Young Aggressive Prostate Tumors Exhibit Increased Genomic Instability and an Exploratory RNA–CNA-Concordant Transcriptomic Pattern

Abstract

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.