Extraneural metastases of glioblastoma (GBM), although rare, are becoming an increasingly recognized occurrence. Currently, the biological mechanism underlying this rare occurrence is not understood. To explore the potential genomic drivers of extraneural metastasis in GBM, we present the molecular features of 4 extraneural metastatic GBMs, along with a comprehensive review and analysis of previously reported cases that had available molecular characterization. In addition to our 4 cases, 42 patients from 35 publications are reviewed. To compare the molecular profiles between GBM cases with extraneural metastasis and the general GBM population, genomic data from GBM samples in The Cancer Genome Atlas (TCGA) database were also analyzed. We found that 64.5% (20/31) of the cases with extraneural metastasis that were tested for TP53 changes had at least 1 TP53 pathogenic variant detected in either 1 or both primary and metastatic tumors. In contrast, TP53 mutation was significantly less frequent in the unselected GBM from TCGA (22.6%, 56/248) (P=0.000). In addition, O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation was more common in unselected TCGA GBM cases (48.6%, 170/350) than in cases with extraneural metastasis (31.8%, 7/22), although not statistically significant. Although isocitrate dehydrogenase (IDH) mutation is a rare occurrence in high-grade astrocytomas, IDH-mutant grade 4 astrocytomas are at least as likely to metastasize as IDH wild-type GBMs; 3 metastatic cases definitively harbored an IDH1 (p.R132H) mutation in our analysis. Our findings not only provide potential biomarkers for earlier screening of extraneural metastasis, but could also suggest clues to understanding biological mechanisms underlying GBM metastasis, and for the development of therapeutic modalities.

中文翻译：

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胶质母细胞瘤的 TP53 突变和神经外转移：来自机构经验和综合文献综述的见解。

胶质母细胞瘤（GBM）的神经外转移虽然罕见，但越来越多地被认识到。目前，这种罕见现象背后的生物学机制尚不清楚。为了探索 GBM 神经外转移的潜在基因组驱动因素，我们介绍了 4 种神经外转移性 GBM 的分子特征，并对先前报道的具有可用分子特征的病例进行了全面回顾和分析。除了我们的 4 例病例外，还对来自 35 篇出版物的 42 名患者进行了审查。为了比较具有神经外转移的 GBM 病例与一般 GBM 人群之间的分子谱，还分析了癌症基因组图谱 (TCGA) 数据库中 GBM 样本的基因组数据。我们发现，在进行 TP53 变化检测的神经外转移病例中，64.5% (20/31) 在原发性肿瘤和转移性肿瘤中至少检测到 1 个 TP53 致病性变异。相比之下，TCGA 中未选择的 GBM 中 TP53 突变的频率明显较低 (22.6%, 56/248) (P=0.000)。此外，O-6-甲基鸟嘌呤-DNA 甲基转移酶 (MGMT) 启动子甲基化在未选择的 TCGA GBM 病例中 (48.6%, 170/350) 比神经外转移病例 (31.8%, 7/22) 更常见，尽管没有统计学意义重要的。尽管异柠檬酸脱氢酶 (IDH) 突变在高级星形细胞瘤中很少发生，但 IDH 突变 4 级星形细胞瘤至少与 IDH 野生型 GBM 一样有可能发生转移；在我们的分析中，3 例转移病例明确携带 IDH1 (p.R132H) 突变。我们的研究结果不仅为神经外转移的早期筛查提供了潜在的生物标志物，而且还为理解 GBM 转移的生物学机制和治疗方式的开发提供了线索。