Journal Article

DKFZ-2026-01275

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Polygenic risk score with KLK3 SNP-SNP interaction pairs for predicting prostate cancer aggressiveness.

Lin, H.-Y. ; Sarkar, I. ; Mazumder, H. ; Huang, P.-Y. ; Muir, K. R. ; Schleutker, J. ; Pashayan, N. ; Batra, J. ; Neal, D. E. ; Grönberg, H. ; Nielsen, S. F. ; Nordestgaard, B. G. ; Tangen, C. M. ; MacInnis, R. J. ; Wolk, A. ; Albanes, D. ; Travis, R. C. ; Stanford, J. L. ; Mucci, L. A. ; Kibel, A. S. ; Cussenot, O. ; Berndt, S. I. ; Koutros, S. ; Sørensen, K. D. ; Cybulski, C. ; Grindedal, E. M. ; Hoegel, J. ; Maier, C. ; Hamilton, R. J. ; Rosenstein, B. S. ; Vega, A. ; Kogevinas, M. ; Wiklund, F. ; Penney, K. L. ; Teixeira, M. R. ; Brenner, H.DKFZ* ; John, E. M. ; Kaneva, R. ; Logothetis, C. J. ; Neuhausen, S. L. ; De Ruyck, K. ; Ost, P. ; Gamulin, M. ; Usmani, N. ; Claessens, F. ; Castelao, J. E. ; Townsend, P. A. ; UKGPCS collaborators (Collaboration Author) ; BioResource, A. (Collaboration Author) ; Kote-Jarai, Z. ; Haiman, C. A. ; Eeles, R. A. ; consortium, P. (Collaboration Author) ; Park, J. Y. ; De Ruyck, K. (Contributor)

2026
Springer Nature [London]

Abstract: 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.

Note: epub

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Contributing Institute(s):

1. Klinische Epidemiologie der Krebsfrüherkennung (C070)
2. DKTK HD zentral (HD01)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2026

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; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Emerging Sources Citation Index ; Fees ; SCOPUS ; Web of Science Core Collection

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