Background: Prostate cancer (PCa) is heterogeneous, making risk stratification essential for clinical care. Although polygenic risk scores (PRSs) with main effects of single-nucleotide polymorphisms (SNPs) can help identify individuals at high risk before biological and clinical onset, a PRS for predicting PCa aggressiveness remains underdeveloped. The KLK3, which encodes prostate-specific antigen (PSA), is linked to PCa aggressiveness. Recent findings on KLK3 SNP-SNP interactions show promise for predicting PCa aggressiveness. The objective of this study is to develop a PRS (PRS-KLK3int) by examining KLK3 SNP-SNP interaction pairs.
Methods: The PRS-KLK3int was developed based on a discovery set (10,836 PCa patients) and two validation sets with 14,348 and 16,584 patients of European ancestry. A total of 3145 SNP pairs and two published PRSs were evaluated.
Results: This study developed a PRS-KLK3int with 284 SNPs, combining an existing PRS with 270 SNPs and 12 SNP-SNP interaction pairs with 15 SNPs (one overlapped). All these 12 pairs were involved with at least one SNP from KLK3. The PRS-KLK3int outperformed two existing PRSs in predicting PCa aggressiveness (p-values: 3.5×10-18, 9×10-14, and 1.7×10-20 for the three sets). It effectively distinguished high-risk from low-risk groups across all datasets. The top 1% high-risk group had a higher prevalence of PCa aggressiveness than the middle 50% group (45.5% vs. 25.9%, OR = 2.38, p = 2.2×10-5) in the discovery set, and similar results were observed in validation sets (OR = 2.56, p = 4.3×10-6; OR = 2.07, p = 2.1×10-5).
Conclusions: These findings support PRS-KLK3int as a valuable tool for PCa severity stratification, especially in identifying extremely high-risk PCa patients.
Prostate cancer (PCa) can range from mild to very aggressive, so predicting severity early is important. Genetic tools called polygenic risk scores (PRS) can estimate risk before biological signs appear, helping doctors act sooner. Current PRSs don’t predict aggressiveness well. This study developed a new score, PRS-KLK3int, using genetic interactions in the KLK3 gene, which is linked to prostate-specific antigen (PSA) and cancer severity. Researchers analyzed data from over 10,000 patients and confirmed results in two large groups. PRS-KLK3int, built from 284 genetic markers, outperformed older scores in identifying aggressive cancer. PCa patients in the top 1% risk group were about twice as likely to have aggressive cancer. This tool could guide early screening and prevention before PCa progression starts.
© 2026. The Author(s).