title: A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas.
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.
authors: Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. neuro.husky@gmail.com.|Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan. neuro.husky@gmail.com.
authors: Hideyuki
authors: H
authors: Arita
authors: Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.|Department of Pediatric Hematology and Oncology, Osaka City General Hospital, Osaka, Japan.
authors: Kai
authors: K
authors: Yamasaki
authors: Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.|Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors: Yuko
authors: Y
authors: Matsushita
authors: Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.|Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors: Taishi
authors: T
authors: Nakamura
authors: Department of Mathematics, Faculty of Science, Tokyo University of Science, Tokyo, Japan.
authors: Asanao
authors: A
authors: Shimokawa
authors: Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.|Department of Neurosurgery, The University of Tokyo, Tokyo, Japan.
authors: Hirokazu
authors: H
authors: Takami
authors: Department of Neurosurgery, The University of Tokyo, Tokyo, Japan.
authors: Shota
authors: S
authors: Tanaka
authors: Department of Neurosurgery, The University of Tokyo, Tokyo, Japan.
authors: Akitake
authors: A
authors: Mukasa
authors: Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, Japan.
authors: Mitsuaki
authors: M
authors: Shirahata
authors: Department of Neurosurgery, Kyorin University Faculty of Medicine, Tokyo, Japan.
authors: Saki
authors: S
authors: Shimizu
authors: Department of Neurosurgery, Kyorin University Faculty of Medicine, Tokyo, Japan.
authors: Kaori
authors: K
authors: Suzuki
authors: Department of Neurosurgery, Kyorin University Faculty of Medicine, Tokyo, Japan.
authors: Kuniaki
authors: K
authors: Saito
authors: Department of Neurosurgery, Kyorin University Faculty of Medicine, Tokyo, Japan.
authors: Keiichi
authors: K
authors: Kobayashi
authors: Department of Neurosurgery, Dokkyo Medical University, Tochigi, Japan.
authors: Fumi
authors: F
authors: Higuchi
authors: Department of Neurosurgery, Dokkyo Medical University, Tochigi, Japan.
authors: Takeo
authors: T
authors: Uzuka
authors: Department of Neurosurgery, Dokkyo Medical University, Tochigi, Japan.
authors: Ryohei
authors: R
authors: Otani
authors: Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Kaoru
authors: K
authors: Tamura
authors: Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Kazutaka
authors: K
authors: Sumita
authors: Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors: Makoto
authors: M
authors: Ohno
authors: Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors: Yasuji
authors: Y
authors: Miyakita
authors: Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors: Naoki
authors: N
authors: Kagawa
authors: Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors: Naoya
authors: N
authors: Hashimoto
authors: Department of Neurosurgery, Kyushu University Graduate School of Medical Science, Fukuoka, Japan.
authors: Ryusuke
authors: R
authors: Hatae
authors: Department of Neurosurgery, Kyushu University Graduate School of Medical Science, Fukuoka, Japan.
authors: Koji
authors: K
authors: Yoshimoto
authors: Department of Neurosurgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors: Naoki
authors: N
authors: Shinojima
authors: Department of Neurosurgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors: Hideo
authors: H
authors: Nakamura
authors: Division of Regenerative Medicine, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka, Japan.|Department of Neurosurgery, National Hospital Organization Osaka National Hospital, Osaka, Japan.
authors: Yonehiro
authors: Y
authors: Kanemura
authors: Department of Neurosurgery, National Hospital Organization Osaka National Hospital, Osaka, Japan.
authors: Yoshiko
authors: Y
authors: Okita
authors: Department of Neurosurgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors: Manabu
authors: M
authors: Kinoshita
authors: Department of Neurosurgery, Osaka City General Hospital, Osaka, Japan.
authors: Kenichi
authors: K
authors: Ishibashi
authors: Division of Stem Cell Research, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka, Japan.
authors: Tomoko
authors: T
authors: Shofuda
authors: Central Laboratory and Surgical Pathology, Osaka National Hospital, National Hospital Organization, Osaka, Japan.
authors: Yoshinori
authors: Y
authors: Kodama
authors: Department of Neurosurgery, Kansai Rosai Hospital, Hyogo, Japan.
authors: Kanji
authors: K
authors: Mori
authors: Department of Neurosurgery, Hyogo College of Medicine, Hyogo, Japan.
authors: Yusuke
authors: Y
authors: Tomogane
authors: Department of Neurological Surgery, Wakayama Medical University, Wakayama, Japan.
authors: Junya
authors: J
authors: Fukai
authors: Department of Neurological Surgery, Wakayama Medical University, Wakayama, Japan.
authors: Koji
authors: K
authors: Fujita
authors: Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors: Yuzo
authors: Y
authors: Terakawa
authors: Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors: Naohiro
authors: N
authors: Tsuyuguchi
authors: Department of Neurosurgery, Rinku General Medical Center, Izumisano, Osaka, Japan.
authors: Shusuke
authors: S
authors: Moriuchi
authors: Department of Neurosurgery, National Hospital Organization Osaka National Hospital, Osaka, Japan.
authors: Masahiro
authors: M
authors: Nonaka
authors: Department of Pathology and Laboratory Medicine, National Hospital Organization, Sendai Medical Center, Sendai, Japan.
authors: Hiroyoshi
authors: H
authors: Suzuki
authors: Central Laboratory, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.
authors: Makoto
authors: M
authors: Shibuya
authors: Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Taketoshi
authors: T
authors: Maehara
authors: Department of Neurosurgery, The University of Tokyo, Tokyo, Japan.
authors: Nobuhito
authors: N
authors: Saito
authors: Department of Neurosurgery, Kyorin University Faculty of Medicine, Tokyo, Japan.
authors: Motoo
authors: M
authors: Nagane
authors: Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors: Nobutaka
authors: N
authors: Kawahara
authors: Department of Neurosurgery, Dokkyo Medical University, Tochigi, Japan.
authors: Keisuke
authors: K
authors: Ueki
authors: Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors: Toshiki
authors: T
authors: Yoshimine
authors: Department of Mathematics, Faculty of Science, Tokyo University of Science, Tokyo, Japan.
authors: Etsuo
authors: E
authors: Miyaoka
authors: Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, Japan.
authors: Ryo
authors: R
authors: Nishikawa
authors: Department of Laboratory Medicine and Pathology (Neuropathology), Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
authors: Takashi
authors: T
authors: Komori
authors: Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors: Yoshitaka
authors: Y
authors: Narita
authors: Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. kichimur@ncc.go.jp.
authors: Koichi
authors: K
authors: Ichimura
mesh_terms: D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy / Q000601:surgery; D015331:Cohort Studies; D003131:Combined Modality Therapy; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy / Q000601:surgery; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D007564:Japan; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic; D016019:Survival Analysis; D019098:Telomerase / Q000235:genetics*; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; C538784:IDH2 protein, human; 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; D000077204:Temozolomide
keywords: 1p19q; Glioblastoma; Glioma; IDH1/2; Molecular classification; Prognostic factor; TERT; Temozolomide