Journal Article

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

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

2016

Overview

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 MGM T 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.

• Publisher: BioMed Central,BioMed Central Ltd
• Subject: Adult / Analysis / Antineoplastic Agents, Alkylating - therapeutic use / Biomarkers, Tumor - genetics / Biomedical and Life Sciences / Biomedicine / Brain Neoplasms - drug therapy / Brain Neoplasms - genetics / Brain Neoplasms - radiotherapy / Brain Neoplasms - surgery / Cohort Studies / Combined Modality Therapy / Dacarbazine - analogs & derivatives / Dacarbazine - therapeutic use / DNA Methylation / DNA Modification Methylases - genetics / DNA Repair Enzymes - genetics / Female / Genetic aspects / Glioblastoma - drug therapy / Glioblastoma - genetics / Glioblastoma - radiotherapy / Glioblastoma - surgery / Gliomas / Humans / Isocitrate Dehydrogenase - genetics / Japan / Male / Medical research / Medicine, Experimental / Methylation / Middle Aged / Mutation / Neurology / Neurosciences / Pathology / Promoter Regions, Genetic / Survival Analysis / Telomerase - genetics / Temozolomide / Tumor Suppressor Proteins - genetics