Defining the cutoff value of MGMT gene promoter methylation and its predictive capacity in glioblastoma
Defining the cutoff value of MGMT gene promoter methylation and its predictive capacity in glioblastoma
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DOI：
10.1007/s11060-016-2116-y
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发表时间：
2016-06-01
影响因子：
3.9
通讯作者：
Faedi, Marina
中科院分区：
文献类型：
--
作者：
Brigliadori, Giovanni;Foca, Flavia;Faedi, Marina
尽管胶质母细胞瘤（GBM）的治疗取得了进展，但中位生存期为12-15个月。O 6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）基因启动子甲基化状态被认为是替莫唑胺（TMZ）治疗的预测标志物。当MGMT启动子值落入“甲基化”范围时，预期对化疗的反应更好。然而，区分“甲基化”和“非甲基化”状态的截止值尚未确定。我们的目的是确定最佳的临界值，并找出是否在甲基化谱的变化影响MGMT启动子甲基化的预测能力。分析了2008年至2013年期间接受治疗的105例GBM患者的数据。通过焦磷酸测序分析10个CpG岛来确定MGMT启动子甲基化状态。患者先接受放疗，然后接受TMZ治疗。MGMT启动子甲基化状态分为未甲基化0- 9%、甲基化10- 29%和甲基化30- 100%。统计分析表明，假设的甲基化临界值为9%，会导致对应答者的高估。10- 29%甲基化组的所有患者在18个月评估前复发。甲基化状态为千分之一日元30%的患者的中位总生存期为25.2个月，而所有其他患者的中位总生存期为15.2个月，证实该值为最佳甲基化截止值。尽管个体谱之间存在广泛的变异性，但单CpG岛分析并未揭示单CpG岛甲基化值与复发或死亡之间的任何相关性。特异性CpG岛甲基化状态不影响MGMT的预测价值。MGMT启动子甲基化的预测作用仅在千分之一日元30%的临界值下维持。
Despite advances in the treatment of glioblastoma (GBM), median survival is 12-15 months. O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation status is acknowledged as a predictive marker for temozolomide (TMZ) treatment. When MGMT promoter values fall into a "methylated" range, a better response to chemotherapy is expected. However, a cutoff that discriminates between "methylated" and "unmethylated" status has yet to be defined. We aimed to identify the best cutoff value and to find out whether variability in methylation profiles influences the predictive capacity of MGMT promoter methylation. Data from 105 GBM patients treated between 2008 and 2013 were analyzed. MGMT promoter methylation status was determined by analyzing 10 CpG islands by pyrosequencing. Patients were treated with radiotherapy followed by TMZ. MGMT promoter methylation status was classified into unmethylated 0-9 %, methylated 10-29 % and methylated 30-100 %. Statistical analysis showed that an assumed methylation cutoff of 9 % led to an overestimation of responders. All patients in the 10-29 % methylation group relapsed before the 18-month evaluation. Patients with a methylation status a parts per thousand yen30 % showed a median overall survival of 25.2 months compared to 15.2 months in all other patients, confirming this value as the best methylation cutoff. Despite wide variability among individual profiles, single CpG island analysis did not reveal any correlation between single CpG island methylation values and relapse or death. Specific CpG island methylation status did not influence the predictive value of MGMT. The predictive role of MGMT promoter methylation was maintained only with a cutoff value a parts per thousand yen30 %.