本研究旨在构建和验证一个强大的预后模型，用于预测异柠檬酸脱氢酶（IDH）野生型胶质母细胞瘤（GBM）的总生存率，并使用一种新的度量标准，基因-基因（G × G）相互作用，探索分子和细胞基础。通过对包含800个样本的四个独立的跨种族队列进行单变量和多变量Cox回归。通过系统的文献回顾全面评估和比较了预测效果。通过对综合病灶肿瘤和单细胞基于数据集的整合分析，阐明了COVPRIG的分子基础。利用基于Cox-ph模型的方法，筛选了93,961个G × G相互作用中的6个，形成了一个最佳组合，与年龄一起构成了COVPRIG模型。COVPRIG分别针对RNA-seq和microarray进行设计，并能有效地识别出高风险死亡的患者。COVPRIG的预测性能令人满意，曲线下面积（AUC）范围从0.56（CGGA693，RNA-seq，存活6个月）到0.79（TCGA RNA-seq，存活18个月），可以通过决策曲线进一步验证。分别构建了适用于基于RNA-seq和microarray的队列的个体风险预测的Nomograms。此外，还验证了COVPRIG在包括IDH突变样本在内的GBM中的预后意义。值得注意的是，COVPRIG经过全面评估和外部验证，并且系统回顾揭示COVPRIG在集成判别改进（IDI）为6-16%的当前验证模型中表现更好。此外，综合生物信息学分析预测了METTL1+神经前体样（NPC-like）恶性细胞在驱动不利结局方面的重要作用。本研究为预测IDH野生型GBM的结果提供了强大的工具，并为未来研究提供了初步的分子基础。 © 2023. BioMed Central Ltd., part of Springer Nature.

Accurately predicting the outcome of isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) remains hitherto challenging. This study aims to Construct and Validate a Robust Prognostic Model for IDH wild-type GBM (COVPRIG) for the prediction of overall survival using a novel metric, gene-gene (G × G) interaction, and explore molecular and cellular underpinnings.Univariate and multivariate Cox regression of four independent trans-ethnic cohorts containing a total of 800 samples. Prediction efficacy was comprehensively evaluated and compared with previous models by a systematic literature review. The molecular underpinnings of COVPRIG were elucidated by integrated analysis of bulk-tumor and single-cell based datasets.Using a Cox-ph model-based method, six of the 93,961 G × G interactions were screened to form an optimal combination which, together with age, comprised the COVPRIG model. COVPRIG was designed for RNA-seq and microarray, respectively, and effectively identified patients at high risk of mortality. The predictive performance of COVPRIG was satisfactory, with area under the curve (AUC) ranging from 0.56 (CGGA693, RNA-seq, 6-month survival) to 0.79 (TCGA RNAseq, 18-month survival), which can be further validated by decision curves. Nomograms were constructed for individual risk prediction for RNA-seq and microarray-based cohorts, respectively. Besides, the prognostic significance of COVPRIG was also validated in GBM including the IDH mutant samples. Notably, COVPRIG was comprehensively evaluated and externally validated, and a systemic review disclosed that COVPRIG outperformed current validated models with an integrated discrimination improvement (IDI) of 6-16%. Moreover, integrative bioinformatics analysis predicted an essential role of METTL1+ neural-progenitor-like (NPC-like) malignant cell in driving unfavorable outcome.This study provided a powerful tool for the outcome prediction for IDH wild-type GBM, and preliminary molecular underpinnings for future research.© 2023. BioMed Central Ltd., part of Springer Nature.