DARS2 serves as an independent prognostic factor and participates in multiple biological processes in bladder...

Bladder urothelial carcinoma (BLCA) is a prevalent malignant tumor within the urinary system. Aspartyl-tRNA Synthetase 2, Mitochondrial (DARS2), a key enzyme involved in mitochondrial protein synthesis, is frequently overexpressed in various cancers and is associated with clinical stage. This study aims to explore the potential of DARS2 as a prognostic biomarker and therapeutic target in BLCA, with the ultimate goal of constructing a prognostic model.

Expression profiles of BLCA were obtained from The Cancer Genome Atlas (TCGA) database and the Genotype-Tissue Expression (GTEx) database, encompassing a total of 431 samples. Differential gene expression between tumor and normal tissues was first analyzed using the "limma" R package. To identify independent prognostic genes, we integrated various statistical and machine learning approaches, including univariate and multivariate Cox proportional hazards analyses, with variable selection performed via Cox proportional hazards regression with least absolute shrinkage and selection operator (LASSO). For the key gene DARS2, its expression differences were further analyzed using the edgeR method, followed by gene set enrichment analysis (GSEA) to explore associated functional pathways. Furthermore, immune cell infiltration was evaluated using multiple algorithms. The role of DARS2 in BLCA progression was systematically investigated by integrating analyses of gene mutations, tumor mutational burden (TMB), and survival outcomes. Finally, a prognostic model was constructed based on DARS2 expression levels and validated using the GSE13507 dataset from the Gene Expression Omnibus (GEO) database.

Based on the analytical methods described above, we observed that the expression of DARS2 messenger ribonucleic acid (mRNA) was significantly upregulated in BLCA tissues, and its elevated expression was independently associated with adverse patient prognosis. Immune infiltration analysis revealed that DARS2 expression exhibited a significant negative correlation with major immunologically active cells, such as CD4⁺ T cells and CD8⁺ T cells. In terms of genetic mutations, the somatic mutation rate of DARS2 in BLCA was 2.21%, whereas the receptor tyrosine kinase (RTK)/RAS GTPase signaling pathway (RTK-RAS) represented the most frequently mutated oncogenic pathway (72.97%). DARS2 expression showed a moderate positive correlation with TMB, with factors including advanced age, male sex, and higher tumor grade potentially contributing to elevated TMB. Survival analysis further demonstrated that patients with high DARS2 expression had significantly poorer outcomes in overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI). The risk-scoring model constructed based on DARS2 expression indicated that age, metastasis (M) stage, and risk score all served as independent prognostic factors for BLCA.

Comprehensive analysis suggests that DARS2 holds promise as a potential independent prognostic biomarker for patient stratification in BLCA and may serve as a viable target for the development of immunotherapeutic strategies.