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

被引：206

作者：

Arita, Hideyuki ^{[1
,2
]}

Yamasaki, Kai ^{[1
,3
]}

Matsushita, Yuko ^{[1
,4
]}

Nakamura, Taishi ^{[1
,5
]}

Shimokawa, Asanao ^{[6
]}

Takami, Hirokazu ^{[1
,7
]}

Tanaka, Shota ^{[7
]}

Mukasa, Akitake ^{[7
]}

Shirahata, Mitsuaki ^{[8
]}

Shimizu, Saki ^{[9
]}

Suzuki, Kaori ^{[9
]}

Saito, Kuniaki ^{[9
]}

Kobayashi, Keiichi ^{[9
]}

Higuchi, Fumi ^{[10
]}

Uzuka, Takeo ^{[10
]}

Otani, Ryohei ^{[10
]}

Tamura, Kaoru ^{[11
]}

Sumita, Kazutaka ^{[11
]}

Ohno, Makoto ^{[4
]}

Miyakita, Yasuji ^{[4
]}

Kagawa, Naoki ^{[2
]}

Hashimoto, Naoya ^{[2
]}

Hatae, Ryusuke ^{[12
]}

Yoshimoto, Koji ^{[12
]}

Shinojima, Naoki ^{[13
]}

Nakamura, Hideo ^{[13
]}

Kanemura, Yonehiro ^{[14
,15
]}

Okita, Yoshiko ^{[15
]}

Kinoshita, Manabu ^{[16
]}

Ishibashi, Kenichi ^{[17
]}

Shofuda, Tomoko ^{[18
]}

Kodama, Yoshinori ^{[19
]}

Mori, Kanji ^{[20
]}

Tomogane, Yusuke ^{[21
]}

Fukai, Junya ^{[22
]}

Fujita, Koji ^{[22
]}

Terakawa, Yuzo ^{[23
]}

Tsuyuguchi, Naohiro ^{[23
]}

Moriuchi, Shusuke ^{[24
]}

Nonaka, Masahiro ^{[15
]}

Suzuki, Hiroyoshi ^{[25
]}

Shibuya, Makoto ^{[26
]}

Maehara, Taketoshi ^{[11
]}

Saito, Nobuhito ^{[7
]}

Nagane, Motoo ^{[9
]}

Kawahara, Nobutaka ^{[5
]}

Ueki, Keisuke ^{[10
]}

Yoshimine, Toshiki ^{[2
]}

Miyaoka, Etsuo ^{[6
]}

Nishikawa, Ryo ^{[8
]}

机构：

[1] Natl Canc Ctr, Res Inst, Div Brain Tumor Translat Res, Chuo Ku, 5-1-1 Tsukiji, Tokyo 1040045, Japan

[2] Osaka Univ, Grad Sch Med, Dept Neurosurg, Osaka, Japan

[3] Osaka City Gen Hosp, Dept Pediat Hematol & Oncol, Osaka, Japan

[4] Natl Canc Ctr, Dept Neurosurg & Neurooncol, Tokyo, Japan

[5] Yokohama City Univ, Grad Sch Med, Dept Neurosurg, Yokohama, Kanagawa, Japan

[6] Tokyo Univ Sci, Fac Sci, Dept Math, Tokyo, Japan

[7] Univ Tokyo, Dept Neurosurg, Tokyo, Japan

[8] Saitama Med Univ, Int Med Ctr, Dept Neurooncol Neurosurg, Saitama, Japan

[9] Kyorin Univ, Fac Med, Dept Neurosurg, Tokyo, Japan

[10] Dokkyo Med Univ, Dept Neurosurg, Mibu, Tochigi, Japan

[11] Tokyo Med & Dent Univ, Dept Neurosurg, Tokyo, Japan

[12] Kyushu Univ, Grad Sch Med Sci, Dept Neurosurg, Fukuoka, Japan

[13] Kumamoto Univ, Grad Sch Life Sci, Dept Neurosurg, Kumamoto, Japan

[14] Natl Hosp Org, Osaka Natl Hosp, Inst Clin Res, Div Regenerat Med, Osaka, Japan

[15] Natl Hosp Org, Osaka Natl Hosp, Dept Neurosurg, Osaka, Japan

[16] Osaka Med Ctr Canc & Cardiovasc Dis, Dept Neurosurg, Osaka, Japan

[17] Osaka City Gen Hosp, Dept Neurosurg, Osaka, Japan

[18] Natl Hosp Org, Osaka Natl Hosp, Inst Clin Res, Div Stem Cell Res, Osaka, Japan

[19] Natl Hosp Org, Osaka Natl Hosp, Cent Lab & Surg Pathol, Osaka, Japan

[20] Kansai Rosai Hosp, Dept Neurosurg, Amagasaki, Hyogo, Japan

[21] Hyogo Coll Med, Dept Neurosurg, Nishinomiya, Hyogo, Japan

[22] Wakayama Med Univ, Dept Neurol Surg, Wakayama, Japan

[23] Osaka City Univ, Grad Sch Med, Dept Neurosurg, Osaka, Japan

[24] Rinku Gen Med Ctr, Dept Neurosurg, Izumisano, Osaka, Japan

[25] Natl Hosp Org, Dept Pathol & Lab Med, Sendai Med Ctr, Sendai, Miyagi, Japan

[26] Tokyo Med Univ, Hachioji Med Ctr, Cent Lab, Tokyo, Japan

[27] Tokyo Metropolitan Neurol Hosp, Dept Lab Med & Pathol Neuropathol, Tokyo, Japan

来源：

ACTA NEUROPATHOLOGICA COMMUNICATIONS | 2016年 / 4卷

关键词：

TERT; Molecular classification; Glioblastoma; Temozolomide; 1p19q; Glioma; IDH1/2; Prognostic factor; IDH1; MUTATIONS; FREQUENT ATRX; TEMOZOLOMIDE; DIFFUSE; GLIOMAS; TUMORS; ASTROCYTOMAS; RADIOTHERAPY; HISTOLOGY; SURVIVAL;

D O I：

10.1186/s40478-016-0351-2

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

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.

引用

页数：14

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