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

Hideyuki Arita, Kai Yamasaki, Yuko Matsushita, Taishi Nakamura, Asanao Shimokawa, Hirokazu Takami, Shota Tanaka, Akitake Mukasa, Mitsuaki Shirahata, Saki Shimizu, Kaori Suzuki, Kuniaki Saito, Keiichi Kobayashi, Fumi Higuchi, Takeo Uzuka, Ryohei Otani, Kaoru Tamura, Kazutaka Sumita, Makoto Ohno, Yasuji MiyakitaNaoki Kagawa, Naoya Hashimoto, Ryusuke Hatae, Koji Yoshimoto, Naoki Shinojima, Hideo Nakamura, Yonehiro Kanemura, Yoshiko Okita, Manabu Kinoshita, Kenichi Ishibashi, Tomoko Shofuda, Yoshinori Kodama, Kanji Mori, Yusuke Tomogane, Junya Fukai, Koji Fujita, Yuzo Terakawa, Naohiro Tsuyuguchi, Shusuke Moriuchi, Masahiro Nonaka, Hiroyoshi Suzuki, Makoto Shibuya, Taketoshi Maehara, Nobuhito Saito, Motoo Nagane, Nobutaka Kawahara, Keisuke Ueki, Toshiki Yoshimine, Etsuo Miyaoka, Ryo Nishikawa, Takashi Komori, Yoshitaka Narita, Koichi Ichimura

Research output: Contribution to journalArticle

54 Citations (Scopus)

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.

Original languageEnglish
Number of pages1
JournalActa neuropathologica communications
Volume4
Issue number1
DOIs
Publication statusPublished - Aug 8 2016

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Glioblastoma
Methylation
Mutation
Glioma
Survival
temozolomide
Proportional Hazards Models
Radiation
Neoplasms
Therapeutics

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas. / Arita, Hideyuki; Yamasaki, Kai; Matsushita, Yuko; Nakamura, Taishi; Shimokawa, Asanao; Takami, Hirokazu; Tanaka, Shota; Mukasa, Akitake; Shirahata, Mitsuaki; Shimizu, Saki; Suzuki, Kaori; Saito, Kuniaki; Kobayashi, Keiichi; Higuchi, Fumi; Uzuka, Takeo; Otani, Ryohei; Tamura, Kaoru; Sumita, Kazutaka; Ohno, Makoto; Miyakita, Yasuji; Kagawa, Naoki; Hashimoto, Naoya; Hatae, Ryusuke; Yoshimoto, Koji; Shinojima, Naoki; Nakamura, Hideo; Kanemura, Yonehiro; Okita, Yoshiko; Kinoshita, Manabu; Ishibashi, Kenichi; Shofuda, Tomoko; Kodama, Yoshinori; Mori, Kanji; Tomogane, Yusuke; Fukai, Junya; Fujita, Koji; Terakawa, Yuzo; Tsuyuguchi, Naohiro; Moriuchi, Shusuke; Nonaka, Masahiro; Suzuki, Hiroyoshi; Shibuya, Makoto; Maehara, Taketoshi; Saito, Nobuhito; Nagane, Motoo; Kawahara, Nobutaka; Ueki, Keisuke; Yoshimine, Toshiki; Miyaoka, Etsuo; Nishikawa, Ryo; Komori, Takashi; Narita, Yoshitaka; Ichimura, Koichi.

In: Acta neuropathologica communications, Vol. 4, No. 1, 08.08.2016.

Research output: Contribution to journalArticle

Arita, H, Yamasaki, K, Matsushita, Y, Nakamura, T, Shimokawa, A, Takami, H, Tanaka, S, Mukasa, A, Shirahata, M, Shimizu, S, Suzuki, K, Saito, K, Kobayashi, K, Higuchi, F, Uzuka, T, Otani, R, Tamura, K, Sumita, K, Ohno, M, Miyakita, Y, Kagawa, N, Hashimoto, N, Hatae, R, Yoshimoto, K, Shinojima, N, Nakamura, H, Kanemura, Y, Okita, Y, Kinoshita, M, Ishibashi, K, Shofuda, T, Kodama, Y, Mori, K, Tomogane, Y, Fukai, J, Fujita, K, Terakawa, Y, Tsuyuguchi, N, Moriuchi, S, Nonaka, M, Suzuki, H, Shibuya, M, Maehara, T, Saito, N, Nagane, M, Kawahara, N, Ueki, K, Yoshimine, T, Miyaoka, E, Nishikawa, R, Komori, T, Narita, Y & Ichimura, K 2016, 'A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas', Acta neuropathologica communications, vol. 4, no. 1. https://doi.org/10.1186/s40478-016-0351-2
Arita, Hideyuki ; Yamasaki, Kai ; Matsushita, Yuko ; Nakamura, Taishi ; Shimokawa, Asanao ; Takami, Hirokazu ; Tanaka, Shota ; Mukasa, Akitake ; Shirahata, Mitsuaki ; Shimizu, Saki ; Suzuki, Kaori ; Saito, Kuniaki ; Kobayashi, Keiichi ; Higuchi, Fumi ; Uzuka, Takeo ; Otani, Ryohei ; Tamura, Kaoru ; Sumita, Kazutaka ; Ohno, Makoto ; Miyakita, Yasuji ; Kagawa, Naoki ; Hashimoto, Naoya ; Hatae, Ryusuke ; Yoshimoto, Koji ; Shinojima, Naoki ; Nakamura, Hideo ; Kanemura, Yonehiro ; Okita, Yoshiko ; Kinoshita, Manabu ; Ishibashi, Kenichi ; Shofuda, Tomoko ; Kodama, Yoshinori ; Mori, Kanji ; Tomogane, Yusuke ; Fukai, Junya ; Fujita, Koji ; Terakawa, Yuzo ; Tsuyuguchi, Naohiro ; Moriuchi, Shusuke ; Nonaka, Masahiro ; Suzuki, Hiroyoshi ; Shibuya, Makoto ; Maehara, Taketoshi ; Saito, Nobuhito ; Nagane, Motoo ; Kawahara, Nobutaka ; Ueki, Keisuke ; Yoshimine, Toshiki ; Miyaoka, Etsuo ; Nishikawa, Ryo ; Komori, Takashi ; Narita, Yoshitaka ; Ichimura, Koichi. / A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas. In: Acta neuropathologica communications. 2016 ; Vol. 4, No. 1.
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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.",
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T1 - A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas

AU - Arita, Hideyuki

AU - Yamasaki, Kai

AU - Matsushita, Yuko

AU - Nakamura, Taishi

AU - Shimokawa, Asanao

AU - Takami, Hirokazu

AU - Tanaka, Shota

AU - Mukasa, Akitake

AU - Shirahata, Mitsuaki

AU - Shimizu, Saki

AU - Suzuki, Kaori

AU - Saito, Kuniaki

AU - Kobayashi, Keiichi

AU - Higuchi, Fumi

AU - Uzuka, Takeo

AU - Otani, Ryohei

AU - Tamura, Kaoru

AU - Sumita, Kazutaka

AU - Ohno, Makoto

AU - Miyakita, Yasuji

AU - Kagawa, Naoki

AU - Hashimoto, Naoya

AU - Hatae, Ryusuke

AU - Yoshimoto, Koji

AU - Shinojima, Naoki

AU - Nakamura, Hideo

AU - Kanemura, Yonehiro

AU - Okita, Yoshiko

AU - Kinoshita, Manabu

AU - Ishibashi, Kenichi

AU - Shofuda, Tomoko

AU - Kodama, Yoshinori

AU - Mori, Kanji

AU - Tomogane, Yusuke

AU - Fukai, Junya

AU - Fujita, Koji

AU - Terakawa, Yuzo

AU - Tsuyuguchi, Naohiro

AU - Moriuchi, Shusuke

AU - Nonaka, Masahiro

AU - Suzuki, Hiroyoshi

AU - Shibuya, Makoto

AU - Maehara, Taketoshi

AU - Saito, Nobuhito

AU - Nagane, Motoo

AU - Kawahara, Nobutaka

AU - Ueki, Keisuke

AU - Yoshimine, Toshiki

AU - Miyaoka, Etsuo

AU - Nishikawa, Ryo

AU - Komori, Takashi

AU - Narita, Yoshitaka

AU - Ichimura, Koichi

PY - 2016/8/8

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AB - 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.

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