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.
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.
Communications medicine. 2026 May 28 [Epub ahead of print]
Hui-Yi Lin, Indrani Sarkar, Harun Mazumder, Po-Yu Huang, Kenneth R Muir, Johanna Schleutker, Nora Pashayan, Jyotsna Batra, David E Neal, Henrik Grönberg, Sune F Nielsen, Børge G Nordestgaard, Catherine M Tangen, Robert J MacInnis, Alicja Wolk, Demetrius Albanes, Ruth C Travis, Janet L Stanford, Lorelei A Mucci, Adam S Kibel, Olivier Cussenot, Sonja I Berndt, Stella Koutros, Karina Dalsgaard Sørensen, Cezary Cybulski, Eli Marie Grindedal, Josef Hoegel, Christiane Maier, Robert J Hamilton, Barry S Rosenstein, Ana Vega, Manolis Kogevinas, Fredrik Wiklund, Kathryn L Penney, Manuel R Teixeira, Hermann Brenner, Esther M John, Radka Kaneva, Christopher J Logothetis, Susan L Neuhausen, Kim De Ruyck, Piet Ost, Marija Gamulin, Nawaid Usmani, Frank Claessens, Jose Esteban Castelao, Paul A Townsend, UKGPCS collaborators , APCB BioResource (Australian Prostate Cancer BioResource) , Zsofia Kote-Jarai, Christopher A Haiman, Rosalind A Eeles, PRACTICAL consortium , Jong Y Park
Biostatistics and Data Science Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA. ., Biostatistics and Data Science Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA., Information and Communications Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan., Division of Population Health, Health Services Research and Primary Care, University of Manchester, Oxford Road, Manchester, UK., Institute of Biomedicine, University of Turku, Turku, Finland., Department of Public Health & Primary Care, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK., School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia., Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK., Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden., Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark., SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Cancer Epidemiology Division, Cancer Council Victoria, East Melbourne, VIC, Australia., Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden., Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA., Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK., Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA., Division of Urologic Surgery, Brigham and Women's Hospital, Boston, MA, USA., Sorbonne Universite, Tenon Hospital, Paris, France., Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark., International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland., Department of Medical Genetics, Oslo University Hospital, Oslo, Norway., Institute for Human Genetics, University Hospital Ulm, Ulm, Germany., Humangenetik Tuebingen, Tuebingen, Germany., Dept. of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada., Department of Radiation Oncology and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Fundación Pública Galega Medicina Xenómica, Santiago de Compostela, Spain., ISGlobal, Barcelona, Spain., Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, USA., Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center, Porto, Portugal., Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany., Departments of Epidemiology & Population Health and of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA., Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, Sofia, Bulgaria., The University of Texas M. D. Anderson Cancer Center, Department of Genitourinary Medical Oncology, Houston, TX, USA., Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA., Ghent University, Faculty of Medicine and Health Sciences, Basic Medical Sciences, Gent, Belgium., Department of Radiotherapy, Ghent University Hospital, Gent, Belgium., Department of Oncology, University Hospital Centre Zagreb, University of Zagreb, School of Medicine, Zagreb, Croatia., Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada., Department of Cellular and Molecular Medicine, Molecular Endocrinology Laboratory, KU Leuven, Belgium., Genetic Oncology Unit, CHUVI Hospital, Complexo Hospitalario Universitario de Vigo, Instituto de Investigación Biomédica Galicia Sur (IISGS), Vigo (Pontevedra), Spain., Division of Cancer Sciences, Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research Centre, Health Innovation Manchester, University of Manchester, Manchester, UK., The Institute of Cancer Research, London, UK., Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA., Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.