不同的遗传改变决定了胶质瘤的侵袭性，然而，疾病过程中对于贡献于肿瘤周围高兴奋性和癫痫发作的体细胞突变的多样性尚不明确。本研究旨在确定与临床显著高兴奋性相关的肿瘤体细胞突变谱。对WHO 1-4级胶质瘤的单一中心成人队列进行了分析，选取了目标外显子测序（n = 1716），并与经过验证的脑电图数据库进行了交叉引用，以确定进行连续脑电图监测的个体子集（n = 206）。高兴奋性的定义为单侧周期放电和/或脑电图抽搐的存在。使用基于经常发生的体细胞突变的交叉验证判别分析模型以确定与高兴奋性相关的变异体。在具有和不具有高兴奋性的患者之间，WHO级别和肿瘤突变负荷的分布相似。判别分析模型无论是否包含IDH1 R132H，都能以总体准确率70.9%对脑电图高兴奋性的存在与否进行分类。预测性变异体包括ATRX和TP53的无义突变，RBBP8和CREBBP的插入缺失突变，以及EGFR、KRAS、PIK3CA、TP53和USP28中预测的有害后果的非同义错义突变。这个谱系在多变量分析中改善了对高兴奋性的估计，控制了年龄、性别、肿瘤位置、综合病理诊断、复发状态和术前癫痫。与没有高兴奋性和没有进行连续脑电图的个体相比，预测的体细胞突变变异体在具有高兴奋性的患者中过度表达。这些发现证明了与胶质瘤相关的癌症基因中多样化的体细胞突变与肿瘤周围高兴奋性有关。肿瘤基因组分型可能有助于胶质瘤相关癫痫的预后评估和管理。由牛津大学出版社代表神经肿瘤学学会2023年出版。这项工作是由美国政府雇员编写的，属于美国公有领域。

Distinct genetic alterations determine glioma aggressiveness, however the diversity of somatic mutations contributing to peritumoral hyperexcitability and seizures over the course of disease is uncertain. This study aimed to identify tumor somatic mutation profiles associated with clinically significant hyperexcitability.A single center cohort of adults with WHO grades 1-4 glioma and targeted exome sequencing (n=1716) was analyzed and cross-referenced with a validated EEG database to identify the subset of individuals who underwent continuous EEG monitoring (n=206). Hyperexcitability was defined by the presence of lateralized periodic discharges and/or electrographic seizures. Cross-validated discriminant analysis models trained exclusively on recurrent somatic mutations were used to identify variants associated with hyperexcitability.The distribution of WHO grades and tumor mutational burdens were similar between patients with and without hyperexcitability. Discriminant analysis models classified the presence or absence of EEG hyperexcitability with an overall accuracy of 70.9%, regardless of IDH1 R132H inclusion. Predictive variants included nonsense mutations in ATRX and TP53, indel mutations in RBBP8 and CREBBP, and nonsynonymous missense mutations with predicted damaging consequences in EGFR, KRAS, PIK3CA, TP53, and USP28. This profile improved estimates of hyperexcitability in multivariate analysis controlling for age, sex, tumor location, integrated pathologic diagnosis, recurrence status, and pre-operative epilepsy. Predicted somatic mutation variants were over-represented in patients with hyperexcitability compared to individuals without hyperexcitability and those who did not undergo continuous EEG.These findings implicate diverse glioma somatic mutations in cancer genes associated with peritumoral hyperexcitability. Tumor genetic profiling may facilitate glioma-related epilepsy prognostication and management.Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.