Adverse prognosis of glioblastoma contacting the subventricular zone: Biological correlates

IntroductionThe subventricular zone (SVZ) in the brain is associated with gliomagenesis and resistance to treatment in glioblastoma. In this study, we investigate the prognostic role and biological characteristics of subventricular zone (SVZ) involvement in glioblastoma.MethodsWe analyzed T1-weighted, gadolinium-enhanced MR images of a retrospective cohort of 647 primary glioblastoma patients diagnosed between 2005–2013, and performed a multivariable Cox regression analysis to adjust the prognostic effect of SVZ involvement for clinical patient- and tumor-related factors. Protein expression patterns of a.o. markers of neural stem cellness (CD133 and GFAP-δ) and (epithelial-) mesenchymal transition (NF-κB, C/EBP-β and STAT3) were determined with immunohistochemistry on tissue microarrays containing 220 of the tumors. Molecular classification and mRNA expression-based gene set enrichment analyses, miRNA expression and SNP copy number analyses were performed on fresh frozen tissue obtained from 76 tumors. Confirmatory analyses were performed on glioblastoma TCGA/TCIA data.ResultsInvolvement of the SVZ was a significant adverse prognostic factor in glioblastoma, independent of age, KPS, surgery type and postoperative treatment. Tumor volume and postoperative complications did not explain this prognostic effect. SVZ contact was associated with increased nuclear expression of the (epithelial-) mesenchymal transition markers C/EBP-β and phospho-STAT3. SVZ contact was not associated with molecular subtype, distinct gene expression patterns, or markers of stem cellness. Our main findings were confirmed in a cohort of 229 TCGA/TCIA glioblastomas.ConclusionIn conclusion, involvement of the SVZ is an independent prognostic factor in glioblastoma, and associates with increased expression of key markers of (epithelial-) mesenchymal transformation, but does not correlate with stem cellness, molecular subtype, or specific (mi)RNA expression patterns.引言 大脑的室下区（subventricular zone, SVZ）与胶质母细胞瘤的肿瘤发生及治疗耐药性密切相关。本研究旨在探讨室下区受累在胶质母细胞瘤中的预后价值及其生物学特征。 方法 我们对2005年至2013年间确诊的647例原发性胶质母细胞瘤患者的回顾性队列的T1加权钆增强磁共振成像（MR）图像进行了分析，并开展多变量Cox回归分析，以校正临床患者及肿瘤相关混杂因素对室下区受累预后效应的影响。我们在包含220例肿瘤的组织微阵列上通过免疫组织化学法检测了多项标志物的蛋白表达谱，包括神经干细胞干性（neural stem cellness）标志物（CD133与GFAP-δ）以及（上皮-）间质转化（epithelial-mesenchymal transition）标志物（NF-κB、C/EBP-β与STAT3）。我们对76例肿瘤的新鲜冷冻组织开展了分子分型、基于mRNA表达的基因集富集分析、miRNA（microRNA）表达与单核苷酸多态性（SNP）拷贝数分析。此外，我们还在胶质母细胞瘤癌症基因组图谱（The Cancer Genome Atlas, TCGA）/癌症影像档案（The Cancer Imaging Archive, TCIA）数据集中完成了验证性分析。 结果 室下区受累是胶质母细胞瘤患者的显著不良预后因素，且独立于年龄、卡氏功能状态评分（Karnofsky Performance Status, KPS）、手术方式与术后治疗方案。肿瘤体积与术后并发症无法解释该预后效应。室下区接触与（上皮-）间质转化标志物C/EBP-β及磷酸化STAT3的核表达升高相关。室下区接触与分子亚型、独特的基因表达模式或神经干细胞干性标志物均无关联。我们的核心研究结果在229例TCGA/TCIA胶质母细胞瘤队列中得到了验证。 结论 综上，室下区受累是胶质母细胞瘤的独立预后因素，且与（上皮-）间质转化关键标志物的表达升高相关，但与神经干细胞干性、分子亚型或特定miRNA表达模式无相关性。