Clinical Outcomes and Genomic Alterations in Gleason Score 10 Prostate Cancer

Background: Gleason score (GS) 10 prostate cancer (PC) is a highly aggressive localized disease. Despite advances in treating high-risk PC, the clinical outcomes and molecular underpinnings of GS 10 remain unclear. This study aimed to determine whether GS 10 PC has distinct clinical outcomes from other "high-risk" cancers (i.e., Gleason 8-9) and identify genomic alterations driving its aggressive phenotype. Methods: A retrospective review of The Cancer Genome Atlas database identified patients with GS 8-10 PC who underwent radical prostatectomy. Clinical factors were compared between GS 10 and GS 8-9 cohorts. Time to biochemical recurrence (BCR) was analyzed using Kaplan-Meier and Cox regression. RNA sequencing identified differentially expressed genes, and protein-protein interaction networks identified hub genes. Results: Of 192 patients, 13 (6.8%) had GS 10 PC. After median follow-up of 37.87 months, GS 10 status was associated with significantly lower time to BCR (AHR, 2.67; 95% CI, 1.18-6.02; p = 0.018) compared to GS 8-9. Multiple genes (e.g., RAD54L, FAAH, AATK, MAST2) showed higher alteration frequencies, and high expression of RAD54L, MAST2, and CCHCR1 correlated with shorter disease-free survival. Six overlapping hub genes (CD8A, CDC20, E2F1, IL10, TNF, VCAM1) were overexpressed in GS 10 tumors, reflecting key pathways in tumor progression. Conclusions: GS 10 PC confers inferior time to BCR and displays a distinct genomic landscape compared to GS 8-9 disease, highlighting the need for biomarker-driven therapeutic strategies. Further studies are needed to validate these genomic targets and improve management for this very high-risk population.