基于eccDNA的三阶段分子分析显著提高了胶质瘤患者的识别、预后评估和复发预测准确性。

A three-stage eccDNA based molecular profiling significantly improves the identification, prognosis assessment and recurrence prediction accuracy in patients with glioma.

作者信息

Li Zesheng, Wang Bo, Liang Hao, Li Ying, Zhang Zhenyu, Han Lei

机构信息

Tianjin Neurological Institute, Key Laboratory of Post-Neuro Injury, Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, Tianjin, 300052, China.

Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 480082, China.

出版信息

Cancer Lett. 2023 Oct 10;574:216369. doi: 10.1016/j.canlet.2023.216369. Epub 2023 Aug 26.

Abstract

Glioblastoma (GBM) progression is influenced by intratumoral heterogeneity. Emerging evidence has emphasized the pivotal role of extrachromosomal circular DNA (eccDNA) in accelerating tumor heterogeneity, particularly in GBM. However, the eccDNA landscape of GBM has not yet been elucidated. In this study, we first identified the eccDNA profiles in GBM and adjacent tissues using circle- and RNA-sequencing data from the same samples. A three-stage model was established based on eccDNA-carried genes that exhibited consistent upregulation and downregulation trends at the mRNA level. Combinations of machine learning algorithms and stacked ensemble models were used to improve the performance and robustness of the three-stage model. In stage 1, a total of 113 combinations of machine learning algorithms were constructed and validated in multiple external cohorts to accurately distinguish between low-grade glioma (LGG) and GBM in patients with glioma. The model with the highest area under the curve (AUC) across all cohorts was selected for interpretability analysis. In stage 2, a total of 101 combinations of machine learning algorithms were established and validated for prognostic prediction in patients with glioma. This prognostic model performed well in multiple glioma cohorts. Recurrent GBM is invariably associated with aggressive and refractory disease. Therefore, accurate prediction of recurrence risk is crucial for developing individualized treatment strategies, monitoring patient status, and improving clinical management. In stage 3, a large-scale GBM cohort (including primary and recurrent GBM samples) was used to fit the GBM recurrence prediction model. Multiple machine learning and stacked ensemble models were fitted to select the model with the best performance. Finally, a web tool was developed to facilitate the clinical application of the three-stage model.

摘要

胶质母细胞瘤(GBM)的进展受肿瘤内异质性影响。新出现的证据强调了染色体外环状DNA(eccDNA)在加速肿瘤异质性中的关键作用,尤其是在GBM中。然而,GBM的eccDNA图谱尚未阐明。在本研究中,我们首先使用来自相同样本的环状和RNA测序数据确定了GBM和邻近组织中的eccDNA图谱。基于在mRNA水平表现出一致上调和下调趋势的携带eccDNA的基因建立了一个三阶段模型。使用机器学习算法和堆叠集成模型的组合来提高三阶段模型的性能和稳健性。在第1阶段,构建了总共113种机器学习算法组合,并在多个外部队列中进行验证,以准确区分胶质瘤患者的低级别胶质瘤(LGG)和GBM。选择在所有队列中曲线下面积(AUC)最高的模型进行可解释性分析。在第2阶段,建立了总共101种机器学习算法组合,并在胶质瘤患者中进行预后预测验证。该预后模型在多个胶质瘤队列中表现良好。复发性GBM总是与侵袭性和难治性疾病相关。因此,准确预测复发风险对于制定个体化治疗策略、监测患者状态和改善临床管理至关重要。在第3阶段,使用一个大规模GBM队列(包括原发性和复发性GBM样本)来拟合GBM复发预测模型。拟合多个机器学习和堆叠集成模型以选择性能最佳的模型。最后,开发了一个网络工具以促进三阶段模型的临床应用。

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