Temozolomide (TMZ) is the major chemotherapy agent in glioma, and isocitrate dehydrogenase (IDH) is a well-known prognostic marker in glioma. O6-methylguanine-DNA methyltransferase promoter methylation (MGMTmethyl) is a predictive biomarker in overall gliomas rather than in IDH mutant gliomas. To discover effective biomarkers that could predict TMZ efficacy in IDH mutant low-grade gliomas (LGGs), we retrieved data of IDH mutant LGGs from TMZ arm of the EORTC22033-26033 trial as the training-set (n = 83), analyzed correlations between long non-coding RNAs (lncRNAs) and progression-free survival (PFS) using Lasso-Cox regression, and created a risk score (RS) to stratify patients. We identified a three-lncRNA signature in TMZ-treated IDH mutant LGGs. All of the three lncRNAs, as well as the RS derived, were significantly correlated with PFS. Patients were classified into high-risk and low-risk groups according to RS. PFS of the high-risk group was significantly worse than that of the low-risk group (P < 0.001). AUCs of the three-, four-, and five-year survival probability predicted by RS were 0.73, 0.79, and 0.76, respectively. The predictive role of the three-lncRNA signature was further validated in an independent testing-set, the TCGA-LGGs, which resulted in a significantly worse PFS (P < 0.001) in the high-risk group. Three-, four-, and five-year survival probabilities predicted by RS were 0.65, 0.69, and 0.84, respectively. Functions of these three lncRNAs involve cell proliferation and differentiation, predicted by their targeting cancer genes. Conclusively, we created a scoring model based on the expression of three lncRNAs, which can effectively predict the survival of IDH mutant LGGs treated with TMZ.

Impact statement

Currently, no biomarkers known could predict the survival time of IDH mutant LGGs effectively. We discovered and validated a risk scoring model based on three lncRNAs. With this model, three-, four-, and five-year survival time of LGGs could be predicted more accurately, and LGGs could be stratified before TMZ therapy, which is helpful for the precision therapy afterward.

中文翻译：

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用于预测替莫唑胺处理的异柠檬酸脱氢酶突变体低级别胶质瘤存活率的三长非编码 RNA 特征的鉴定

替莫唑胺 (TMZ) 是神经胶质瘤的主要化疗药物，异柠檬酸脱氢酶 (IDH) 是众所周知的神经胶质瘤预后标志物。O6-甲基鸟嘌呤-DNA 甲基转移酶启动子甲基化 (MGMTmethyl) 是整体胶质瘤而非 IDH 突变胶质瘤的预测生物标志物。为了发现可以预测 TMZ 在 IDH 突变低级别胶质瘤 (LGG) 中的疗效的有效生物标志物，我们从 EORTC22033-26033 试验的 TMZ 臂检索 IDH 突变 LGG 的数据作为训练集（n = 83)，使用 Lasso-Cox 回归分析长链非编码 RNA (lncRNA) 与无进展生存 (PFS) 之间的相关性，并创建风险评分 (RS) 以对患者进行分层。我们在 TMZ 处理的 IDH 突变 LGGs 中鉴定了一个三 lncRNA 特征。所有三种 lncRNA 以及衍生的 RS 都与 PFS 显着相关。根据RS将患者分为高危组和低危组。高危组的 PFS 显着低于低危组（P  < 0.001）。RS 预测的三年、四年和五年生存概率的 AUC 分别为 0.73、0.79 和 0.76。三 lncRNA 特征的预测作用在独立的测试集 TCGA-LGG 中得到进一步验证，这导致 PFS 显着变差（P < 0.001) 在高危组中。RS 预测的三年、四年和五年生存概率分别为 0.65、0.69 和 0.84。这三种 lncRNA 的功能涉及细胞增殖和分化，由它们的靶向癌症基因预测。最后，我们创建了一个基于三个 lncRNAs 表达的评分模型，可以有效地预测用 TMZ 处理的 IDH 突变 LGGs 的存活率。

影响陈述

目前，尚无已知的生物标志物可以有效预测 IDH 突变 LGGs 的存活时间。我们发现并验证了基于三个 lncRNA 的风险评分模型。该模型可以更准确地预测LGGs的3年、4年和5年生存时间，并且可以在TMZ治疗前对LGGs进行分层，有助于之后的精准治疗。