细胞外基质相关基因预后模型在脑胶质瘤中预测预后能力分析
作者:
作者单位:

1.北京美中爱瑞肿瘤医院,北京 100070;2.解放军医学院,北京 100853;3.解放军联勤保障部队九二〇医院,云南 昆明 650032;4.中南大学湘雅三医院重症医学科,湖南 长沙 410013;5.解放军总医院第一医学中心神经外科医学部,北京 100853

作者简介:

贾牧原(1997—),男,医学硕士,主要从事胶质瘤创新综合治疗研究。Email:gravesjia@163.com。

通信作者:

陈凌,Email:chen_ling301@163.com。

基金项目:

国家自然科学基金(U20A20380, 81672824, 82172680)。


Ability of a prognostic model based on extracellular matrix-associated genes in predicting the prognosis of glioma
Author:
Affiliation:

1.Arion Cancer Center, Beijing 100070, China;2.Medical School of Chinese PLA, Beijing 100853, China;3.Department of Neurosurgery, The 920th Hospital of Joint Logistics Support Force, Kunming, Yunnan 650032, China;4.Department of Critical Care Medicine, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China;5.Department of Neurosurgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China

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    摘要:

    目的 构建细胞外基质(ECM)相关基因预后模型,评价其预测胶质瘤患者预后的能力,探索基于该模型的胶质瘤免疫微环境特征。方法 基于肿瘤基因组图谱(TCGA)和基因型-组织表达(GTEx)数据库中胶质瘤以及正常脑组织数据,筛选获得差异基因(DEGs);基于基因本体论(GO)数据库获取ECM相关基因,基于单因素Cox回归分析获取胶质瘤预后基因。将上述三部分取交集获得重叠候选基因,再经由Lasso分析获取最佳的4基因预后模型,并于TCGA以及中国脑胶质瘤图谱数据库(CGGA)中胶质瘤队列中进行生存分析和Cox回归分析。基于4基因预后模型以及TCGA患者预后数据构建预后列线图,并在CGGA胶质瘤队列中进行验证。最后,基于富集分析、免疫检查点分析以及免疫浸润分析探索4基因预后模型相关的免疫微环境特征。结果 22个重叠候选基因经由Lasso分析后获得最佳4基因预后模型,该模型的风险评分能够较好地预测TCGA以及CGGA胶质瘤患者的预后,并且是危险因素。细胞系验证实验中提示U251细胞系(人源胶质瘤细胞)最佳4基因表达均高于HA1800(人源星形胶质细胞),符合TCGA以及CGGA数据库分析结果。基于4基因预后模型构建的预后列线图同样具有较好地预测患者预后的能力。高风险组患者肿瘤组织内具有较高水平的M2型巨噬细胞浸润且免疫检查点相关分子(PD-L1,B7-H3,CTLA4,PD1,TIM3以及LAG3)高于低风险组。结论 ECM相关基因模型以及预后列线图均能够较好地预测胶质瘤患者的预后,高风险组患者具有抑制性免疫微环境特征,免疫检查点抑制剂可能是该类患者的潜在治疗方式。

    Abstract:

    Objective To construct a prognostic model based on extracellular matrix (ECM)-associated genes, to evaluate its ability in predicting the prognosis of glioma patients, and to investigate the characteristics of the immune microenvironment of glioma based on this model.Methods The TCGA and GTEx databases were used to obtain the data of glioma and normal brain tissue, and then differentially expressed genes were obtained. The Gene Ontology (GO) database was used to obtain ECM-related genes, and a univariate Cox regression analysis was used to obtain the genes associated with the prognosis of glioma. The above three groups of genes were intersected to obtain overlapping candidate genes, and a LASSO analysis was used to obtain the optimal four-gene prognostic model. The glioma cohorts in the TCGA and CGGA databases were used for survival analysis and the Cox regression analysis. A prognostic nomogram was constructed based on the four-gene prognostic model and the prognostic data of patients in TCGA, which was validated in the glioma cohort in CGGA. Finally, enrichment analysis, immune checkpoint analysis, and immune infiltration analysis were used to investigate the characteristics of immune microenvironment associated with the four-gene prognostic model.Results The LASSO analysis was performed for the 22 overlapping candidate genes to obtain the optimal four-gene prognostic model, and the risk score of this model could better predict the prognosis of glioma patients in TCGA and CGGA and was a risk factor for the poor prognosis of patients. Cell line validation experiments showed that the U251 cell line (human-derived glioma cells) had higher expression levels of all four optimal genes than the HA1800 cell line (human-derived astrocytes cells), which was consistent with the results of data analysis for TCGA and CGGA databases. The prognostic nomogram constructed based on the four-gene prognostic model also had a good ability to predict patient prognosis. Compared with the low-risk group, the high-risk group had higher levels of M2 macrophage infiltration and immune checkpoint-related molecules (PD-L1, B7-H3, CTLA4, PD1, TIM3, and LAG3) in tumor tissue.Conclusion Both the model based on ECM-associated genes and the prognostic nomogram can well predict the prognosis of glioma patients. Patients in the high-risk group have the characteristics of suppressive immune microenvironment, and immune checkpoint inhibitors may be a potential treatment modality for such patients.

    图1 预后模型重叠基因的筛选及候选基因鉴定Fig.1
    图3 风险评分是TCGA胶质瘤患者的预后指标Fig.3
    图4 风险评分是CGGA胶质瘤患者的预后指标Fig.4
    图2 预后模型中候选基因的验证Fig.2
    图5 TCGA和CGGA数据库中风险评分与胶质瘤临床病理特征的关联Fig.5
    图6 构建并验证ECM相关基因风险评分的预后列线图Fig.6
    图7 高、低风险组胶质瘤患者间富集分析结果Fig.7
    图8 高、低风险组胶质瘤患者间肿瘤免疫微环境分析Fig.8
    图9 风险评分与肿瘤免疫检查点相关性分析Fig.9
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贾牧原,刘羽阳,胡文涛,陈俊燚,张洪俊,龚欢欢,吴剑慧,任博文,刘嘉霖,陈凌456.细胞外基质相关基因预后模型在脑胶质瘤中预测预后能力分析[J].国际神经病学神经外科学杂志,2024,51(2):35-47111JIA Muyuan, LIU Yuyang, HU Wentao, CHEN Junyi, ZHANG Hongjun, GONG Huanhuan, WU Jianhui, REN Bowen, LIU Jialin, CHEN Ling222. Ability of a prognostic model based on extracellular matrix-associated genes in predicting the prognosis of glioma[J]. Journal of International Neurology and Neurosurgery,2024,51(2):35-47

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  • 收稿日期:2023-08-29
  • 最后修改日期:2024-03-27
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  • 在线发布日期: 2024-06-19
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