Glioblastoma (GBM) derived from the “stem cell” rich subventricular zone (SVZ) may constitute a therapy-refractory subgroup of tumors associated with poor prognosis. Risk stratification for these cases is necessary but is curtailed by error prone imaging-based evaluation. Therefore, we aimed to establish a robust DNA methylome-based classification of SVZ GBM and subsequently decipher underlying molecular characteristics. MRI assessment of SVZ association was performed in a retrospective training set of IDH-wildtype GBM patients (n = 54) uniformly treated with postoperative chemoradiotherapy. DNA isolated from FFPE samples was subject to methylome and copy number variation (CNV) analysis using Illumina Platform and cnAnalysis450k package. Deep next-generation sequencing (NGS) of a panel of 130 GBM-related genes was conducted (Agilent SureSelect/Illumina). Methylome, transcriptome, CNV, MRI, and mutational profiles of SVZ GBM were further evaluated in a confirmatory cohort of 132 patients (TCGA/TCIA). A 15 CpG SVZ methylation signature (SVZM) was discovered based on clustering and random forest analysis. One third of CpG in the SVZM were associated with MAB21L2/LRBA. There was a 14.8% (n = 8) discordance between SVZM vs. MRI classification. Re-analysis of these patients favored SVZM classification with a hazard ratio (HR) for OS of 2.48 [95% CI 1.35–4.58], p = 0.004 vs. 1.83 [1.0–3.35], p = 0.049 for MRI classification. In the validation cohort, consensus MRI based assignment was achieved in 62% of patients with an intraclass correlation (ICC) of 0.51 and non-significant HR for OS (2.03 [0.81–5.09], p = 0.133). In contrast, SVZM identified two prognostically distinct subgroups (HR 3.08 [1.24–7.66], p = 0.016). CNV alterations revealed loss of chromosome 10 in SVZM– and gains on chromosome 19 in SVZM– tumors. SVZM– tumors were also enriched for differentially mutated genes (p < 0.001). In summary, SVZM classification provides a novel means for stratifying GBM patients with poor prognosis and deciphering molecular mechanisms governing aggressive tumor phenotypes.

源自富含“干细胞”的脑室下区 (SVZ) 的胶质母细胞瘤 (GBM) 可能构成与预后不良相关的治疗难治性肿瘤亚组。这些病例的风险分层是必要的，但由于容易出错的基于成像的评估而受到限制。因此，我们的目标是建立一个稳健的基于 DNA 甲基化组的 SVZ GBM 分类，并随后破译潜在的分子特征。SVZ 关联的 MRI 评估在 IDH 野生型 GBM 患者（n = 54) 统一接受术后放化疗。使用 Illumina Platform 和 cnAnalysis450k 包对从 FFPE 样品中分离的 DNA 进行甲基化组和拷贝数变异 (CNV) 分析。对一组 130 个 GBM 相关基因进行了深度下一代测序 (NGS) (Agilent SureSelect/Illumina)。SVZ GBM 的甲基化组、转录组、CNV、MRI 和突变谱在 132 名患者 (TCGA/TCIA) 的确认队列中得到进一步评估。基于聚类和随机森林分析发现了 15 CpG SVZ 甲基化特征 (SVZM)。SVZM 中三分之一的 CpG 与MAB21L2 / LRBA相关。有 14.8% ( n = 8) SVZM 与 MRI 分类之间的不一致。对这些患者的重新分析倾向于 SVZM 分类，其 OS 的风险比 (HR) 为 2.48 [95% CI 1.35–4.58]，p  = 0.004 与 1.83 [1.0–3.35]， MRI 分类的p  = 0.049。在验证队列中，62% 的患者实现了基于 MRI 的共识分配，组内相关性 (ICC) 为 0.51，OS 的 HR 不显着（2.03 [0.81-5.09]，p  = 0.133）。相比之下，SVZM 确定了两个预后不同的亚组（HR 3.08 [1.24–7.66]，p  = 0.016）。CNV 改变显示 SVZM 中 10 号染色体缺失，而 SVZM 肿瘤中 19 号染色体增加。SVZM-肿瘤也富含差异突变基因（p < 0.001)。总之，SVZM 分类为对预后不良的 GBM 患者进行分层和破译控制侵袭性肿瘤表型的分子机制提供了一种新方法。