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

Authors

• Hui-Yi Lin, LSU Health Sciences Center - New OrleansFollow
• Indrani Sarkar, LSU Health Sciences Center - New OrleansFollow
• Harun Mazumder, LSU Health Sciences Center - New OrleansFollow
• Po-Yu Huang, Industrial Technology Research Institute, Hsinchu, Taiwan
• Kenneth R. Muir, University of Manchester, Oxford Road, Manchester, UK
• Johanna Schleutker, University of Turku, Turku, Finland
• Nora Pashayan, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK
• Jyotsna Batra, Queensland University of Technology, Brisbane, QLD, Australia
• David E. Neal, University of Oxford, Oxford, UK
• Henrik Grönberg, Karolinska Institutet, Stockholm, Sweden
• Sune F. Nielsen, Copenhagen University Hospital, Herlev, Denmark
• Børge G. Nordestgaard, Copenhagen University Hospital, Herlev, Denmark
• Catherine M. Tangen, Fred Hutchinson Cancer Research Center, Seattle, WA
• Robert J. MacInnis, Cancer Council Victoria, East Melbourne, VIC, Australia
• Alicja Wolk, Karolinska Institutet, Stockholm, Sweden
• Demetrius Albanes, National Cancer Institute, NIH, Bethesda, MD
• Ruth C. Travis, University of Oxford, Oxford, UK
• Janet L. Stanford, Fred Hutchinson Cancer Research Center, Seattle, WA
• Lorelei A. Mucci, Harvard T. H. Chan School of Public Health, Boston, MA
• Adam S. Kibel, Brigham and Women's Hospital, Boston, MA
• Olivier Cussenot, Tenon Hospital, Paris, France
• Sonja I. Berndt, National Cancer Institute, NIH, Bethesda, MD
• Stella Koutros, National Cancer Institute, NIH, Bethesda, MD
• Karina Dalsgaard Sørensen, Aarhus University Hospital, Aarhus N, Denmark
• Cezary Cybulski, Pomeranian Medical University, Szczecin, Poland
• Eli Marie Grindedal, Oslo University Hospital, Oslo, Norway
• Josef Hoegel, University Hospital Ulm, Ulm, Germany
• Christiane Maier, Humangenetik Tuebingen, Tuebingen, Germany
• Robert J. Hamilton, Princess Margaret Cancer Centre, Toronto, ON, Canada
• et al

Document Type

Article

Publication Date

5-28-2026

Publication Title

Communications Medicine

Abstract

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, 9×10, and 1.7×10 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) in the discovery set, and similar results were observed in validation sets (OR = 2.56, p = 4.3×10; OR = 2.07, p = 2.1×10).
CONCLUSIONS: These findings support PRS-KLK3int as a valuable tool for PCa severity stratification, especially in identifying extremely high-risk PCa patients.

First Page

1

Last Page

31

PubMed ID

42204244

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Lin, Hui-Yi; Sarkar, Indrani; Mazumder, Harun; Huang, Po-Yu; Muir, Kenneth R.; Schleutker, Johanna; Pashayan, Nora; Batra, Jyotsna; Neal, David E.; Grönberg, Henrik; Nielsen, Sune F.; Nordestgaard, Børge G.; Tangen, Catherine M.; MacInnis, Robert J.; Wolk, Alicja; Albanes, Demetrius; Travis, Ruth C.; Stanford, Janet L.; Mucci, Lorelei A.; Kibel, Adam S.; Cussenot, Olivier; Berndt, Sonja I.; Koutros, Stella; Sørensen, Karina Dalsgaard; Cybulski, Cezary; Grindedal, Eli Marie; Hoegel, Josef; Maier, Christiane; Hamilton, Robert J.; and al, et, "Polygenic risk score with KLK3 SNP-SNP interaction pairs for predicting prostate cancer aggressiveness" (2026). School of Public Health Faculty Publications. 589.
https://digitalscholar.lsuhsc.edu/soph_facpubs/589
10.1038/s43856-026-01645-z