Department of Neurology, Erasmus MC, Rotterdam, The Netherlands.
Cancer Computational Biology Center, Erasmus MC, Rotterdam, The Netherlands.
Neuro Oncol. 2022 Mar 12;24(3):429-441. doi: 10.1093/neuonc/noab231.
EGFR is among the genes most frequently altered in glioblastoma, with exons 2-7 deletions (EGFRvIII) being among its most common genomic mutations. There are conflicting reports about its prognostic role and it remains unclear whether and how it differs in signaling compared with wildtype EGFR.
To better understand the oncogenic role of EGFRvIII, we leveraged 4 large datasets into 1 large glioblastoma transcriptome dataset (n = 741) alongside 81 whole-genome samples from 2 datasets.
The EGFRvIII/EGFR expression ratios differ strongly between tumors and range from 1% to 95%. Interestingly, the slope of relative EGFRvIII expression is near-linear, which argues against a more positive selection pressure than EGFR wildtype. An absence of selection pressure is also suggested by the similar survival between EGFRvIII-positive and -negative glioblastoma patients. EGFRvIII levels are inversely correlated with pan-EGFR (all wildtype and mutant variants) expression, which indicates that EGFRvIII has a higher potency in downstream pathway activation. EGFRvIII-positive glioblastomas have a lower CDK4 or MDM2 amplification incidence than EGFRvIII-negative (P = .007), which may point toward crosstalk between these pathways. EGFRvIII-expressing tumors have an upregulation of "classical" subtype genes compared to those with EGFR-amplification only (P = 3.873e-6). Genomic breakpoints of the EGFRvIII deletions have a preference toward the 3'-end of the large intron-1. These preferred breakpoints preserve a cryptic exon resulting in a novel EGFRvIII variant and preserve an intronic enhancer.
These data provide deeper insights into the complex EGFRvIII biology and provide new insights for targeting EGFRvIII mutated tumors.
表皮生长因子受体（EGFR）是胶质母细胞瘤中最常发生改变的基因之一，其外显子 2-7 缺失（EGFRvIII）是最常见的基因组突变之一。关于其预后作用存在相互矛盾的报道，目前尚不清楚它在信号转导方面是否与野生型 EGFR 不同以及如何不同。
为了更好地了解 EGFRvIII 的致癌作用，我们利用 4 个大型数据集构建了 1 个大型胶质母细胞瘤转录组数据集（n=741），并结合来自 2 个数据集的 81 个全基因组样本。
EGFRvIII/EGFR 的表达比例在肿瘤之间差异很大，范围从 1%到 95%。有趣的是，相对 EGFRvIII 表达的斜率近乎线性，这表明其受到的选择压力不如野生型 EGFR 高。EGFRvIII 阳性和阴性胶质母细胞瘤患者的生存情况相似，这也表明不存在选择压力。EGFRvIII 水平与泛 EGFR（所有野生型和突变型变体）表达呈负相关，这表明 EGFRvIII 在下游通路激活中具有更高的效力。与 EGFRvIII 阴性相比，EGFRvIII 阳性的胶质母细胞瘤 CDK4 或 MDM2 扩增发生率较低（P=0.007），这可能表明这些通路之间存在串扰。与仅 EGFR 扩增的肿瘤相比，表达 EGFRvIII 的肿瘤中“经典”亚型基因的上调更为明显（P=3.873e-6）。EGFRvIII 缺失的基因组断点倾向于大内含子 1 的 3'端。这些首选断点保留了一个隐藏的外显子，导致新的 EGFRvIII 变体，并保留了一个内含子增强子。
这些数据提供了对复杂的 EGFRvIII 生物学的更深入了解，并为靶向 EGFRvIII 突变肿瘤提供了新的见解。
