A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas.
A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas.
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DOI：
10.1186/s40478-016-0351-2
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发表时间：
2016-08-08
影响因子：
7.1
通讯作者：
Ichimura K
中科院分区：
文献类型：
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作者：
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
TERT突变的预后影响在IDH野生型肿瘤中一直存在争议，特别是在胶质母细胞瘤（GBM）中。争议可能归因于潜在的混杂因素，如MGMT甲基化状态或患者的治疗。本研究旨在评估大量成人弥漫性胶质瘤患者中，与各种因素相关的TERT状态对患者预后的影响。我们分析了两个队列（队列1，n = 758;队列2，n = 193）共951例成人弥漫性胶质瘤的IDH 1/2、1 p/19 q和TERT启动子状态。联合IDH/TERT分类将队列1分为四个具有不同结局的分子组。IDH野生型/TERT突变组的总生存期（OS）最短，主要由GBM组成（P < 0.0001）。为了研究TERT突变和MGMT甲基化对GBM患者生存期的相关性，分析了来自453例接受放疗和替莫唑胺治疗的IDH-野生型GBM病例的组合队列的样品。多变量考克斯回归模型显示，TERT和MGMT之间的相互作用对OS有显著性影响（P = 0.0064）。与TERT突变体-MGMT未甲基化GBM相比，包含相互作用的OS的风险比（HR）在TERT突变体-MGMT甲基化GBM中最低（HR，0.266），其次是TERT野生型-MGMT甲基化（HR，0.317）和TERT野生型-MGMT未甲基化GBM（HR，0.542）。因此，具有TERT突变体-MGMT未甲基化GBM的患者具有最差的预后。我们的研究结果表明，IDH，TERT和MGMT的组合细化II-IV级弥漫性胶质瘤的分类。本文的在线版本（doi：10.1186/s40478-016-0351-2）包含补充材料，可供授权用户使用。
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. The online version of this article (doi:10.1186/s40478-016-0351-2) contains supplementary material, which is available to authorized users.