Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility in men. The non-synonymous KLK3 single nucleotide polymorphism (SNP), rs17632542 (c.536 T > C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity mediates prostate cancer pathogenesis. The 'Thr' PSA variant leads to small subcutaneous tumours, supporting reduced prostate cancer risk. However, 'Thr' PSA also displays higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterisation of this PSA variant demonstrates markedly reduced proteolytic activity that correlates with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele have reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes.
Nature communications. 2024 Nov 06*** epublish ***
Srilakshmi Srinivasan, Thomas Kryza, Nathalie Bock, Brian W C Tse, Kamil A Sokolowski, Panchadsaram Janaththani, Achala Fernando, Leire Moya, Carson Stephens, Ying Dong, Joan Röhl, Saeid Alinezhad, Ian Vela, Joanna L Perry-Keene, Katie Buzacott, Robert Nica, IMPACT Study , Manuela Gago-Dominguez, PROFILE Study Steering Committee , Johanna Schleutker, Christiane Maier, Kenneth Muir, Catherine M Tangen, Henrik Gronberg, Nora Pashayan, Demetrius Albanes, Alicja Wolk, Janet L Stanford, Sonja I Berndt, Lorelei A Mucci, Stella Koutros, Olivier Cussenot, Karina Dalsgaard Sorensen, Eli Marie Grindedal, Ruth C Travis, Christopher A Haiman, Robert J MacInnis, Ana Vega, Fredrik Wiklund, David E Neal, Manolis Kogevinas, Kathryn L Penney, Børge G Nordestgaard, Hermann Brenner, Esther M John, Marija Gamulin, Frank Claessens, Olle Melander, Anders Dahlin, Pär Stattin, Göran Hallmans, Christel Häggström, Robert Johansson, Elin Thysell, Ann-Charlotte Rönn, Weiqiang Li, Nigel Brown, Goce Dimeski, Benjamin Shepherd, Tokhir Dadaev, Mark N Brook, Amanda B Spurdle, Ulf-Håkan Stenman, Hannu Koistinen, Zsofia Kote-Jarai, Robert J Klein, Hans Lilja, Rupert C Ecker, Rosalind Eeles, Practical Consortium , Australian Prostate Cancer BioResource , Judith Clements, Jyotsna Batra
School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland (QLD), Australia., Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, Australia., Preclinical Imaging Facility, Translational Research Institute, Woolloongabba, Brisbane, QLD, Australia., Pathology Queensland, Sunshine Coast University Hospital Laboratory, Birtinya, Sunshine Coast, QLD, Australia., TissueGnostics GmbH, Vienna, Austria., Health Research Institute of Santiago de Compostela (IDIS), Galicia Public Foundation IDIS, SERGAS, Cancer Genetics and Epidemiology Group, Genomic Medicine Group, Santiago de Compostela, Spain., Institute of Biomedicine, Kiinamyllynkatu 10, FI-20014 University of Turku, Turku, Finland., Humangenetik Tuebingen, Paul-Ehrlich-Str 23, D-72076, Tuebingen, Germany., Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester, M13 9PL, UK., SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Department of Medical Epidemiology and Biostatistics, Karolinska Institute, SE-171 77, Stockholm, Sweden., Department of Applied Health Research, University College London, London, WC1E 7HB, UK., Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, 20892, USA., Institute of Environmental Medicine, Karolinska Institutet, 177 77, Stockholm, Sweden., Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA., Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA., CeRePP, Tenon Hospital, F-75020, Paris, France., Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensen Boulevard 99, 8200, Aarhus N, Denmark., Department of Medical Genetics, Oslo University Hospital, 0424, Oslo, Norway., Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK., Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA., Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Grattan Street, Parkville, VIC, 3010, Australia., Fundación Pública Galega Medicina Xenómica, Santiago de Compostela, 15706, Spain., Nuffield Department of Surgical Sciences, University of Oxford, Oxford, England., ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain., Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, 02115, USA., Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark., Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany., Departments of Epidemiology & Population Health and of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94304, USA., School of Medicine, University of Zagreb, Salata 3, 10 000, Zagreb, Croatia., Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, BE-3000, Belgium., Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden., Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Umeå, Sweden., The Biobank Research Unit, Umeå University, Umeå, Sweden., Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden., Translational Analysis in Molecular Medicine, Karolinska University Hospital, Huddinge, Sweden., Icahn Institute for Data Science and Genome Technology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Department of Chemical Pathology, Pathology Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, QLD, Australia., Department of Anatomical Pathology, Pathology Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, QLD, Australia., The Institute of Cancer Research, London, SM2 5NG, UK., Molecular Cancer Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD, Australia., Department of Clinical Chemistry and Haematology, University of Helsinki, Helsinki, Finland., Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland (QLD), Australia. .