Developmental Neurogenetics Laboratory, Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
Ben and Catherine Ivy Center for Advanced Brain Tumor Treatment, Swedish Neuroscience Institute, Seattle, WA, USA.
Cell Rep Med. 2024 Aug 20;5(8):101691. doi: 10.1016/j.xcrm.2024.101691.
The cortical microenvironment surrounding malignant glioblastoma is a source of depolarizing crosstalk favoring hyperexcitability, tumor expansion, and immune evasion. Neosynaptogenesis, excess glutamate, and altered intrinsic membrane currents contribute to excitability dyshomeostasis, yet only half of the cases develop seizures, suggesting that tumor and host genomics, along with location, rather than mass effect, play a critical role. We analyzed the spatial contours and expression of 358 clinically validated human epilepsy genes in the human glioblastoma transcriptome compared to non-tumor adult and developing cortex datasets. Nearly half, including dosage-sensitive genes whose expression levels are securely linked to monogenic epilepsy, are strikingly enriched and aberrantly regulated at the leading edge, supporting a complex epistatic basis for peritumoral epileptogenesis. Surround hyperexcitability induced by complex patterns of proepileptic gene expression may explain the limited efficacy of narrowly targeted antiseizure medicines and the persistence of epilepsy following tumor resection and clarify why not all brain tumors provoke seizures.
围绕恶性神经胶质瘤的皮质微环境是去极化串扰的来源，有利于过度兴奋、肿瘤扩张和免疫逃避。新生突触形成、谷氨酸过多和内在膜电流改变导致兴奋性动态平衡失调，但只有一半的病例发生癫痫，这表明肿瘤和宿主的基因组，以及位置，而不是肿块效应，起着关键作用。我们分析了 358 个人类癫痫相关基因在人类神经胶质瘤转录组中的空间轮廓和表达，与非肿瘤成人和发育中皮质数据集进行了比较。近一半的基因（包括表达水平与单基因癫痫密切相关的剂量敏感基因）在前沿区域明显富集和异常调控，支持了肿瘤周围癫痫发生的复杂上位遗传基础。由致痫基因表达的复杂模式诱导的周围过度兴奋可能解释了针对狭窄靶点的抗癫痫药物疗效有限，以及肿瘤切除后癫痫持续存在的原因，也阐明了为什么不是所有的脑瘤都会引发癫痫。
