铜死亡相关特征与脑胶质瘤患者肿瘤微环境和预后的相关性。

BACKGROUND: Copper ions are essential for cellular physiology. Cuproptosis is a novel method of copper-dependent cell death, and the cuproptosis-based signature for glioma remains less studied. METHODS: Several glioma datasets with clinicopathological information were collected from TCGA, GEO and CGGA. Robust Multichip Average (RMA) algorithm was used for background correction and normalization, cuproptosis-related genes (CRGs) were then collected. The TCGA-glioma cohort was clustered using ConsensusClusterPlus. Univariate Cox regression analysis and the Random Survival Forest model were performed on the differentially expressed genes to identify prognostic genes. The cuproptosis-signature was constructed by calculating CuproptosisScore using Multivariate Cox regression analysis. Differences in terms of genomic mutation, tumor microenvironment, and enrichment pathways were evaluated between high- or low-CuproptosisScore. Furthermore, drug response prediction was carried out utilizing pRRophetic. RESULTS: Two subclusters based on CRGs were identified. Patients in cluster2 had better clinical outcomes. The cuproptosis-signature was constructed based on CuproptosisScore. Patients with higher CuproptosisScore had higher WHO grades and worse prognosis, while patients with lower grades were more likely to develop IDH mutations or MGMT methylation. Univariate and Multivariate Cox regression analysis demonstrated CuproptosisScore was an independent prognostic factor. The accuracy of the signature in prognostic prediction was further confirmed in 11 external validation datasets. In groups with high-CuproptosisScore, PIK3CA, MUC16, NF1, TTN, TP53, PTEN, and EGFR showed high mutation frequency. IDH1, TP53, ATRX, CIC, and FUBP1 demonstrated high mutation frequency in low-CuproptosisScore group. The level of immune infiltration increased as CuproptosisScore increased. SubMap analysis revealed patients with high-CuproptosisScore may respond to anti-PD-1 therapy. The IC50 values of Bexarotene, Bicalutamide, Bortezomib, and Cytarabine were lower in the high-CuproptosisScore group than those in the low-CuproptosisScore group. Finally, the importance of IGFBP2 in TCGA-glioma cohort was confirmed. CONCLUSION: The current study revealed the novel cuproptosis-based signature might help predict the prognosis, biological features, and appropriate treatment for patients with glioma.

背景：铜离子是细胞生理学所必需的。铜死亡是一种新的依赖铜的细胞死亡方式，基于铜死亡的脑胶质瘤特征研究较少。

方法：从 TCGA、GEO 和 CGGA 收集了具有临床病理信息的多个脑胶质瘤数据集。使用稳健多芯片平均（RMA）算法进行背景校正和归一化，然后收集铜死亡相关基因（CRGs）。使用 ConsensusClusterPlus 对 TCGA 脑胶质瘤队列进行聚类。使用单变量 Cox 回归分析和随机生存森林模型对差异表达基因进行分析，以确定预后基因。使用多变量 Cox 回归分析计算铜死亡评分来构建铜死亡特征。评估基因组突变、肿瘤微环境和富集途径之间的差异，以确定高或低铜死亡评分的差异。此外，利用 pRRophetic 进行药物反应预测。

结果：基于 CRGs 鉴定出两个亚群。亚群 2 中的患者具有更好的临床结局。基于铜死亡评分构建了铜死亡特征。具有较高铜死亡评分的患者具有更高的 WHO 分级和更差的预后，而具有较低分级的患者更有可能发生 IDH 突变或 MGMT 甲基化。单变量和多变量 Cox 回归分析表明，铜死亡评分是独立的预后因素。该特征在 11 个外部验证数据集中的预后预测准确性得到进一步证实。在高铜死亡评分组中，PIK3CA、MUC16、NF1、TTN、TP53、PTEN 和 EGFR 表现出较高的突变频率。在低铜死亡评分组中，IDH1、TP53、ATRX、CIC 和 FUBP1 表现出较高的突变频率。随着铜死亡评分的升高，免疫浸润水平增加。SubMap 分析显示，高铜死亡评分组患者可能对抗 PD-1 治疗有反应。高铜死亡评分组的 IC50 值低于低铜死亡评分组的 Bexarotene、Bicalutamide、Bortezomib 和 Cytarabine。最后，在 TCGA 脑胶质瘤队列中证实了 IGFBP2 的重要性。

结论：本研究揭示了新的基于铜死亡的特征，可能有助于预测脑胶质瘤患者的预后、生物学特征和适当的治疗方法。