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Abstract：
OBJECTIVE: 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%.
CONCLUSIONS: 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.
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%.
CONCLUSIONS: 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.
摘要：
目的：与室管膜下区（SVZ）接触的胶质母细胞瘤（GBM）先前已与特定的表观遗传指纹相关。我们旨在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IDHwtGBM患者进行甲基化阵列分析。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±)。三位有经验的读者独立审查了磁共振成像（MRI）（T1ce）的SVZ接触。
结果：70个样本中有65个被归类为RTKI，II,和MES。在54例中观察到基于T1ceMRI的完整评分者共识，将其保留用于进一步分析。表观遗传SVZM分类和SVZ强相关(OR:15.0,p=0.003)。十四个差异CpG中的十三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+肿瘤与较短的OS（风险比（HR）：3.80，p=0.02）相关（SVZM的时间依赖性，p<0.05)。考虑到SVZ共识作为基本事实，SVZM分类产生96.6%的灵敏度，特异性36.0%，阳性预测值（PPV）为63.6%，阴性预测值(NPV)为90.0%。
结论：此处，我们验证了SVZ附近GBM中的特定表观遗传特征,并强调了部分LRBA/MAB21L2基因位点甲基化的重要性.SVZM是否可以取代基于MRI的SVZ分配作为一种预后和诊断工具，将需要大量的前瞻性研究，同质队列。
方法：对在我们机构治疗的IDHwtGBM患者进行甲基化阵列分析。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±)。三位有经验的读者独立审查了磁共振成像（MRI）（T1ce）的SVZ接触。
结果：70个样本中有65个被归类为RTKI，II,和MES。在54例中观察到基于T1ceMRI的完整评分者共识，将其保留用于进一步分析。表观遗传SVZM分类和SVZ强相关(OR:15.0,p=0.003)。十四个差异CpG中的十三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+肿瘤与较短的OS（风险比（HR）：3.80，p=0.02）相关（SVZM的时间依赖性，p<0.05)。考虑到SVZ共识作为基本事实，SVZM分类产生96.6%的灵敏度，特异性36.0%，阳性预测值（PPV）为63.6%，阴性预测值(NPV)为90.0%。
结论：此处，我们验证了SVZ附近GBM中的特定表观遗传特征,并强调了部分LRBA/MAB21L2基因位点甲基化的重要性.SVZM是否可以取代基于MRI的SVZ分配作为一种预后和诊断工具，将需要大量的前瞻性研究，同质队列。
