Wang Peng, Wang Jiayi, Fang Zheng, Chen Qiaodong, Zhang Ying, Qiu Xiaoguang, Bao Zhaoshi
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
BMC Cancer. 2025 Apr 30;25(1):815. doi: 10.1186/s12885-025-14176-y.
Although IDH-mutant glioma generally has a better prognosis than their IDH-wildtype counterparts, considerable prognostic heterogeneity persists among patients with the same IDH mutation. Current study has primarily focused on the different IDH statuses or grades, while the metabolic heterogeneity within IDH-mutant gliomas remains insufficiently characterized. This study aims to identify transcriptomic metabolic subtypes and associated immune microenvironment differences to better understand survival variability and potential therapeutic targets in IDH-mutant glioma.
Patients with IDH-mutant gliomas were included from four public datasets (TCGA, n = 373; CGGA325, n = 167; CGGA693, n = 333; GLASS, n = 100), supplemented by 22 cases from Beijing Tiantan Hospital as an independent cohort. Consensus clustering was used to define novel metabolic subtypes. Clinical features were assessed using chi-square tests and Kaplan-Meier analysis. Metabolic profiles were characterized through enrichment analysis and GSVA; immune infiltration was analyzed using CIBERSORTx and ESTIMATE. Tumor samples from the independent cohort underwent untargeted metabolomics for validation. LASSO regression was applied to select metabolic signatures, and the CGP2014 drug library was used for drug screening.
Three metabolic subtypes (C1-C3) with distinct prognoses (p < 0.05) were identified. C1 exhibited enhanced carbohydrate and nucleotide metabolism; C2 displayed upregulated amino acid and lipid metabolism; and C3 demonstrated elevated lipid, nucleotide, and vitamin metabolism. These patterns were validated in the independent cohort. Subtypes were also correlated with immune infiltration. A 13-gene metabolic signature was established to stratify prognostic risk and suggest subtype-specific drug sensitivities.
Our study provided a novel metabolic subtype for IDH-mutant glioma and highlighted these patients' metabolic heterogeneity and potential therapeutic strategies.
尽管异柠檬酸脱氢酶（IDH）突变型胶质瘤的预后通常优于IDH野生型胶质瘤，但相同IDH突变的患者之间仍存在相当大的预后异质性。目前的研究主要集中在不同的IDH状态或分级上，而IDH突变型胶质瘤内的代谢异质性仍未得到充分表征。本研究旨在识别转录组代谢亚型及相关免疫微环境差异，以更好地理解IDH突变型胶质瘤的生存变异性和潜在治疗靶点。
从四个公共数据集（TCGA，n = 373；CGGA325，n = 167；CGGA693，n = 333；GLASS，n = 100）纳入IDH突变型胶质瘤患者，并补充北京天坛医院的22例患者作为独立队列。采用一致性聚类来定义新的代谢亚型。使用卡方检验和Kaplan-Meier分析评估临床特征。通过富集分析和基因集变异分析（GSVA）表征代谢谱；使用CIBERSORTx和ESTIMATE分析免疫浸润。独立队列的肿瘤样本进行非靶向代谢组学验证。应用套索回归选择代谢特征，并使用CGP2014药物库进行药物筛选。
识别出三种具有不同预后（p < 0.05）的代谢亚型（C1 - C3）。C1表现出碳水化合物和核苷酸代谢增强；C2显示氨基酸和脂质代谢上调；C3表现出脂质、核苷酸和维生素代谢升高。这些模式在独立队列中得到验证。亚型也与免疫浸润相关。建立了一个13基因的代谢特征来分层预后风险并提示亚型特异性药物敏感性。
我们的研究为IDH突变型胶质瘤提供了一种新的代谢亚型，并突出了这些患者的代谢异质性和潜在治疗策略。
