Nature Communications (Nov 2024)
A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer
- 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,
- The IMPACT Study,
- Manuela Gago-Dominguez,
- The 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,
- The Practical Consortium,
- The Australian Prostate Cancer BioResource,
- Judith Clements,
- Jyotsna Batra
Affiliations
- Srilakshmi Srinivasan
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology
- Thomas Kryza
- Mater Research Institute - The University of Queensland, Translational Research Institute, Woolloongabba
- Nathalie Bock
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology
- Brian W. C. Tse
- Preclinical Imaging Facility, Translational Research Institute, Woolloongabba
- Kamil A. Sokolowski
- Preclinical Imaging Facility, Translational Research Institute, Woolloongabba
- Panchadsaram Janaththani
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology
- Achala Fernando
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology
- Leire Moya
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology
- Carson Stephens
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology
- Ying Dong
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology
- Joan Röhl
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology
- Saeid Alinezhad
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology
- Ian Vela
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology
- Joanna L. Perry-Keene
- Pathology Queensland, Sunshine Coast University Hospital Laboratory, Birtinya
- Katie Buzacott
- Pathology Queensland, Sunshine Coast University Hospital Laboratory, Birtinya
- Robert Nica
- TissueGnostics GmbH
- The IMPACT Study
- Manuela Gago-Dominguez
- Health Research Institute of Santiago de Compostela (IDIS), Galicia Public Foundation IDIS, SERGAS, Cancer Genetics and Epidemiology Group, Genomic Medicine Group
- The PROFILE Study Steering Committee
- Johanna Schleutker
- Institute of Biomedicine, Kiinamyllynkatu 10, FI-20014 University of Turku
- Christiane Maier
- Humangenetik Tuebingen
- Kenneth Muir
- Division of Population Health, Health Services Research and Primary Care, University of Manchester
- Catherine M. Tangen
- SWOG Statistical Center, Fred Hutchinson Cancer Research Center
- Henrik Gronberg
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute
- Nora Pashayan
- Department of Applied Health Research, University College London
- Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH
- Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institutet
- Janet L. Stanford
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center
- Sonja I. Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH
- Lorelei A. Mucci
- Department of Epidemiology, Harvard T. H. Chan School of Public Health
- Stella Koutros
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH
- Olivier Cussenot
- CeRePP, Tenon Hospital
- Karina Dalsgaard Sorensen
- Department of Molecular Medicine, Aarhus University Hospital
- Eli Marie Grindedal
- Department of Medical Genetics, Oslo University Hospital
- Ruth C. Travis
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford
- Christopher A. Haiman
- Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center
- Robert J. MacInnis
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne
- Ana Vega
- Fundación Pública Galega Medicina Xenómica
- Fredrik Wiklund
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute
- David E. Neal
- Nuffield Department of Surgical Sciences, University of Oxford
- Manolis Kogevinas
- ISGlobal, Barcelona Institute for Global Health
- Kathryn L. Penney
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital/Harvard Medical School
- Børge G. Nordestgaard
- Faculty of Health and Medical Sciences, University of Copenhagen
- Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ)
- Esther M. John
- Departments of Epidemiology & Population Health and of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine
- Marija Gamulin
- School of Medicine, University of Zagreb
- Frank Claessens
- Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine
- Olle Melander
- Department of Clinical Sciences Malmö, Lund University
- Anders Dahlin
- Department of Clinical Sciences Malmö, Lund University
- Pär Stattin
- Institute of Environmental Medicine, Karolinska Institutet
- Göran Hallmans
- Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University
- Christel Häggström
- The Biobank Research Unit, Umeå University
- Robert Johansson
- The Biobank Research Unit, Umeå University
- Elin Thysell
- Department of Medical Biosciences, Pathology, Umeå University
- Ann-Charlotte Rönn
- Translational Analysis in Molecular Medicine, Karolinska University Hospital
- Weiqiang Li
- Icahn Institute for Data Science and Genome Technology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
- Nigel Brown
- Department of Chemical Pathology, Pathology Queensland, Princess Alexandra Hospital, Woolloongabba
- Goce Dimeski
- Department of Chemical Pathology, Pathology Queensland, Princess Alexandra Hospital, Woolloongabba
- Benjamin Shepherd
- Department of Anatomical Pathology, Pathology Queensland, Princess Alexandra Hospital, Woolloongabba
- Tokhir Dadaev
- The Institute of Cancer Research
- Mark N. Brook
- The Institute of Cancer Research
- Amanda B. Spurdle
- Molecular Cancer Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Herston
- Ulf-Håkan Stenman
- Department of Clinical Chemistry and Haematology, University of Helsinki
- Hannu Koistinen
- Department of Clinical Chemistry and Haematology, University of Helsinki
- Zsofia Kote-Jarai
- The Institute of Cancer Research
- Robert J. Klein
- Icahn Institute for Data Science and Genome Technology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
- Hans Lilja
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center
- Rupert C. Ecker
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology
- Rosalind Eeles
- The Institute of Cancer Research
- The Practical Consortium
- The Australian Prostate Cancer BioResource
- Judith Clements
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology
- Jyotsna Batra
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology
- DOI
- https://doi.org/10.1038/s41467-024-52472-6
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 21
Abstract
Abstract 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.
