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Multicenter Study
. 2016 Aug 8;4(1):79.
doi: 10.1186/s40478-016-0351-2.

A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas

Hideyuki Arita  1   2 , Kai Yamasaki  3   4 , Yuko Matsushita  3   5 , Taishi Nakamura  3   6 , Asanao Shimokawa  7 , Hirokazu Takami  3   8 , Shota Tanaka  8 , Akitake Mukasa  8 , Mitsuaki Shirahata  9 , Saki Shimizu  10 , Kaori Suzuki  10 , Kuniaki Saito  10 , Keiichi Kobayashi  10 , Fumi Higuchi  11 , Takeo Uzuka  11 , Ryohei Otani  11 , Kaoru Tamura  12 , Kazutaka Sumita  12 , Makoto Ohno  5 , Yasuji Miyakita  5 , Naoki Kagawa  13 , Naoya Hashimoto  13 , Ryusuke Hatae  14 , Koji Yoshimoto  14 , Naoki Shinojima  15 , Hideo Nakamura  15 , Yonehiro Kanemura  16   17 , Yoshiko Okita  17 , Manabu Kinoshita  18 , Kenichi Ishibashi  19 , Tomoko Shofuda  20 , Yoshinori Kodama  21 , Kanji Mori  22 , Yusuke Tomogane  23 , Junya Fukai  24 , Koji Fujita  24 , Yuzo Terakawa  25 , Naohiro Tsuyuguchi  25 , Shusuke Moriuchi  26 , Masahiro Nonaka  17 , Hiroyoshi Suzuki  27 , Makoto Shibuya  28 , Taketoshi Maehara  12 , Nobuhito Saito  8 , Motoo Nagane  10 , Nobutaka Kawahara  6 , Keisuke Ueki  11 , Toshiki Yoshimine  13 , Etsuo Miyaoka  7 , Ryo Nishikawa  9 , Takashi Komori  29 , Yoshitaka Narita  5 , Koichi Ichimura  30
Affiliations
Multicenter Study

A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas

Hideyuki Arita et al. Acta Neuropathol Commun. .

Abstract

The prognostic impact of TERT mutations has been controversial in IDH-wild tumors, particularly in glioblastomas (GBM). The controversy may be attributable to presence of potential confounding factors such as MGMT methylation status or patients' treatment. This study aimed to evaluate the impact of TERT status on patient outcome in association with various factors in a large series of adult diffuse gliomas. We analyzed a total of 951 adult diffuse gliomas from two cohorts (Cohort 1, n = 758; Cohort 2, n = 193) for IDH1/2, 1p/19q, and TERT promoter status. The combined IDH/TERT classification divided Cohort 1 into four molecular groups with distinct outcomes. The overall survival (OS) was the shortest in IDH wild-type/TERT mutated groups, which mostly consisted of GBMs (P < 0.0001). To investigate the association between TERT mutations and MGMT methylation on survival of patients with GBM, samples from a combined cohort of 453 IDH-wild-type GBM cases treated with radiation and temozolomide were analyzed. A multivariate Cox regression model revealed that the interaction between TERT and MGMT was significant for OS (P = 0.0064). Compared with TERT mutant-MGMT unmethylated GBMs, the hazard ratio (HR) for OS incorporating the interaction was the lowest in the TERT mutant-MGMT methylated GBM (HR, 0.266), followed by the TERT wild-type-MGMT methylated (HR, 0.317) and the TERT wild-type-MGMT unmethylated GBMs (HR, 0.542). Thus, patients with TERT mutant-MGMT unmethylated GBM have the poorest prognosis. Our findings suggest that a combination of IDH, TERT, and MGMT refines the classification of grade II-IV diffuse gliomas.

Keywords: 1p19q; Glioblastoma; Glioma; IDH1/2; Molecular classification; Prognostic factor; TERT; Temozolomide.

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Figures

Fig. 1
Fig. 1
Flowchart of patient selection. For Cohort 1, 758 out of 881 Grade II-IV cases collected met the eligibility criteria and were analyzed for the prognostic impact of IDH and TERT status in adult diffuse gliomas. From Cohort 1, 260 GBM patients concurrently treated with TMZ and RT were further selected (Cohort 1 GBM). For Cohort 2, 193 IDH wild-type GBM cases treated with TMZ plus RT were selected (Cohort 2 GBM). Cohort 1 GBM and Cohort 2 GBM were analyzed for the influences of TERT and MGMT status on survival. GBM, glioblastoma; NF, neurofibromatosis; RT, radiation therapy; TMZ, temozolomide
Fig. 2
Fig. 2
A diagram of molecular classification of Cohort 1. All 758 tumors in Cohort 1 are sorted according to their molecular classification based on their IDH and TERT statuses. The mutation statuses of IDH, TERT, H3F3A, the copy number statuses of 1p/19q and CDKN2A/B BRAF, and MGMT methylation are shown. Centrally reviewed histology is indicated at the bottom. Gray or colored cells indicate absence or presence of alterations, respectively. Blank cells denote no data. Group A, IDH mutated-TERT mutated; Group B, IDH mutated-TERT wild-type; Group C, IDH wild-type-TERT wild-type; Group D, IDH mutated-TERT mutated. AA, anaplastic astrocytoma; AO, anaplastic oligodendroglioma; AOA, anaplastic oligoastrocytoma; DA, diffuse astrocytoma; Del, Deletion; GBM, glioblastoma; OA, oligoastrocytoma; OL, oligodendroglioma
Fig. 3
Fig. 3
Kaplan-Meier analysis of progression free survival (PFS) and overall survival (OS) of molecular groups in Cohort 1. a. PFS of each molecular group (n = 734). Median PFS was 113.4 months for Group A, 66.5 months for Group B, 11.7 months for Group C, and 8.2 months for Group D (P < 0.0001, Log-rank test). Notably, Group D showed significantly shorter PFS than other groups (P < 0.0001, Log-rank test). b. OS of each molecular group (n = 758). Median OS was not reached for Groups A and B, 25.3 months for Group C, and 16.3 months for Group D (P < 0.0001, Log-rank test). Group D showed significantly shorter survival than any other groups (P < 0.0001, Log-rank test). Group A, IDH mutated- TERT mutated; Group B, IDH mutated-TERT wild-type; Group C, IDH wild-type-TERT wild-type; Group D, IDH mutated-TERT mutated
Fig. 4
Fig. 4
Kaplan-Meier analysis for survival, stratified by TERT and MGMT statuses in 453 GBM cases treated with radiation plus temozolomide. a. PFS of GBM cases (see text for definition). Median PFS was 14.5 months for TERT mutated-MGMT methylated (Mut/Met), 12.8 months for TERT wild-type-MGMT methylated (WT/Met), 9.8 months for TERT wild-type-MGMT unmethylated (WT/Un-met), and 7.2 months for TERT mutated-MGMT unmethylated (Mut/Un-met) (P < 0.0001, Log-rank test). The Mut/Un-met group showed shorter PFS than WT/Un-met (P = 0.0003, Log-rank test), whereas the differences in PFS between the MGMT methylated groups (between Mut/Met and WT/Met) was not significant (P = 0.62, Log-rank test). b. OS of the GBM cases. Median OS was 30.0 months for Mut/Met, 26.5 months for WT/Met, 18.8 months for WT/Un-met, and 14.6 months for Mut/Un-met (P < 0.0001, Log-rank test). The Mut/Un-met group had shorter OS than WT/Un-met (P < 0.0001, Log-rank test), whereas the difference in OS between Mut/Met and WT/Met was not significant (P = 0.83, Log-rank test). GBM, glioblastoma; OS, overall survival; PFS, progression free survival
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