Polygenic risk score with KLK3 SNP-SNP interaction pairs for predicting prostate cancer aggressiveness

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.

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.

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).

These findings support PRS-KLK3int as a valuable tool for PCa severity stratification, especially in identifying extremely high-risk PCa patients.