Abstract
Background
Lung adenocarcinoma (LUAD) is a major subtype of nonsmall cell lung cancer with substantial clinical heterogeneity. Nucleotide metabolism‐related genes may contribute to tumor progression and immune microenvironment remodeling, but their prognostic value in LUAD remains incompletely defined.
Methods
Bulk transcriptomic and clinical data from TCGA‐LUAD and GEO datasets were analyzed to define nucleotide metabolism‐related molecular subtypes and construct a subtype‐derived prognostic signature from subtype‐associated differentially expressed genes. The TCGA‐LUAD cohort was randomly divided into a training cohort and an internal validation cohort at a ratio of 4:1. Univariate Cox regression and LASSO regression analyses were performed exclusively in the training cohort to construct the prognostic signature, which was subsequently evaluated in the internal validation cohort and the independent external bulk‐transcriptomic GSE30219 cohort. Consensus clustering, survival analysis, ROC analysis, immune infiltration analysis, mutation analysis, predicted drug sensitivity analysis, and exploratory single‐cell transcriptomic characterization were also performed. In vitro assays were used to evaluate the functional relevance of IRX5 in A549 LUAD cells.
Results
A total of 152 subtype‐associated differentially expressed genes were identified from pairwise comparisons among the three nucleotide metabolism‐related molecular subtypes, and a nine‐gene subtype‐derived prognostic signature consisting of SEMA3C, PTTG1, BARX1, CDCA5, TGFBI, MKI67, TSPAN7, GADD45G, and IRX5 was constructed. The signature stratified LUAD patients into high‐ and low‐risk groups with distinct overall survival and remained an independent prognostic factor. The risk score was associated with TP53 mutation frequency, immune cell infiltration patterns, cytokine‐ and exhaustion‐related scores, and predicted IC50 values for several anticancer agents. Single‐cell analysis revealed cell‐type–specific expression patterns of signature genes and potential intercellular communication features in the LUAD microenvironment. Functionally, IRX5 knockdown inhibited proliferation, migration, and invasion, promoted apoptosis, and induced G0/G1 cell‐cycle arrest in A549 cells.
Conclusion
This study identified a subtype‐derived prognostic signature based on nucleotide metabolism‐related molecular classification with potential value for LUAD risk stratification and provided exploratory evidence linking signature genes to tumor immune features and cellular phenotypes.