Molecular subtypes of epilepsy associated with post-surgical seizure recurrence.
Molecular subtypes of epilepsy associated with post-surgical seizure recurrence.
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DOI：
10.1093/braincomms/fcad251
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发表时间：
2023
影响因子：
4.8
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中科院分区：
文献类型：
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大约 50% 接受癫痫切除手术的患者会出现癫痫复发。临床、影像学和电生理学变量无法完全解释术后结果的异质性。我们假设分子特征可能有助于理解手术反应，并且癫痫患者可以分为与手术切除后无癫痫发作或复发相关的分子亚型。从 40 名颞叶癫痫患者的队列中收集了术前血样、脑组织和术后癫痫结果，其中 23 人经历了术后癫痫复发。对从血液和组织样本中提取的信使 RNA 和 microRNA 进行了测序。血液和大脑中的信使 RNA 和 microRNA 表达水平均经过新颖的聚类方法与多重逻辑回归相结合，将个体分为遗传簇，从而识别与术后癫痫结果相关的新亚型。然后，我们比较了来自患者血液和脑组织的与每种亚型显着相关的 microRNA 和信使 RNA，以确定对于结果同样过度或不足的特征，并且更有可能代表具有常见分子病因学的内表型。通过通路分析进一步表征这些靶标 microRNA 和信使 RNA，以评估它们在癫痫中的功能作用。利用血液来源的 microRNA 和信使 RNA 表达水平，我们确定了与癫痫复发显着相关的两种癫痫亚型（A1 和 B4 簇）（调整后 P < 0.20）。总共 551 个 microRNA 和 2486 个信使 RNA 分别与簇 A1 和 B4 相关（调整后 P < 0.05）。脑组织信使 RNA 表达水平的聚类揭示了与癫痫复发相关的另一种亚型 (C2)，其失调的信使 RNA 转录本与 B4 簇高度重叠。 A1、B4 和 C2 簇也有显着的受试者重叠，这共同表明 microRNA 和信使 RNA 转录本可能与癫痫发作复发有关的协调机制。癫痫亚型 A1、B4 和 C2 揭示了癫痫复发中已知和新型的 microRNA 和信使 RNA 靶标。此外，A1 和 B4 中确定的目标可以在术前血液样本中进行量化，并且有可能作为手术切除结果的生物标志物。赫什伯格等人。对 microRNA (miRNA) 和信使 RNA (mRNA) 表达数据应用一种新颖的聚类方法，以确定与术后癫痫复发显着相关的癫痫患者的两种重叠亚型。两种亚型之间 miRNA 和靶基因的同时失调表明与癫痫复发相关的共同机制。
Approximately 50% of individuals who undergo resective epilepsy surgery experience seizure recurrence. The heterogenous post-operative outcomes are not fully explained by clinical, imaging and electrophysiological variables. We hypothesized that molecular features may be useful in understanding surgical response, and that individuals with epilepsy can be classified into molecular subtypes that are associated with seizure freedom or recurrence after surgical resection. Pre-operative blood samples, brain tissue and post-operative seizure outcomes were collected from a cohort of 40 individuals with temporal lobe epilepsy, 23 of whom experienced post-operative seizure recurrence. Messenger RNA and microRNA extracted from the blood and tissue samples were sequenced. The messenger RNA and microRNA expression levels from the blood and brain were each subjected to a novel clustering approach combined with multiple logistic regression to separate individuals into genetic clusters that identify novel subtypes associated with post-operative seizure outcomes. We then compared the microRNAs and messenger RNAs from patient blood and brain tissue that were significantly associated with each subtype to identify signatures that are similarly over- or under-represented for an outcome and more likely to represent endophenotypes with common molecular aetiology. These target microRNAs and messenger RNAs were further characterized by pathway analysis to assess their functional role in epilepsy. Using blood-derived microRNA and messenger RNA expression levels, we identified two subtypes of epilepsy that were significantly associated with seizure recurrence (clusters A1 and B4) (adjusted P < 0.20). A total of 551 microRNAs and 2486 messenger RNAs were associated with clusters A1 and B4, respectively (adjusted P < 0.05). Clustering of brain–tissue messenger RNA expression levels revealed an additional subtype (C2) associated with seizure recurrence that had high overlap of dysregulated messenger RNA transcripts with cluster B4. Clusters A1, B4 and C2 also shared significant overlap of subjects, which altogether suggests a coordinated mechanism by which microRNA and messenger RNA transcripts may be related to seizure recurrence. Epileptic subtypes A1, B4 and C2 reveal both known and novel microRNA and messenger RNA targets in seizure recurrence. Furthermore, targets identified in A1 and B4 are quantifiable in pre-operative blood samples and could potentially serve as biomarkers for surgical resection outcomes. Hershberger et al. apply a novel clustering approach to microRNA (miRNA) and messenger RNA (mRNA) expression data to identify two overlapping subtypes of patients with epilepsy that are significantly associated with post-operative seizure recurrence. Concurrent dysregulation of miRNAs and target genes between the two subtypes suggests a common mechanism associated with seizure recurrence.