Chang Xiaozan, Huang Yingxuan, Qu Ying, Guo Yu, Fan Wenwen, Zhen Haining
Henan Provincial People's Hospital, Cerebrovascular Disease Hospital, Zhengzhou, 450003, Henan, China.
Pediatric Intensive Care Unit, The Affiliated Hospital of Youjiang Medical University for Nationalities; Key Laboratory of Research and Development on Clinical Molecular Diagnosis for High-Incidence Diseases of Baise, Baise, China.
Discov Oncol. 2025 Apr 5;16(1):465. doi: 10.1007/s12672-025-02201-2.
Mitochondrial dysfunction has emerged as a critical factor in the progression and prognosis of low-grade glioma (LGG). In this study, we explored the role of mitochondrial-related genes through consensus clustering analysis using multi-omics data from the TCGA, CGGA, and other independent datasets. Patients were categorized into three clusters (Cluster A, B, and C), with Cluster B consistently associated with poorer prognosis. Mutation landscape analysis revealed distinct genetic alterations and copy number variations among clusters, particularly in Cluster B, which exhibited unique genetic signatures. Immune infiltration analysis showed that Cluster B had higher expression levels of immune checkpoint genes, stronger immune evasion activity, and greater immune cell infiltration, suggesting an immunosuppressive tumor microenvironment. Furthermore, we identified mitochondrial-related prognostic markers and developed a MITscore based on gene expression patterns, which stratified patients into high- and low-risk groups. High MITscore groups displayed stronger stemness characteristics, poorer survival outcomes, and differential responses to chemotherapy and immunotherapy. Cross-validation with drug sensitivity and immunotherapy cohorts indicated that high MITscore patients were more sensitive to certain chemotherapeutic agents and responded better to immunotherapy. Finally, using the SRGA method, we identified novel biomarkers (KDR, LRRK2, SQSTM1) closely associated with mitochondrial function, which may serve as potential targets for therapeutic intervention. These findings highlight the critical role of mitochondrial dysfunction in LGG prognosis, tumor microenvironment regulation, and treatment response, providing new avenues for precision oncology.
线粒体功能障碍已成为低级别胶质瘤（LGG）进展和预后的关键因素。在本研究中，我们使用来自TCGA、CGGA和其他独立数据集的多组学数据，通过共识聚类分析探索了线粒体相关基因的作用。患者被分为三个簇（簇A、B和C），其中簇B始终与较差的预后相关。突变图谱分析揭示了各簇之间不同的基因改变和拷贝数变异，特别是在簇B中，其表现出独特的基因特征。免疫浸润分析表明，簇B具有更高的免疫检查点基因表达水平、更强的免疫逃逸活性和更大的免疫细胞浸润，提示存在免疫抑制性肿瘤微环境。此外，我们确定了线粒体相关的预后标志物，并基于基因表达模式开发了MITscore，将患者分为高风险和低风险组。高MITscore组表现出更强的干性特征、更差的生存结果以及对化疗和免疫治疗的不同反应。与药物敏感性和免疫治疗队列的交叉验证表明，高MITscore患者对某些化疗药物更敏感，对免疫治疗反应更好。最后，使用SRGA方法，我们确定了与线粒体功能密切相关的新型生物标志物（KDR、LRRK2、SQSTM1），它们可能作为治疗干预的潜在靶点。这些发现突出了线粒体功能障碍在LGG预后、肿瘤微环境调节和治疗反应中的关键作用，为精准肿瘤学提供了新的途径。
