IDH mutation and MGMT promoter methylation in glioblastoma: results of a prospective registry.
IDH mutation and MGMT promoter methylation in glioblastoma: results of a prospective registry.
复制标题
胶质母细胞瘤中的 IDH 突变和 MGMT 启动子甲基化：前瞻性登记结果。
DOI：
10.18632/oncotarget.5683
复制
发表时间：
2015-12-01
期刊：
影响因子：
--
通讯作者：
Jiang T
中科院分区：
文献类型：
--
作者：
Yang P;Zhang W;Wang Y;Peng X;Chen B;Qiu X;Li G;Li S;Wu C;Yao K;Li W;Yan W;Li J;You Y;Chen CC;Jiang T
异柠檬酸脱氢酶突变（mIDH）和o6 -甲基鸟嘌呤- dna甲基转移酶启动子甲基化（methMGMT）作为胶质母细胞瘤生物标志物的相对贡献仍然知之甚少。我们在274例胶质母细胞瘤患者的前瞻性分子登记中研究了methMGMT和mIDH与无进展生存期和总生存期之间的关系。对于接受替莫唑胺和放疗的胶质母细胞瘤患者，同时携带mIDH和methMGMT的肿瘤患者的OS和PFS最有利（中位OS: 35.8个月，中位PFS: 27.5个月）；使用mIDH或methMGMT治疗的胶质母细胞瘤患者表现出中等的OS和PFS （mOS分别为36和17.1个月，mPFS分别为12.2和9.9个月）；MGMT启动子未甲基化的野生型IDH1 （wtIDH1）胶质母细胞瘤的OS和PFS最差（mOS: 15个月，mPFS: 9.7个月）。对于wtIDH胶质母细胞瘤患者，相对于接受RT治疗的患者，TMZ+RT与改善的OS和PFS相关（OS: 15.4个月vs 9.6个月，p < 0.001; PFS: 9.9个月vs 6.5个月，p < 0.001）。虽然TMZ+RT和RT治疗的mIDH患者相对于wtIDH患者表现出更高的总生存率，但TMZ+RT组和RT组之间没有差异。这些结果表明mIDH1赋予了对TMZ的抗性。支持这一假设的是，在独立星形细胞瘤/胶质母细胞瘤细胞系中外源表达mIDH1导致TMZ耐药性在长期传代后增加3-10倍。我们的研究表明，IDH突变和MGMT启动子甲基化状态与TMZ+RT治疗胶质母细胞瘤患者的良好预后独立相关。然而，这些生物标志物对临床TMZ反应的影响是不同的。
The relative contribution of isocitrate dehydrogenase mutations (mIDH) and O6-methylguanine-DNA methyltransferase promoter methylation (methMGMT) as biomarkers in glioblastoma remain poorly understood. We investigated the association between methMGMT and mIDH with progression free survival and overall survival in a prospectively collected molecular registry of 274 glioblastoma patients. For glioblastoma patients who underwent Temozolomide and Radiation Therapy, OS and PFS was most favorable for those with tumors harboring both mIDH and methMGMT (median OS: 35.8 mo, median PFS: 27.5 mo); patients afflicted glioblastomas with either mIDH or methMGMT exhibited intermediate OS and PFS (mOS: 36 and 17.1 mo; mPFS: 12.2 mo and 9.9 mo, respectively); poorest OS and PFS was observed in wild type IDH1 (wtIDH1) glioblastomas that were MGMT promoter unmethylated (mOS: 15 mo, mPFS: 9.7 mo). For patients with wtIDH glioblastomas, TMZ+RT was associated with improved OS and PFS relative to patients treated with RT (OS: 15.4 mo v 9.6 mo, p < 0.001; PFS: 9.9 mo v 6.5 mo, p < 0.001). While TMZ+RT and RT treated mIDH patients exhibited improved overall survival relative to those with wtIDH, there were no differences between the TMZ+RT or RT group. These results suggest that mIDH1 conferred resistance to TMZ. Supporting this hypothesis, exogenous expression of mIDH1 in independent astrocytoma/glioblastoma lines resulted in a 3–10 fold increase in TMZ resistance after long-term passage. Our study demonstrates IDH mutation and MGMT promoter methylation status independently associate with favorable outcome in TMZ+RT treated glioblastoma patients. However, these biomarkers differentially impact clinical TMZ response.