MGMT启动子甲基化对神经胶质瘤患者治疗及预后的临床意义

韩雪涛; 周欢娣; 薛晓英

doi:10.3969/j.issn.1000-8179.2019.12.327

MGMT启动子甲基化对神经胶质瘤患者治疗及预后的临床意义

doi: 10.3969/j.issn.1000-8179.2019.12.327

韩雪涛^①,,
周欢娣^{①, ②},
薛晓英^①, ,

①.
河北医科大学第二医院放疗科（石家庄市 050000）
②.
河北医科大学第二医院中心实验室（石家庄市 050000）

详细信息

作者简介:
韩雪涛专业方向为放射肿瘤学。E-mail：hxt9088@163.com

通讯作者:
薛晓英 xxy0636@163.com

计量
- 文章访问数: 397
- HTML全文浏览量: 65
- PDF下载量: 21
- 被引次数: 0
出版历程
- 收稿日期: 2019-04-03
- 修回日期: 2019-06-14
- 刊出日期: 2019-06-30

The clinical significance of MGMT promoter methylation in the treatment and prognosis of glioma patients

Han Xuetao^{①
,},
Zhou Huandi^{①, ②},
Xue Xiaoying^{①
, ,}

①.
Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China
②.
Department of Central Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China

More Information

Corresponding author: Xiaoying Xue; Email:xxy0636@163.com

摘要

摘要: 目前以替莫唑胺（temozolomide，TMZ）为基础的化疗已成为神经胶质瘤术后辅助治疗的标准方案，然而TMZ对部分患者疗效欠佳。DNA修复蛋白O6-甲基鸟嘌呤-DNA甲基转移酶（O6-methylguanine-DNA methyltransferase，MGMT）启动子甲基化是胶质瘤患者的重要分子标志物，与胶质瘤预后及烷基化药物如TMZ的耐药有关。在新诊断的胶质母细胞瘤中，MGMT启动子甲基化已成为独立预后指标。MGMT启动子甲基化是抑制MGMT蛋白表达的关键机制，可抑制DNA修复，增加TMZ化疗敏感性。本文综述了MGMT启动子甲基化与神经胶质瘤患者预后、疗效的最新数据及临床试验，对MGMT启动子甲基化在临床中的应用进行总结，以期为神经胶质瘤患者的个体化治疗提供参考。
- 神经胶质瘤 /
- MGMT启动子甲基化 /
- 预后 /
- 治疗方案
Abstract: Adjuvant temozolomide- based chemotherapy has become the standard of care for most postoperative glioma patients. However, a large proportion of these patients do not respond to temozolomide. DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation has emerged as an important molecular marker in patients with gliomas. It is associated with prognosis and resistance to alkylated drugs such as temozolomide. MGMT promoter methylation is the key mechanism of MGMT gene silencing, thereby inhibiting DNA repair and increasing the sensitivity of chemotherapy. We reviewed current data on the prognostic and predictive relevance of MGMT testing and clinical trials, summarized the clinical application of MGMT promoter methylation, in order to provide reference for the individualized treatment of glioma patients.
- gliomas /
- MGMT promoter methylation /
- prognosis /
- therapeutic regimen

HTML全文

参考文献(24)

[1]	Ostrom QT, Gittleman H, Liao P, et al. CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014[J]. Neuro Oncol, 2017, 19(suppl_5): v1-v88. doi: 10.1093/neuonc/nox158
[2]	Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase Ⅲ study: 5- year analysis of the EORTC-NCIC trial[J]. Lancet Oncol, 2009, 10(5): 459-466. doi: 10.1016/S1470-2045(09)70025-7
[3]	Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma[J]. N Engl J Med, 2005, 352(10):997-1003. doi: 10.1056/NEJMoa043331
[4]	Nakagawachi T, Soejima H, Urano T, et al. Silencing effect of CpG island hypermethylation and histone modifications on O6- methylguanine- DNA methyltransferase (MGMT) gene expression in human cancer[J]. Oncogene, 2003, 22(55):8835-8844. doi: 10.1038/sj.onc.1207183
[5]	Weller M, Felsberg J, Hartmann C, et al. Molecular predictors of progression- free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network[J]. J Clin Oncol, 2009, 27(34):5743-5750. doi: 10.1200/JCO.2009.23.0805
[6]	Gorlia T, van den Bent MJ, Hegi ME, et al. Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3[J]. Lancet Oncol, 2008, 9(1):29-38. doi: 10.1016/S1470-2045(07)70384-4
[7]	Herrlinger U, Tzaridis T, Mack F, et al. Lomustine- temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial[J]. Lancet, 2019, 393(10172):678-688. doi: 10.1016/S0140-6736(18)31791-4
[8]	Okada M, Miyake K, Tamiya T. Glioblastoma Treatment in the Elderly [J]. Neurol Med Chir(Tokyo), 2017, 57(12):667-676. doi: 10.2176/nmc.ra.2017-0009
[9]	Reifenberger G, Hentschel B, Felsberg J, et al. Predictive impact of MGMT promoter methylation in glioblastoma of the elderly[J]. Int J Cancer, 2012, 131(6):1342-1350. doi: 10.1002/ijc.27385
[10]	Wick W, Platten M, Meisner C, et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial[J]. Lancet Oncol, 2012, 13(7):707-715. doi: 10.1016/S1470-2045(12)70164-X
[11]	Malmström A, Grφnberg BH, Marosi C, et al. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial[J]. Lancet Oncol, 2012, 13(9):916-926. doi: 10.1016/S1470-2045(12)70265-6
[12]	Zarnett OJ, Sahgal A, Gosio J, et al. Treatment of elderly patients with glioblastoma: a systematic evidence-based analysis[J]. JAMA Neurol, 2015, 72(5):589-596. doi: 10.1001/jamaneurol.2014.3739
[13]	Schaub C, Kebir S, Junold N, et al. Tumor growth patterns of MGMT-nonmethylated glioblastoma in the randomized GLARIUS trial[J]. J Cancer Res Clin Oncol, 2018, 144(8):1581-1589. doi: 10.1007/s00432-018-2671-z
[14]	Brandes AA, Finocchiaro G, Zagonel V, et al. AVAREG: a phase Ⅱ, randomized, noncomparative study of fotemustine or bevacizumab for patients with recurrent glioblastoma[J]. Neuro Oncol, 2016, 18(9): 1304-1312. doi: 10.1093/neuonc/now035
[15]	Weller M, Tabatabai G, Kästner B, et al. MGMT Promoter methylation is a strong prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive glioblastoma: The DIRECTOR Trial[J]. Clin Cancer Res, 2015, 21(9):2057-2064. doi: 10.1158/1078-0432.CCR-14-2737
[16]	Stupp R, Hegi ME, Gorlia T, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial[J]. Lancet Oncol, 2014, 15(10):1100-1108. doi: 10.1016/S1470-2045(14)70379-1
[17]	Kessler T, Sahm F, Sadik A, et al. Molecular differences in IDH wildtype glioblastoma according to MGMT promoter methylation[J]. Neuro Oncol, 2018, 20(3):367-379. doi: 10.1093/neuonc/nox160
[18]	Arita H, Yamasaki K, Matsushita Y, et al. A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas[J]. Acta Neuropathol Commun, 2016, 4(1):79. doi: 10.1186/s40478-016-0351-2
[19]	Zhao H, Wang S, Song C, et al. The prognostic value of MGMT promoter status by pyrosequencing assay for glioblastoma patients' survival: a meta-analysis[J]. World J Surg Oncol, 2016, 14(1):261. doi: 10.1186/s12957-016-1012-4
[20]	Binabaj MM, Bahrami A, ShahidSales S, et al. The prognostic value of MGMT promoter methylation in glioblastoma: A meta- analysis of clinical trials[J]. J Cell Physiol, 2018, 233(1):378-386. doi: 10.1002/jcp.25896
[21]	Nakagawa Y, Sasaki H, Ohara K, et al. Clinical and molecular prognostic factors for long-term survival of patients with glioblastomas in singleinstitutional consecutive cohort[J]. World Neurosurg, 2017, 106:165- 173. doi: 10.1016/j.wneu.2017.06.126
[22]	Lee A, Youssef I, Osborn VW, et al. The utilization of MGMT promoter methylation testing in United States hospitals for glioblastoma and its impact on prognosis[J]. J Clin Neurosci, 2018, 51:85-90. doi: 10.1016/j.jocn.2018.02.009
[23]	Bell EH, Zhang P, Fisher BJ, et al. Association of MGMT promoter methylation status with survival outcomes in patients with high-risk glioma treated with radiotherapy and temozolomide: an analysis from the nrg oncology/rtog 0424 trial[J]. JAMA Oncol, 2018, 4(10):1405- 1409. doi: 10.1001/jamaoncol.2018.1977
[24]	Franceschi E, Tosoni A, Minichillo S, et al. The prognostic roles of gender and o6-methylguanine-dna methyltransferase methylation status in glioblastoma patients: the female power[J]. World Neurosurg, 2018, 112:e342-e347. doi: 10.1016/j.wneu.2018.01.045