基于免疫相关基因构建神经母细胞瘤预后模型及潜在干预药物预测  

Construction of neuroblastoma prognostic model and prediction of potential intervention drugs based on immune-related genes

作　　者：马云飞 史学[1] 黄静 尤圣杰 刘畅[1] 苏雁[2] 赵文[2] 黄程[2] 秦静 胡艳[1] 倪鑫[4] MA Yunfei;SHI Xue;HUANG Jing;YOU Shengjie;LIU Chang;SU Yan;ZHAO Wen;HUANG Cheng;QIN Jing;HU Yan;NI Xin(Department of Traditional Chinese Medicine,Beijing Children’s Hospital,Capital Medical University,National Center for Children’s Health,Beijing 100045,China;Department of Medical Oncology,Pediatric Oncology Center,Beijing Children’s Hospital,Capital Medical University,National Center for Children’s Health,Beijing 100045,China;Pediatric Deparment of Xiyuan Hospitalr,China Academy of Chinese Medical Sciences,Beijing 100091,China;Department of National Center for Pediatric Cancer Surveillance,Beijing Children’s Hospital,Capital Medical University,National Center for Children’s Health,Beijing 100045,China)

机构地区：[1]国家儿童医学中心,首都医科大学附属北京儿童医院中医科,北京100045 [2]国家儿童医学中心,首都医科大学附属北京儿童医院儿童肿瘤中心肿瘤内科,北京100045 [3]中国中医科学院西苑医院儿科,北京100091 [4]国家儿童医学中心,首都医科大学附属北京儿童医院,国家儿童肿瘤监测中心,北京100045

出　　处：《中草药》2024年第13期4478-4489,共12页Chinese Traditional and Herbal Drugs

基　　金：北京“十四五”中医药重点专科项目(领超类和示范类)(BJZKLC005)。

摘　　要：目的基于免疫相关基因构建神经母细胞瘤预后模型,探讨其在神经母细胞瘤中的作用,并预测挖掘潜在的干预中药。方法通过limma包对TARGET-NBL数据集中高危患者组和非高危组表达谱数据进行差异分析。差异基因与ImmPort数据库中的免疫相关基因取交集,对差异免疫相关基因进行富集分析。应用单因素/多因素Cox回归分析、Lasso回归分析进一步筛选预后相关免疫差异基因,据此建立预后模型。采用CIBERSORT和单样本基因集富集分析(single-sample gene-set enrichment analysis,ssGSEA)评估高风险评分组和低风险评分组样本中免疫细胞的丰度。通过CTD和COREMINE数据库预测与预后模型中基因高度相关的化合物和中药。结果在高危患者中147个差异免疫相关基因显著富集在Janus激酶(Janus kinase,JAK)/信号转导和转录激活因子(signal transducer and activator of transcription,STAT)、Ras、B细胞受体、环磷酸腺苷(cyclic adenosine monophosphate,c AMP)、磷脂酰肌醇-3-羟激酶(phosphatidylinositol-3-hydroxykinase,PI3K)/蛋白激酶B(protein kinase B,Akt)、Rap1、丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)、转化生长因子-β(transforming growth factor-β,TGF-β)等多个信号通路。单因素/多因素Cox回归分析显示促甲状腺激素β亚基(thyroid stimulating hormone subunit beta,TSHB),肽脱甲酰基酶、线粒体(peptide deformylase,mitochondrial,PDF),血管生成素样蛋白3(angiopoietin like 3,ANGPTL3),前列腺素E受体1(prostaglandin E receptor 1,PTGER1)是高危神经母细胞瘤预后的独立影响因素。基于Lasso分析构建的免疫预后模型中,高风险评分组较低风险组评分组预后差(HR=4.49,95%CI:2.40~8.38,P<0.001),Calibration校正曲线和决策曲线也证明了该模型具有较好的预后效能和一定的临床实用性。CIBERSORT和ssGSEA免疫分析均显示CD8+T细胞在预后模型低风险评分组中浸润水平较高风险评分组显著升高(P<Objective To construct a neuroblastoma prognostic model based on immune-related genes,explore its role in neuroblastoma,and predict potential intervention Chinese medicine.Methods Limma package was used to analyze the difference between the expression profile data of high-risk patients and non-high-risk patients in the TARGET-NBL dataset.Differential genes were overlapped with immune-related genes from ImmPort database,and the resulting differential immune-related genes were enriched and analyzed.Univariate/multifactor Cox regression analysis and Lasso regression analysis were used to further screen prognostic-related immune differential genes,and the prognostic model was established.CIBERSORT and single-sample gene-set enrichment analysis(ssGSEA)were used to assess the abundance of immune cells in high risk score and low risk score samples.CTD and COREMINE databases were used to predict the compounds and Chinese medicines that highly interact with genes in the prognostic model.Results In high-risk patients,147 differentially immune-related genes were significantly enriched in Janus kinase/signal transducer and activator of transcription(JAK/STAT),Ras,B cell receptor,cyclic adenosine monophosphate(cAMP),phosphatidylinositol-3-hydroxykinase/protein kinase B(PI3K/Akt),Rap1,mitogen-activated protein kinase(MAPK),transforming growth factor-β(TGF-β)and other signaling pathways.Univariate/multivariate Cox regression analysis showed that thyroid stimulating hormone subunit beta(TSHB),peptide deformylase,mitochondrial(PDF),angiopoietin like 3(ANGPTL3),prostaglandin E receptor 1(PTGER1)were independent prognostic factors of high-risk neuroblastoma.In the immune prognosis model constructed based on Lasso analysis,the high risk group had worse prognosis than the low risk group(HR=4.49,95%CI:2.40-8.38,P<0.001).Calibration curve and decision curve also prove that the model had good prognostic efficacy and certain clinical practicability.Both CIBERSORT and ssGSEA results showed that CD8+T cells infiltration level was signifi

关 键 词：神经母细胞瘤 免疫相关基因 预后模型 双酚A 菟丝子 茶树根 生物信息学 

分 类 号：R285[医药卫生—中药学]