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. 2025 Mar 21;17(7):1055.
doi: 10.3390/cancers17071055.

Clinical Outcomes and Genomic Alterations in Gleason Score 10 Prostate Cancer

Luke W Chen  1 , Yetkin Tuac  2 , Sophia Li  1 , Jonathan E Leeman  1 , Martin T King  1 , Peter F Orio  1 , Paul L Nguyen  1 , Anthony V D'Amico  1 , Cagdas Aktan  3 , Mutlay Sayan  1
Affiliations

Clinical Outcomes and Genomic Alterations in Gleason Score 10 Prostate Cancer

Luke W Chen et al. Cancers (Basel). .

Abstract

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.

Keywords: Gleason score; biomarkers; disease-free survival; gene expression profiling; prostate cancer.

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Conflict of interest statement

The authors declare that the research was conducted without any commercial or financial relationships that could be construed as potential conflicts of interest.

Figures

Figure 1
Figure 1
Covariate-adjusted estimates of time to biochemical recurrence stratified by Gleason score.
Figure 2
Figure 2
Comparison of genomic alterations between Gleason score (GS) 10 and GS 8–9. The genes shown are those with significant differences, defined by p-values < 0.05.
Figure 3
Figure 3
Protein–protein interaction network analysis of differentially expressed genes in patients with GS 10. (A) The module with the highest molecular complex detection score (17.674). The hub genes were identified using degree (B), betweenness (C), and closeness (D) algorithms in the Cytohubba plug-in of the Cytoscape software v3.10.1. The nodes represent proteins, and the edges represent the predicted functional associations. Red color represents the highest degree of connectivity for a protein, while yellow indicates the lowest. (E) The Venn diagram illustrates the overalapping hub genes identified through the MCODE and Cytohubba analyses using the degree, betweenness, and closeness algorithms.
Figure 4
Figure 4
The mRNA expression level of the overlapping hub genes. Abbreviations: GS, Gleason score.
Figure 5
Figure 5
The disease-free survival (DFS) based on the DAGs (A) and the hub genes (B). The DFS curve is represented by the solid line, bound by dotted lines representing the 95% confidence interval. Blue lines represent cohorts with lower expression of a specific gene of interest, and red lines represent cohorts with higher expression of that gene. The hazard ratio (HR) measures the relative risk of an event between the high- and low-expression groups, while p(HR) assesses its statistical significance, with values below 0.05 indicating a meaningful difference. A log-rank test p-value < 0.05 was considered statistically significant.
Figure 5
Figure 5
The disease-free survival (DFS) based on the DAGs (A) and the hub genes (B). The DFS curve is represented by the solid line, bound by dotted lines representing the 95% confidence interval. Blue lines represent cohorts with lower expression of a specific gene of interest, and red lines represent cohorts with higher expression of that gene. The hazard ratio (HR) measures the relative risk of an event between the high- and low-expression groups, while p(HR) assesses its statistical significance, with values below 0.05 indicating a meaningful difference. A log-rank test p-value < 0.05 was considered statistically significant.
Figure 6
Figure 6
Gene ontology (GO) and pathway enrichment analysis of differentially expressed hub genes. The x-axis represents the number of enriched differentially expressed hub genes, and the y-axis shows the enriched GO and KEGG pathway terms. Green bars represent molecular function, blue bars represent cellular components, red bars represent biological processes, and yellow bars represent KEGG pathways.
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