A PDCD4-Based Gene Expression Signature Predicts Overall Survival in Renal Cell Carcinoma: A TCGA-Based Discovery and External Validation Study

Renal cell carcinoma (RCC) is a heterogeneous disease with variable clinical outcomes. PDCD4 functions as a tumor suppressor, but its role in RCC prognosis remains unclear. We aimed to develop and validate a PDCD4-based gene expression signature for predicting overall survival in RCC. We analyzed RNA-seq data from 541 clear cell RCC patients in The Cancer Genome Atlas (TCGA-KIRC). We identified 100 genes (50 positively and 50 negatively correlated with PDCD4) to create a prognostic signature. Patients were stratified into high- and low-signature groups using median cutoff. Kaplan-Meier analysis and Cox regression models assessed prognostic value. External validation was performed in four independent cohorts: GSE29609, GSE73731, GSE53757, and GSE40435. Low PDCD4 signature scores were associated with significantly worse overall survival (HR = 2.17, 95% CI: 1.58-2.98, <i>p</i> < 0.001) and advanced tumor stage. The median survival difference was approximately 46 months. In multivariate analysis adjusting for age, gender, stage, and grade, the signature remained an independent prognostic factor (HR = 1.57, 95% CI: 1.11-2.22, <i>p</i> = 0.011). The signature demonstrated consistent prognostic patterns across platforms, with high signature scores associated with early-stage disease and low-grade tumors, and with potential clinical utility for risk stratification and treatment planning.