GBM. Less aggressive GBM with TERTp wild type may be a distinct clinical and molecular subtype of IDH wild-type GBM.

Highlights

Mutations in the promoter region of the telomerase reverse transcriptase (TERTp) gene are the most common alterations in glioblastoma (GBM), their clinical significance remains unclear
We found that TERTp mutation, absence of gross total resection, and MGMT gene promoter unmethylation were independent unfavorable prognostic factors for Progression-free survival (PFS) (Table 3)
To understand the poor prognosis of GBM with TERTp mutations, we hypothesized that malignant clinical features exist in this group

Summary

Introduction

Mutations in the promoter region of the telomerase reverse transcriptase (TERTp) gene are the most common alterations in glioblastoma (GBM), their clinical significance remains unclear. Six patients with isocitrate dehydrogenase 1 (IDH1) or H3F3A gene mutations were excluded from this study. Among the 147 cases of IDH wild-type GBM, 92 (62.6%) had the TERTp mutation. Immunohistochemical, and genetic factors (BRAF, TP53 gene mutation, CD133, ATRX expression, O6-methylguanine-DNA methyltransferase [MGMT] promoter methylation) and copy number alterations (CNAs) were investigated. GBM patients with the TERTp mutation were older at first diagnosis versus those with TERTp wild type (66.0 vs 60.0 years, respectively, P = .034), and had shorter progression-free survival (7 vs 10 months, respectively, P = .015) and overall survival (16 vs 24 months, respectively, P = .017). TERTp mutations were strongly correlated with multifocal/distant lesions and poor prognosis in patients with IDH wild-type GBM.

Methods

Results

Conclusion