Purpose

Glioblastomas (GBM) with subventricular zone (SVZ) contact have previously been associated with a specific epigenetic fingerprint. We aim to validate a reported bulk methylation signature to determine SVZ contact.

Methods

Methylation array analysis was performed on IDHwt GBM patients treated at our institution. The v11b4 classifier was used to ensure the inclusion of only receptor tyrosine kinase (RTK) I, II, and mesenchymal (MES) subtypes. Methylation-based assignment (SVZM ±) was performed using hierarchical cluster analysis. Magnetic resonance imaging (MRI) (T1ce) was independently reviewed for SVZ contact by three experienced readers.

Results

Sixty-five of 70 samples were classified as RTK I, II, and MES. Full T1ce MRI-based rater consensus was observed in 54 cases, which were retained for further analysis. Epigenetic SVZM classification and SVZ were strongly associated (OR: 15.0, p = 0.003). Thirteen of fourteen differential CpGs were located in the previously described differentially methylated LRBA/MAB21L2 locus. SVZ + tumors were linked to shorter OS (hazard ratio (HR): 3.80, p = 0.02) than SVZM + at earlier time points (time-dependency of SVZM, p < 0.05). Considering the SVZ consensus as the ground truth, SVZM classification yields a sensitivity of 96.6%, specificity of 36.0%, positive predictive value (PPV) of 63.6%, and negative predictive value (NPV) of 90.0%.

Conclusion

Herein, we validated the specific epigenetic signature in GBM in the vicinity of the SVZ and highlighted the importance of methylation of a part of the LRBA/MAB21L2 gene locus. Whether SVZM can replace MRI-based SVZ assignment as a prognostic and diagnostic tool will require prospective studies of large, homogeneous cohorts.

中文翻译：

---

胶质母细胞瘤脑室下区基于甲基化特征的验证

目的

与室下区（SVZ）接触的胶质母细胞瘤（GBM）先前已被认为与特定的表观遗传指纹相关。我们的目标是验证报告的批量甲基化特征以确定 SVZ 接触。

方法

对在我们机构治疗的IDHwt GBM 患者进行甲基化芯片分析。 v11b4 分类器用于确保仅包含受体酪氨酸激酶 (RTK) I、II 和间充质 (MES) 亚型。使用层次聚类分析进行基于甲基化的分配（SVZM ±）。三位经验丰富的读者对 SVZ 接触情况的磁共振成像 (MRI) (T1ce) 进行了独立审查。

结果

70 个样本中的 65 个被分类为 RTK I、II 和 MES。在 54 例病例中观察到基于完整 T1ce MRI 的评分者共识，并将其保留以供进一步分析。表观遗传 SVZM 分类和 SVZ 密切相关（OR：15.0，p  = 0.003）。 14 个差异 CpG 中的 13 个位于先前描述的差异甲基化 LRBA/MAB21L2 基因座中。在较早的时间点，SVZ + 肿瘤与 SVZM + 相比，OS 较短（风险比 (HR)：3.80，p  = 0.02）（SVZM 的时间依赖性，p  < 0.05）。考虑到 SVZ 共识作为基本事实，SVZM 分类的敏感性为 96.6%，特异性为 36.0%，阳性预测值 (PPV) 为 63.6%，阴性预测值 (NPV) 为 90.0%。

结论

在此，我们验证了 SVZ 附近 GBM 中的特定表观遗传特征，并强调了 LRBA/MAB21L2 基因座部分甲基化的重要性。 SVZM 是否可以取代基于 MRI 的 SVZ 分配作为预后和诊断工具，需要对大型同质队列进行前瞻性研究。