Background: GS is the most powerful prognostic predictor in prostate adenocarcinoma. However, the underlying reasons of disease aggressiveness as a function of GS are currently unknown. Herein we sought to investigate the corresponding differences in gene expression profiles of pts with prostate adenocarcinoma with respect to GS. Methods: In this IRB approved retrospective study, eligibility criteria included histologically confirmed prostate adenocarcinoma and available RNA sequencing results from treatment naïve primary prostate tissue by a CLIA certified lab. Pts were categorized into two cohorts: low GS (GS <8) and high GS (GS ≥ 8). The DEseq2 pipeline was used to analyze differentially expressed genes between the groups. The data included the Log2 fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differentially expressed gene. These results were subjected to Gene Set Enrichment software analysis (GSEA) in order to identify pathways enriched in each cohort. All bioinformatic analyses were undertaken using R v4.2. Results: Fifty-seven pts were eligible, of which 13 had a GS <8 and 44 had a GS ≥8. Tumor tissues with high GS had a significantly higher expression of genes involved in the immune pathways (e.g., inflammatory response, interferon-γ, allograft rejection, and interferon-α), epithelial-mesenchymal transition, KRAS signaling, E2F targets and G2M checkpoint (q for all <0.01). The genes involved in the androgen response pathway were significantly more expressed in biopsies with a low GS (q<0.01). Normalized enrichment scores are reported in the table. Differential individual gene expression profiles will be presented at the meeting. Conclusions: Pts with prostatic adenocarcinoma with a GS ≥8 demonstrated a different transcriptomic profile than those with a GS <8. Higher GS tumor tissues had upregulated of inflammatory, proliferation, and KRAS signaling. Lower GS tumor tissues had upregulated androgen signaling pathway. These hypothesis-generating results upon external validation may provide the rationale for personalized therapy in men with prostatic cancer.

*Negative NES = downregulation in low GS pts, Positive NES= upregulation in low GS pts.