Multi-Omic Analysis of Glioma Identifies RRM2 as a Prognostic Biomarker Associated With Tumor Stemness and Cell Cycle–Related Pathways

Introduction Glioma is the most common primary malignant tumor of the central nervous system and remains associated with poor prognosis and limited effective biomarkers. Ribonucleotide reductase M2 (RRM2), a key enzyme involved in DNA synthesis, is frequently upregulated in multiple cancers; however, its pan-cancer characteristics and clinical significance in glioma remain incompletely defined. Methods This retrospective study integrated data from The Cancer Genome Atlas (TCGA), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and Genotype-Tissue Expression (GTEx) to characterize RRM2 expression patterns and prognostic relevance across 34 solid tumor types. Glioma (GBMLGG) was further analyzed to assess associations between RRM2 expression and Mutant-Allele Tumor Heterogeneity (MATH), stemness indices, clinicopathological features, and survival outcomes. An RRM2-based prognostic nomogram was constructed and externally validated. Differential expression analysis combined with Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) was performed to explore RRM2-associated biological pathways. Results RRM2 was significantly upregulated in 33 of 34 cancer types, with the strongest prognostic effect observed in GBMLGG. In glioma, RRM2 expression was markedly higher than in normal brain tissue (P < 0.001) and showed high diagnostic accuracy (AUC = 0.967). Elevated RRM2 expression was associated with advanced age, higher WHO grade, and Isocitrate Dehydrogenase (IDH) wild-type status, and predicted significantly poorer overall survival, disease-specific survival, and progression-free interval (all P < 0.001). A nomogram incorporating RRM2 expression, age, WHO grade, and IDH status demonstrated robust predictive performance for 1-, 3-, and 5-year survival. RRM2 expression was positively correlated with tumor stemness and negatively correlated with intratumoral heterogeneity, and was associated with enrichment of cell cycle and immune-related pathways. Conclusion RRM2 is markedly overexpressed in glioma and is strongly associated with tumor aggressiveness and poor prognosis. These findings support the potential value of RRM2 as a prognostic biomarker in glioma and suggest that it is associated with stemness-related and cell cycle-related biological features. Further studies are needed to clarify its mechanistic and therapeutic relevance.