MGMT promoter methylation and hypermutant recurrence in IDH mutant lower-grade glioma.
MGMT promoter methylation and hypermutant recurrence in IDH mutant lower-grade glioma.
复制标题
IDH 突变低级别胶质瘤中的 MGMT 启动子甲基化和超突变复发。
DOI：
10.1093/neuonc/noaa212
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发表时间：
2020
期刊：
影响因子：
15.9
通讯作者：
Cahill,DanielP
中科院分区：
文献类型：
--
作者：
Miller,JulieJ;Cahill,DanielP
浸润性低级别胶质瘤（LGG）是年轻人（18-45岁）最常见的原发性脑癌。1，2这些弥漫性胶质瘤在修订后的世界卫生组织诊断分类3中为组织学II级或III级，并且含有异柠檬酸脱氢酶（IDH）1或2突变。它们通常最初生长缓慢，对手术和放射治疗有反应。此外，辅助烷化剂化疗最近已被证明在低级别IDH突变型胶质瘤中有效，在国际随机临床试验中证明了放射与丙卡巴肼/洛莫司汀/长春新碱（PCV）方案4-6或口服化疗剂替莫唑胺（TMZ）的联合治疗可延长生存期。7尽管有这种效果，但不幸的是，这些化疗缺乏持久性-在相当一部分患者中出现复发，许多病例转化为恶性亚克隆引起的更高级别的肿瘤，这些恶性亚克隆导致致命的疾病进展。8，9烷化剂后胶质瘤复发可以显示化疗的靶向选择压力的突变特征，因为可以通过错配修复缺陷的超突变基因组进化介导DNA损伤监视的逃逸。10-12这种现象在用TMZ治疗后的IDH突变型胶质瘤患者中特别常见。13-15化疗后的这种失败模式激发了研究工作，以确定治疗前肿瘤中的潜在生物标志物，这些生物标志物可以作为超突变最终发展的预测因子。在这期《神经肿瘤学》杂志上报道的一项综合研究中，Mathur及其同事提出了令人信服的证据，表明较高水平的前期O 6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）启动子甲基化及其在复发中的维持与IDH突变型胶质瘤中超突变的发展有关。16他们详细描述了37例最初诊断为LGG的TMZ治疗配对病例的临床特征和复发时的高突变状态。这些肿瘤中有18个在复发时表现出高突变的迹象。有趣的是，当将这18例病例与19例非超突变病例进行比较时，患者的年龄和TMZ周期数均与超突变的发生无关。然后，研究人员使用亚硫酸氢盐扩增子测序以定量方式仔细表征了MGMT启动子区域的甲基化水平。他们观察到，来自最终高突变复发的初始肿瘤标本通常显示MGMT启动子内胞嘧啶-鸟嘌呤二核苷酸位点的甲基化水平增加。最有趣的是，对于复发时发生超突变的患者，这些甲基化水平在初始肿瘤和复发之间没有显著变化。相比之下，MGMT启动子甲基化水平显着下降之间的初始肿瘤和复发的患者谁没有发展高突变复发。这些数据表明，竞争机制途径可以介导TMZ处理下的逃避选择：（i）通过未甲基化的MGMT启动子和原发性抗性的上调表达，相对于（ii）另一种通过错配基因修复缺陷表现出的超突变。总而言之，这些发现的影响是多方面的。首先，虽然MGMT启动子甲基化作为高级别IDH野生型队列中TMZ反应性的预测因子具有良好的证据基础，但这些结果代表了对低级别IDH突变型胶质瘤患者MGMT启动子甲基化的新的和微妙的临床考虑。这些发现表明，虽然...
Infiltrative lower-grade gliomas (LGGs) are the most common primary brain cancer of younger adults (ages 18–45 y). 1, 2 These diffuse gliomas are histological grades II or III within the revised World Health Organization diagnostic classification 3 and harbor mutations in isocitrate dehydrogenase (IDH) 1 or 2. They are often initially slow growing and responsive to treatment with surgery and radiation. In addition, adjuvant alkylating chemotherapy has recently been proven effective in lower-grade IDH mutant gliomas, with extended survival demonstrated in international randomized clinical trials combining radiation with the procarbazine/lomustine/vincristine (PCV) regimen 4–6 or oral chemotherapeutic temozolomide (TMZ). 7 Despite this effectiveness, these chemotherapies unfortunately lack durability—recurrences emerge in a substantial fraction of patients, with many cases transforming to a higher-grade tumor arising from malignant subclones that drive lethal disease progression. 8, 9 Post-alkylator glioma recurrences can display the mutational signature of an on-target selective pressure of chemotherapy, as escape from DNA damage surveillance can be mediated by mismatch repair‒deficient hypermutant genomic evolution. 10–12 This phenomenon is particularly frequent in IDH mutant glioma patients after treatment with TMZ. 13–15 This failure pattern after chemotherapy has motivated research efforts to identify potential biomarkers in pretreatment tumors that could serve as predictors of the eventual development of hypermutation. In a comprehensive study reported in this issue of Neuro-Oncology, Mathur and colleagues present convincing evidence that higher levels of upfront O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and their maintenance through recurrence, are associated with the development of hypermutation in IDH mutant gliomas. 16 They detail the clinical characteristics and hypermutation status at recurrence in 37 TMZ-treated paired cases that were initially diagnosed as LGG. Eighteen of these tumors showed signs of hypermutation at recurrence. Interestingly, when comparing these 18 cases with the 19 non-hypermutant cases, neither age of the patient nor the number of TMZ cycles was related to the development of hypermutation. The investigators then carefully characterized methylation levels in the MGMT promoter region in a quantitative manner using bisulfite amplicon sequencing. They observe that the initial tumor specimen from an eventual hypermutated recurrence generally showed increased methylation levels across cytosine-guanine dinucleotide sites within the MGMT promoter. Most interestingly, for patients who developed hypermutation at recurrence, these methylation levels did not significantly change between initial tumors and recurrences. In contrast, MGMT promoter methylation levels significantly decreased between initial tumors and recurrences for patients who did not develop hypermutation at recurrence. These data suggest that competing mechanistic pathways can mediate escape from selection under TMZ treatment:(i) via unmethylated MGMT promoter and upregulated expression for primary resistance versus (ii) another manifesting hypermutation via mismatch gene repair defects. All told, the implications of these findings are several. First, while MGMT promoter methylation has a well-established evidence base as a predictor of TMZ responsiveness in high-grade IDH wild-type cohorts, 17, 18 these results represent a new and nuanced clinical consideration for MGMT promoter methylation in patients with lower-grade IDH mutant gliomas. These findings suggest that, while …