The optimal treatment for patients with low-grade glioma (LGG) WHO grade II remains controversial. Overall survival ranges from 2 to over 15 years depending on molecular and clinical factors. Hence, risk-adjusted treatments are required for optimizing outcome and quality of life. We aim at identifying mechanisms and associated molecular markers predictive for benefit from radiotherapy (RT) or temozolomide (TMZ) in LGG patients treated in the randomized phase III trial EORTC 22033. As candidate biomarkers for these genotoxic treatments, we considered the DNA methylome of 410 DNA damage response (DDR) genes. We first identified 62 functionally relevant CpG sites located in the promoters of 24 DDR genes, using the LGG data from The Cancer Genome Atlas. Then we tested their association with outcome [progression-free survival (PFS)] depending on treatment in 120 LGG patients of EORTC 22033, whose tumors were mutant for isocitrate dehydrogenase 1 or 2 (IDHmt), the molecular hallmark of LGG. The results suggested that seven CpGs of four DDR genes may be predictive for longer PFS in one of the treatment arms that comprised MGMT, MLH3, RAD21, and SMC4. Most interestingly, the two CpGs identified for MGMT are the same, previously selected for the MGMT-STP27 score that is used to determine the methylation status of the MGMT gene. This score was higher in the LGG with 1p/19q codeletion, in this and other independent LGG datasets. It was predictive for PFS in the TMZ, but not in the RT arm of EORTC 22033. The results support the hypothesis that a high score predicts benefit from TMZ treatment for patients with IDHmt LGG, regardless of the 1p/19q status. This MGMT methylation score may identify patients who benefit from first-line treatment with TMZ, to defer RT for long-term preservation of cognitive function and quality of life.

低级别胶质瘤 (LGG) WHO II 级患者的最佳治疗仍存在争议。根据分子和临床因素，总生存期从 2 年到超过 15 年不等。因此，需要经过风险调整的治疗来优化结果和生活质量。我们的目标是确定在随机 III 期试验 EORTC 22033 中治疗的 LGG 患者中预测放疗 (RT) 或替莫唑胺 (TMZ) 获益的机制和相关分子标志物。作为这些基因毒性治疗的候选生物标志物，我们考虑了 410 的 DNA 甲基化组DNA 损伤反应 (DDR) 基因。我们首先使用来自 The Cancer Genome Atlas 的 LGG 数据确定了位于 24 个 DDR 基因启动子中的 62 个功能相关的 CpG 位点。然后，我们在 120 名 EORTC 22033 的 LGG 患者中测试了它们与结果 [无进展生存期 (PFS)] 的关联，这些患者的肿瘤是异柠檬酸脱氢酶 1 或 2 (IDHmt) 的突变体，这是 LGG 的分子标志。结果表明，四个 DDR 基因的七个 CpG 可能预示着其中一个治疗组的 PFS 更长，该治疗组包括MGMT、MLH3、RAD21和SMC4。最有趣的是，为MGMT鉴定的两个 CpG是相同的，之前选择用于确定 MGMT 基因甲基化状态的 MGMT-STP27评分。在这个和其他独立的 LGG 数据集中，这个分数在 1p/19q 代码缺失的 LGG 中更高。它可以预测 TMZ 中的 PFS，但不能预测 EORTC 22033 的 RT 组。结果支持这样的假设，即无论 1p/19q 状态如何，高分都可以预测 IDHmt LGG 患者从 TMZ 治疗中获益。本次 MGMT甲基化评分可以识别从 TMZ 一线治疗中受益的患者，以推迟放疗以长期保存认知功能和生活质量。