Table_3_A prognostic NAD+ metabolism-related gene signature for predicting response to immune checkpoint inhibitor in glioma.docx

BackgroundNicotinamide adenine dinucleotide (NAD+) metabolism is involved in a series of cancer pathogenesis processes, and is considered a promising therapeutic target for cancer treatment. However, a comprehensive analysis of NAD+ metabolism events on immune regulation and cancer survival has not yet been conducted. Here, we constructed a prognostic NAD+ metabolism-related gene signature (NMRGS) associated with immune checkpoint inhibitor (ICI) efficacy in glioma.
Methods40 NAD+ metabolism-related genes (NMRGs) were obtained from the Reactome database and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Glioma cases with transcriptome data and clinical information were obtained from Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA). NMRGS was constructed based on the calculated risk score using univariate analysis, Kaplan–Meier analysis, multivariate Cox regression, and nomogram. This NMRGS was verified in training (CGGA693) and validation (TCGA and CGGA325) cohorts. The immune characteristics, mutation profile, and response to ICI therapy were subsequently analyzed for different NMRGS subgroups.
ResultsSix NAD+ metabolism-related genes, including CD38, nicotinamide adenine dinucleotide kinase (NADK), nicotinate phosphoribosyltransferase (NAPRT), nicotinamide/nicotinic acid mononucleotide adenylyltransferase 3 (NMNAT3), poly(ADP-Ribose) polymerase family member 6 (PARP6), and poly(ADP-Ribose) polymerase family member 9 (PARP9), were ultimately used to construct a comprehensive risk model for glioma patients. Patients in the NMRGS-high group showed a poorer survival outcome than those in the NMRGS-low group. The area under curve (AUC) indicated that NMRGS has good potential in glioma prognostic prediction. A nomogram with improved accuracy was established based on independent prognostic factors (NMRGS score, 1p19q codeletion status, and WHO grade). Furthermore, patients in the NMRGS-high group showed a more immunosuppressive microenvironment, higher tumor mutation burden (TMB), higher human leucocyte antigen (HLA) expression and a more therapeutic response to ICI therapy.
ConclusionsThis study constructed a prognostic NAD+ metabolism-related signature associated with the immune landscape in glioma, which can be used for guiding individualized ICI therapy.

背景：烟酰胺腺嘌呤二核苷酸（Nicotinamide adenine dinucleotide, NAD+）代谢参与一系列癌症发生发展过程，被认为是癌症治疗极具潜力的治疗靶点。然而，目前尚未有针对NAD+代谢事件在免疫调控与癌症生存方面的全面分析。本研究构建了一种与胶质瘤免疫检查点抑制剂（Immune Checkpoint Inhibitor, ICI）疗效相关的预后性NAD+代谢相关基因特征（NAD+ metabolism-related gene signature, NMRGS）。

方法：从Reactome数据库与京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）中获取40个NAD+代谢相关基因（NAD+ metabolism-related genes, NMRGs）。从中国胶质瘤基因组图谱（Chinese Glioma Genome Atlas, CGGA）以及癌症基因组图谱（The Cancer Genome Atlas, TCGA）中获取携带转录组数据与临床信息的胶质瘤病例。基于单变量分析、Kaplan-Meier分析、多因素Cox回归以及列线图（nomogram）计算风险评分，构建NMRGS。分别在训练队列（CGGA693）与验证队列（TCGA与CGGA325）中对该NMRGS进行验证。随后针对不同NMRGS亚组，分析其免疫特征、突变谱以及免疫检查点抑制剂治疗响应情况。

结果：最终筛选出6个NAD+代谢相关基因，包括CD38、烟酰胺腺嘌呤二核苷酸激酶（nicotinamide adenine dinucleotide kinase, NADK）、烟酸磷酸核糖转移酶（nicotinate phosphoribosyltransferase, NAPRT）、烟酰胺/烟酸单核苷酸腺苷转移酶3（nicotinamide/nicotinic acid mononucleotide adenylyltransferase 3, NMNAT3）、多聚ADP-核糖聚合酶家族成员6（poly(ADP-Ribose) polymerase family member 6, PARP6）以及多聚ADP-核糖聚合酶家族成员9（poly(ADP-Ribose) polymerase family member 9, PARP9），以此构建胶质瘤患者的综合风险模型。NMRGS高分组患者的生存预后较低分组更差。受试者工作特征曲线下面积（area under curve, AUC）结果表明，NMRGS在胶质瘤预后预测中具有良好潜力。基于独立预后因素（NMRGS评分、1p19q共缺失状态以及WHO分级）构建了准确度更高的列线图。此外，NMRGS高分组患者呈现出更强的免疫抑制微环境、更高的肿瘤突变负荷（tumor mutation burden, TMB）、更高的人类白细胞抗原（human leucocyte antigen, HLA）表达水平，以及对免疫检查点抑制剂治疗更佳的响应效果。

结论：本研究构建了一种与胶质瘤免疫微环境相关的预后性NAD+代谢相关基因特征，可用于指导个体化免疫检查点抑制剂治疗。