Young Aggressive Prostate Tumors Exhibit Increased Genomic Instability and an Exploratory RNA-CNA-Concordant...

Prostate cancer (PCa) is a highly heterogeneous disease, and the molecular features underlying differences in tumor aggressiveness remain incompletely understood. This study aimed to characterize the molecular differences between young aggressive (YA) and old indolence-associated (OI) prostate tumors using an integrative multi-omics approach. RNA sequencing, copy number alteration (CNA), and clinical data from The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) cohort were analyzed. YA tumors (age ≤ 58 years, Gleason score ≥ 8; n = 30) were compared with OI tumors (age ≥ 67 years, Gleason score ≤ 7; n = 41). YA tumors exhibited higher FGA and a greater nominal frequency of homozygous PTEN deletion, consistent with increased genomic instability. Transcriptomic analysis identified 1083 differentially expressed genes, whereas integrative RNA-CNA analysis prioritized 40 exploratory concordant genes, 35 of which showed copy-number loss-associated downregulation. Sensitivity analyses showed that 8 of 40 genes retained both the predefined FDR and effect-size criteria after tumor-purity adjustment, whereas only one gene retained both criteria after additional adjustment for pT and N. Functional enrichment and network analyses identified metabolic and homeostatic programs and a central interaction module within the original prioritized gene set. These findings provide exploratory hypotheses regarding molecular differences between the two predefined extreme phenotypes.