Clinical data of GEO cohort.

BackgroundProstate cancer (PCa) patients with low prostate-specific antigen (PSA) levels can occasionally present high-grade disease. These patients often exhibit resistance to androgen deprivation therapy and have poor outcomes. The mechanisms underlying these observations remain poorly understood. This study aimed to investigate the clinical characteristics and potential gene expression mechanisms in this subgroup.Patients and MethodsClinical data from 365,558 PCa patients were categorized into four groups based on PSA levels and Gleason score (GS): Group 1 (PSA ≤ 2.5 ng/mL, GS 2.5 ng/mL, GS 2.5 ng/mL, GS ≥ 8). Clinical characteristics were compared using Kruskal-Wallis H and Pearson’s chi-squared tests. Competing-risks regression assessed prostate cancer-specific mortality (PCSM). Gene set enrichment analysis (GSEA) was performed on 219 PCa patients to compare Group A (PSA ≤ 2.5 ng/mL, GS ≥ 8) with Group B (PSA > 2.5 ng/mL, GS ≥ 8).ResultsGroup 2 had a significantly higher tumor stage (p ConclusionPCa patients with low PSA levels and high GS demonstrated an increased risk of PCSM. They were characterized by the aberrant activation of multiple signaling pathways. Targeted therapeutic strategies aimed at these pathways warrant further investigation for their potential to improve outcomes in this aggressive PCa subtype.