Princess Margaret Cancer Center and MacFeeters-Hamilton Center for Neuro-Oncology Research, University Health Network, Toronto, Ontario, Canada.
Faculty of Science, Thompson Rivers University, Kamloops, British Columbia, Canada.
Neuro Oncol. 2023 Nov 2;25(11):2028-2041. doi: 10.1093/neuonc/noad126.
Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Within isocitrate dehydrogenase (IDH)-mutant gliomas, there is a high variability in survival and a need to more accurately predict outcome.
To identify and characterize a predictive signature of outcome in gliomas, we utilized an integrative molecular analysis (using methylation, mRNA, copy number variation (CNV), and mutation data), analyzing a total of 729 IDH-mutant samples including a test set of 99 from University Health Network (UHN) and 2 validation cohorts including the German Cancer Research Center (DKFZ) and The Cancer Genome Atlas (TCGA).
Cox regression analysis of methylation data from the UHN cohort identified CpG-based signatures that split the glioma cohort into 2 prognostic groups strongly predicting survival that were validated using 2 independent cohorts from TCGA and DKFZ (all P-values < .0001). The methylation signatures that predicted poor outcomes also exhibited high CNV instability and hypermethylation of HOX gene probes. Integrated multi-platform analyses using mRNA and methylation (iRM) showed that parallel HOX gene overexpression and simultaneous hypermethylation were significantly associated with increased mutational load, high aneuploidy, and worse survival (P-value < .0001). A 7-HOX gene signature was developed and validated using the most significantly associated HOX genes with patient outcome in both 1p/19q codeleted and non-codeleted IDHmut gliomas.
HOX gene methylation and expression provide important prognostic information in IDH-mutant gliomas that are not captured by current molecular diagnostics. A 7-HOX gene signature of outcome shows significant survival differences in both 1p/19q codeleted and non-codeleted IDH-mutant gliomas.
弥漫性神经胶质瘤占恶性脑肿瘤的 80%以上，包括从低级别到侵袭性高级别的病变。在异柠檬酸脱氢酶（IDH）突变型神经胶质瘤中，生存存在很大的变异性，需要更准确地预测预后。
为了确定和描述 IDH 突变型神经胶质瘤中预后的预测性特征，我们利用整合的分子分析（使用甲基化、mRNA、拷贝数变异（CNV）和突变数据），分析了总共 729 例 IDH 突变型样本，包括 UHN 队列的 99 例测试集和 2 个验证队列，包括德国癌症研究中心（DKFZ）和癌症基因组图谱（TCGA）。
UHN 队列的甲基化数据 Cox 回归分析确定了基于 CpG 的特征，将神经胶质瘤队列分为 2 个预后组，强烈预测生存，使用 TCGA 和 DKFZ 的 2 个独立队列进行验证（均 P 值<.0001）。预测不良预后的甲基化特征也表现出高 CNV 不稳定性和 HOX 基因探针的高甲基化。使用 mRNA 和甲基化的综合多平台分析（iRM）显示，HOX 基因的平行过表达和同时的高甲基化与突变负荷增加、高非整倍体和更差的生存显著相关（P 值<.0001）。使用与 IDHmut 神经胶质瘤患者预后最显著相关的 HOX 基因，开发并验证了一个 7-HOX 基因特征。
HOX 基因甲基化和表达在 IDH 突变型神经胶质瘤中提供了重要的预后信息，这些信息不能被当前的分子诊断所捕捉。7-HOX 基因预后特征在 1p/19q 联合缺失和非联合缺失的 IDHmut 神经胶质瘤中显示出显著的生存差异。
