A Hypoxia and Immune Escape-Related Gene Signature for the Diagnosis of Prostate Cancer: An Integrated Bioinformatics Study.

Abstract

Prostate cancer remains a major global health concern for men, with hypoxia and immune escape being key drivers of tumor progression; however, no reliable diagnostic signature integrating both processes has been established for clinical use. In this study, we integrated RNA sequencing and microarray data from The Cancer Genome Atlas (TCGA)-PRAD, Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) datasets to identify hypoxia and immune escape-related genes (HIERGs). Through differential expression analysis, functional enrichment, and machine learning algorithms including Random Forest, SVM-RFE, and LASSO regression, we constructed a robust six-gene diagnostic signature comprising RBMS3, ALDH2, SLC7A11, FGFR2, GDF15, and NCAM1. The model demonstrated high diagnostic accuracy, with area under the curve (AUC) values exceeding 0.9 across all validation cohorts, as confirmed by calibration curves, decision curve analysis, and receiver operating characteristic curves. Functional analysis revealed significant enrichment in translation-related pathways and smooth muscle contraction, and the RiskScore was significantly associated with altered immune cell infiltration in the tumor microenvironment. Regulatory network analysis further uncovered potential upstream regulators and therapeutic agents targeting the key genes. In conclusion, we developed and validated a hypoxia and immune escape-related gene signature with robust diagnostic performance for prostate cancer. Exploratory grouping by the model-derived RiskScore revealed differences in pathway and immune infiltration patterns, suggesting an association between the signature and intratumoral molecular heterogeneity. These exploratory findings primarily serve to characterize the biological features related to the model and provide supplementary clues for understanding molecular alterations in prostate cancer; they should be interpreted with caution.