基于单细胞测序数据分析微环境中配体-受体对对IDH突变型脑胶质瘤预后的预测价值
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国家自然科学基金 (82102764,82272870);国家资助博士后研究人员计划 (GZC20231749)


Prognostic value of ligand-receptor pairs in microenvironment based on single-cell sequencing data for IDH mutation gliomas
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    摘要:

    目的 分析异柠檬酸脱氢酶(IDH)突变型脑胶质瘤微环境中细胞通讯的特征及意义。 方法 利 用 Seurat 和 clusterProfiler 分 析IDH突 变 型 脑 胶 质 瘤 组 织 中 细 胞 类 型、占 比 及 功 能,采 用 CellphoneDB 分析细胞 - 细胞通讯特征并筛选有显著差异的配体 - 受体(LR)对,采用单因素 Cox 回归分 析判断 LR 对表达与IDH突变型脑胶质瘤患者总体生存期的关系。基于 LR 对的表达与预后信息采用一 致性聚类将患者分为不同亚型。采用 Log-rank、基因集富集分析(GSEA)、ESTIMATE 和 CIBERSORT 分 别比较不同亚型患者的生存差异、功能差异以及免疫特征,根据 LR 对的表达相关性和最小绝对收缩和 选择算子(LASSO)分析构建风险预测模型,分析风险评分与患者亚型、病理指标的关系。采用 Kaplan-Meier 生存曲线、Log-rank 检验和 Cox 回归模型评价风险评分与IDH突变型脑胶质瘤患者生存期的关系。 结果 共获取了 27 154 个细胞,注释后分为 6 个细胞类型。在 CGGA693 和 CGGA325 数据集的IDH突变 患者中,分别有 140 个和 131 个 LR 对与患者预后有关(P< 0.05),可将患者分为预后有显著差异的 2 个分 子亚型(P< 0.05)。与预后较好的亚型 1 相比,亚型 2 中Ⅳ级和 1p/19q 共缺失的脑胶质瘤患者占比更多 (P< 0.05)。Hallmark 富集分析显示,亚型 2 与 MYC 靶基因、DNA 修复、氧化磷酸化有关。KEGG 通路富 集分析显示,亚型 2 主要与核糖体、氧化磷酸化、帕金森病、亨廷顿病、阿尔茨海默病有关。与亚型 1 相 比,亚型 2 的肿瘤纯度更低,免疫浸润程度更高。配体和受体的表达相关系数> 0.5 的 LR 对有 14 个,利 用 LASSO 回归分析构建了由 DLL4-NOTCH3、CXCL12-CXCR4、COPA-SORT1、PLAU-PLAUR 和 EPHB2- EFNB1 组成的风险评分模型。LR 对风险评分在亚型 2 中更高(P< 0.05),其随病理级别的上升而增加 (P< 0.05);LR 对风险评分在 1p/19q 共缺失组中更高(P< 0.05);在IDH突变型、IDH突变及 1p/19q 非共缺 失脑胶质瘤患者中,高风险组患者较低风险组生存期短(P< 0.000 1)。单因素和多因素 Cox 回归分析结 果显示,WHO病理学分级(Ⅲ级均P<0.05;Ⅳ级均P<0.001)、1p/19q状态(均P<0.05)、风险评分(均P< 0.001)是IDH突变型脑胶质瘤患者总体生存期的影响因素。结论 LR 对可作为IDH突变型脑胶质瘤患 者分子亚型和预后的预测因子。

    Abstract:

    Objective To analyze the characteristics and significance of cell communication in the microenvironment of isocitrate dehydrogenase (IDH) mutation gliomas. Methods Seurat and clusterProfiler were used to analyze cell types, proportions, and functions in IDH mutation glioma tissues. CellphoneDB was used to analyze cell-cell communication characteristics and screen ligand-receptor (LR) pairs with significant differences. Univariate Cox regression was used to analyze the association between LR pairs expression and overall survival in IDH mutation glioma patients. Patients were classified into different subtypes using consistent clustering based on LR pairs expression and prognostic information. Log-rank, Gene Set Enrichment Analysis (GSEA), ESTIMATE, and CIBERSORT were used to compare the survival differences, functional differences, and immune characteristics of patients with different subtypes. Based on the correlation of LR pairs expression and least absolute shrinkage and selection operator (LASSO) analysis, a risk prediction model was constructed to analyze the association between risk scores, patient subtypes and pathological indicators. Kaplan-Meier survival curve, Log-rank test and Cox regression model were used to evaluate the relationship between risk score and survival of IDH mutation glioma patients. Results A total of 27 154 cells were obtained, annotated and divided into six cell types. In the IDH mutation patients of CGGA693 and CGGA325 datasets, there were 140 and 131 LR pairs, respectively, that were associated with patient prognosis (P< 0.05), and patients were divided into two molecular subtypes with significant differences in prognosis (P < 0.05), and the differences were statistically significant. Compared with subtype 1 with good prognosis, subtype 2 had a higher proportion of glioma patients with grade Ⅳ and 1p/19q co deletion (P< 0.05). Hallmark enrichment analysis showed that subtype 2 was associated with MYC target genes, DNA repair, and oxidative phosphorylation. KEGG pathway enrichment analysis showed that subtype 2 was mainly associated with ribosomes, oxidative phosphorylation, Parkinson's disease, Huntington's disease, and Alzheimer's disease. Compared with subtype 1, subtype 2 had lower tumor purity and higher degree of immune infiltration. There were 14 LR pairs with expression correlation coefficients greater than 0.5 between ligands and receptors. A risk scoring model consisting of DLL4-NOTCH3, CXCL12-CR4, COPA-SORT1, PLAU-PLAUR, and EPHB2-EFNB1 was constructed using LASSO regression. LR pair risk score was higher in subtype 2 (P< 0.05), which increased with pathological grade (P< 0.05), and LR pair risk score was higher in the 1p/19q co deletion group (P< 0.05), and the differences were statistically significant. In patients with IDH mutation, IDH mutation, and 1p/19q non deficient gliomas, the high-risk group had a shorter survival period compared to the low-risk group with a statistical difference (P < 0.000 1). Univariate and multivariate Cox regression analysis showed that WHO pathological grade (grade Ⅲ all P<0.05; grade Ⅳ all P<0.001), 1p/19q status (all P<0.05), and risk score (all P<0.001) were statistically significant factors affecting the overall survival of patients with IDH mutation gliomas. Conclusions LR pairs can serve as a predictive factor for molecular subtypes and prognosis in patients with IDH mutation gliomas

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张莹,孙志延,陈乔冬,曾凡,王志亮.基于单细胞测序数据分析微环境中配体-受体对对IDH突变型脑胶质瘤预后的预测价值[J].神经疾病与精神卫生,2025,25(1):26-35
DOI :10.3969/j. issn.1009-6574.2025.01.004.

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  • 在线发布日期: 2025-01-20