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Subtype-specific clinical significance of RRM1 and RRM2 expression in non-small cell lung cancer: a TCGA-based analysis.

Se-Young Yun·Yunha Lee·Junchae Lee·Hyowon Hong·Jae-Ho Lee
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Abstract

BACKGROUND: Non-small cell lung cancer (NSCLC), including lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), exhibits significant molecular heterogeneity. Ribonucleotide reductase (RNR), composed of RRM1 and RRM2, is essential for DNA synthesis and repair, but its subtype-specific clinical significance in NSCLC remains unclear. OBJECTIVE: To investigate the clinical and prognostic significance of RRM1 and RRM2 expression in NSCLC, with a focus on subtype-specific differences between LUAD and LUSC. METHODS: We analyzed RNA expression and clinical data from 980 NSCLC patients in The Cancer Genome Atlas (TCGA). Associations with clinicopathologic characteristics, overall survival, and oncogenic driver alterations were assessed. RESULTS: In LUAD, high RRM2 expression was significantly associated with advanced pathologic stage (p = 0.004), nodal involvement (p = 0.005), higher T stage (p = 0.030), and gender (p = 0.046). In LUSC, RRM2 was associated with age (p = 0.008), pathologic stage (p = 0.006), and N stage (p = 0.001). RRM1 showed no significant associations with stage-related parameters in either subtype. Correlation analyses revealed modest associations between RRM1 and multiple oncogenic drivers, whereas RRM2 showed stronger subtype-specific correlations, particularly with KRAS/BRAF in LUAD and CDKN2A/SOX2 in LUSC. Kaplan-Meier analysis demonstrated that high expression of both RRM1 and RRM2 was associated with poorer overall survival in LUAD, but not in LUSC. However, neither marker remained significant after adjustment for clinicopathological variables in multivariate analysis. CONCLUSION: RRM2 is associated with tumor progression in both NSCLC subtypes, while the prognostic associations of RRM1 and RRM2 are confined to LUAD. Although neither marker demonstrated independent prognostic significance in multivariate analysis, the findings support subtype-dependent roles of RNR components and highlight the potential biological and therapeutic relevance of nucleotide metabolism pathways in LUAD.

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Carcinoma, Non-Small-Cell LungLung NeoplasmsClinical RelevanceRibonucleoside Diphosphate ReductasePrognosisAdenocarcinoma of LungRNA, NeoplasmGene Expression Regulation, NeoplasticKaplan-Meier EstimateHumansMaleFemaleMiddle AgedAgedBiomarkers, TumorNSCLCRRM1RRM2TCGAComparative StudyJournal Article

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Se-Young Yun, Yunha Lee, Junchae Lee, Hyowon Hong, Jae-Ho Lee. 2026-07-07. Subtype-specific clinical significance of RRM1 and RRM2 expression in non-small cell lung cancer: a TCGA-based analysis.. https://doi.org/10.1007/s13258-026-01788-2

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