A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer
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.
Authors
- Marija Gamulin (ORCID: https://orcid.org/0000-0003-2431-7910)
- Maria Elena Martinez
- Elizabeth Bancroft (ORCID: https://orcid.org/0000-0002-5482-5660)
- Phyllis J. Goodman (ORCID: https://orcid.org/0000-0001-9660-7074)
- Xin Gao (ORCID: https://orcid.org/0000-0002-5160-1725)
- J Melia
- Sarah J. Lewis (ORCID: https://orcid.org/0000-0003-4311-6890)
- Steve Hazell
- Steven Joniau (ORCID: https://orcid.org/0000-0003-3195-9890)
- Peter Kraft
- Melissa Papargiris
- Anders Dahlin
- Ben Schöttker (ORCID: https://orcid.org/0000-0002-1217-4521)
- Pär Stattin (ORCID: https://orcid.org/0000-0002-8306-0687)
- Rosalind A. Eeles (ORCID: https://orcid.org/0000-0002-3698-6241)
- Teuvo L.J. Tammela (ORCID: https://orcid.org/0000-0002-3529-4649)
- Freddie C. Hamdy (ORCID: https://orcid.org/0000-0003-2627-2154)
- Géraldine Cancel‐Tassin (ORCID: https://orcid.org/0000-0002-9583-6382)
- Leire Moya (ORCID: https://orcid.org/0000-0001-9127-344X)
- Robert J. Klein (ORCID: https://orcid.org/0000-0003-3539-5391)
- Hannu Koistinen (ORCID: https://orcid.org/0000-0003-0926-3109)
- Angela Wood (ORCID: https://orcid.org/0000-0002-8640-0245)
- Ian M. Thompson (ORCID: https://orcid.org/0000-0003-0833-952X)
- Nora Pashayan (ORCID: https://orcid.org/0000-0003-0843-2468)
- Justyna Sobczak
- Christos Mikropoulos (ORCID: https://orcid.org/0000-0001-8070-2851)
- Goce Dimeski (ORCID: https://orcid.org/0000-0002-0228-0742)
- Naami Mcaddy
- Jose E. Castelao (ORCID: https://orcid.org/0000-0001-7110-1376)
- Joan Röhl (ORCID: https://orcid.org/0000-0002-6872-8730)
- Wayne D. Tilley (ORCID: https://orcid.org/0000-0003-1893-2626)
- Eli Marie Grindedal
- Manuela Gago-Domínguez (ORCID: https://orcid.org/0000-0001-6713-4351)
- Henrik Grönberg (ORCID: https://orcid.org/0000-0002-1073-2753)
- Tokhir Dadaev (ORCID: https://orcid.org/0000-0002-8268-0438)
- William J. Blot (ORCID: https://orcid.org/0000-0002-5581-5069)
- Jan Lubiński (ORCID: https://orcid.org/0000-0003-2931-3003)
- Mohnish Suri (ORCID: https://orcid.org/0000-0001-9037-701X)
- Tobias Nordström (ORCID: https://orcid.org/0000-0003-4915-7546)
- Rahamthulla S. Shaik (ORCID: https://orcid.org/0000-0002-4174-4490)
- Manolis Kogevinas (ORCID: https://orcid.org/0000-0002-9605-0461)
- Jana McHugh
- R. R. Hall (ORCID: https://orcid.org/0009-0002-5334-9460)
- David P. Dearnaley (ORCID: https://orcid.org/0000-0002-3954-2806)
- Vincent J. Gnanapragasam (ORCID: https://orcid.org/0000-0003-4722-4207)
- Kathryn Myhill
- Syed Arshad Hussain (ORCID: https://orcid.org/0000-0002-3298-6260)
- Robert N. Hoover
- Demetrius Albanes (ORCID: https://orcid.org/0000-0001-8330-4293)
- Fredrik Wiklund (ORCID: https://orcid.org/0000-0002-4623-0544)
- Katie Buzacott
- Judith A. Clements (ORCID: https://orcid.org/0000-0001-6026-1964)
- Anne-Marie Borges Da Silva
- Anthony Chamberlain
- Jeri Kim (ORCID: https://orcid.org/0000-0001-6254-7755)
- Anssi Auvinen (ORCID: https://orcid.org/0000-0003-1125-4818)
- Ana Vega (ORCID: https://orcid.org/0000-0002-7416-5137)
- Kenneth Muir (ORCID: https://orcid.org/0000-0001-6429-988X)
- Ruth C. Travis (ORCID: https://orcid.org/0000-0002-9571-0763)
- F. Ménégaux (ORCID: https://orcid.org/0000-0003-3363-6411)
- Davor Lessel (ORCID: https://orcid.org/0000-0003-4496-244X)
- Robert Johansson (ORCID: https://orcid.org/0000-0001-5547-3866)
- Barry S. Rosenstein (ORCID: https://orcid.org/0000-0002-3149-3237)
- Matthew Hogben (ORCID: https://orcid.org/0000-0003-3416-345X)
- Rupert Ecker (ORCID: https://orcid.org/0000-0002-1095-8592)
- Tomislav Kuliš (ORCID: https://orcid.org/0000-0002-0895-5691)
- Jeff Bamber
- Frank Claessens (ORCID: https://orcid.org/0000-0002-8676-7709)
- Edward L. Giovannucci (ORCID: https://orcid.org/0000-0002-6123-0219)
- Alexander Dias (ORCID: https://orcid.org/0000-0002-1284-6623)
- Jacob Merson (ORCID: https://orcid.org/0000-0002-6813-6532)
- Olivier Cussenot (ORCID: https://orcid.org/0000-0002-9912-0533)
- Antonis C. Antoniou (ORCID: https://orcid.org/0000-0001-9223-3116)
- Alison M. Dunning (ORCID: https://orcid.org/0000-0001-6651-7166)
- Stephanie J. Weinstein (ORCID: https://orcid.org/0000-0002-3834-1535)
- Aslam Sohaib (ORCID: https://orcid.org/0000-0001-7774-9886)
- Laura Fachal (ORCID: https://orcid.org/0000-0002-7256-9752)
- Roger Laughlin Milne (ORCID: https://orcid.org/0000-0001-5764-7268)
- Fredrick R. Schumacher (ORCID: https://orcid.org/0000-0002-3073-7463)
- Sue Moss (ORCID: https://orcid.org/0000-0001-8463-3160)
- Thomas Kryza (ORCID: https://orcid.org/0000-0003-1668-8551)
- Stella Koutros (ORCID: https://orcid.org/0000-0001-5294-5485)
- Brian Wan-Chi Tse (ORCID: https://orcid.org/0000-0002-5982-8369)
- Jyotsna Batra (ORCID: https://orcid.org/0000-0003-4646-6247)
- Josef Hoegel
- Markus Aly (ORCID: https://orcid.org/0000-0002-7602-9198)
- Chris Ogden (ORCID: https://orcid.org/0000-0002-0757-6366)
- Ali Amin Al Olama (ORCID: https://orcid.org/0000-0002-7178-3431)
- Lorelei Ann Mucci (ORCID: https://orcid.org/0000-0002-2551-4927)
- Lisa M. Butler (ORCID: https://orcid.org/0000-0003-2698-3220)
- Esther M. John (ORCID: https://orcid.org/0000-0003-3259-8003)
- Ulf‐Håkan Stenman (ORCID: https://orcid.org/0000-0002-2695-3454)
- Lucy Side
- Zsofia Kote‐Jarai (ORCID: https://orcid.org/0000-0002-6329-5155)
- Xin Sheng (ORCID: https://orcid.org/0000-0002-6844-2740)
- Mark N. Brook (ORCID: https://orcid.org/0000-0002-8969-2378)
- Loı̈c Le Marchand (ORCID: https://orcid.org/0000-0001-5013-980X)
- Lisa Cannon‐Albright (ORCID: https://orcid.org/0000-0003-2602-3668)
- Janet L. Stanford (ORCID: https://orcid.org/0000-0001-5062-4784)
- Thomas Schnoeller (ORCID: https://orcid.org/0000-0003-3617-1111)
- Hans Lilja (ORCID: https://orcid.org/0000-0001-5871-7846)
- Nathalie Bock (ORCID: https://orcid.org/0000-0001-9331-4698)
- Saeid Alinezhad (ORCID: https://orcid.org/0000-0002-1610-4520)
- Audrey Ardern‐Jones
- Robert Nica
- Timothy J. Key (ORCID: https://orcid.org/0000-0003-2294-307X)
- Susan L. Neuhausen (ORCID: https://orcid.org/0000-0001-5053-0390)
- Joanna Perry‐Keene (ORCID: https://orcid.org/0000-0001-6276-8144)
- Martin Andreas Røder (ORCID: https://orcid.org/0000-0002-0019-5333)
- Anita Mitra
- Christopher A. Haiman (ORCID: https://orcid.org/0000-0002-0097-9971)
- Yong‐Jie Lu (ORCID: https://orcid.org/0000-0001-6174-6621)
- Nigel N. Brown (ORCID: https://orcid.org/0000-0001-5437-6802)
- Adam S. Kibel
- Benjamin Shepherd
- Clare Moynihan
- Antonio Gómez‐Caamaño (ORCID: https://orcid.org/0000-0002-9773-4590)
- Christel Häggström (ORCID: https://orcid.org/0000-0001-6808-4405)
- Netty Kinsella (ORCID: https://orcid.org/0000-0003-3807-9503)
- Trinidad Dierssen‐Sotos (ORCID: https://orcid.org/0000-0002-6127-0077)
- Robert J. MacInnis (ORCID: https://orcid.org/0000-0002-1627-5047)
- Penny Wilson (ORCID: https://orcid.org/0009-0005-0277-4100)
- Holly Ní Raghallaigh (ORCID: https://orcid.org/0000-0003-0268-4138)
- Mitchell J. Machiela (ORCID: https://orcid.org/0000-0001-6538-9705)
- Ian Vela (ORCID: https://orcid.org/0000-0002-5659-0893)
- Martin Eklund (ORCID: https://orcid.org/0000-0001-5032-5266)
- Carson Stephens
- Johanna Schleutker (ORCID: https://orcid.org/0000-0002-1863-0305)
- Sara Benlloch
- Sue A. Ingles (ORCID: https://orcid.org/0000-0001-9181-8745)
- Stig E. Bojesen (ORCID: https://orcid.org/0000-0002-4061-4133)
- Hein Vincent Stroomberg (ORCID: https://orcid.org/0000-0002-7293-9506)
- Artitaya Lophatananon (ORCID: https://orcid.org/0000-0003-0550-4657)
- J. Schalken
- Alison Falconer
- Lucia D’Mello
- Hermann Brenner (ORCID: https://orcid.org/0000-0002-6129-1572)
- Elena Castro (ORCID: https://orcid.org/0000-0002-3691-6454)
- Renea A. Taylor (ORCID: https://orcid.org/0000-0003-2609-2380)
- Judith Offman (ORCID: https://orcid.org/0000-0001-5604-1635)
- Børge Grønne Nordestgaard (ORCID: https://orcid.org/0000-0002-1954-7220)
- Geoffrey J. Lindeman (ORCID: https://orcid.org/0000-0001-9386-2416)
- Eva McGrowder (ORCID: https://orcid.org/0009-0006-3988-9494)
- Gemma Castaño‐Vinyals (ORCID: https://orcid.org/0000-0003-4468-1816)
- Catharine West (ORCID: https://orcid.org/0000-0002-0839-3449)
- Vincent Khoo (ORCID: https://orcid.org/0000-0002-0763-6832)
- Sibel Saya (ORCID: https://orcid.org/0000-0002-4796-6852)
- Antonio Alcaraz (ORCID: https://orcid.org/0000-0003-2612-5250)
- Ann‐Charlotte Rönn
- Karina D. Sørensen (ORCID: https://orcid.org/0000-0002-4902-5490)
- Gad Rennert (ORCID: https://orcid.org/0000-0002-8512-068X)
- Paul A. Townsend
- Lovise Mæhle
- Kamil A. Sokolowski (ORCID: https://orcid.org/0000-0003-3679-2321)
- Janaththani Panchadsaram (ORCID: https://orcid.org/0000-0002-5579-2661)
- Lisa Glen Horvath (ORCID: https://orcid.org/0000-0001-6842-9223)
- Elin Thysell
- Gerald L. Andriole (ORCID: https://orcid.org/0000-0003-4033-2352)
- Laura E. Beane Freeman (ORCID: https://orcid.org/0000-0003-1294-4124)
- Olle Melander (ORCID: https://orcid.org/0000-0002-2581-484X)
- D. Gareth Evans (ORCID: https://orcid.org/0000-0002-8482-5784)
- Nening M. Dennis (ORCID: https://orcid.org/0000-0001-9488-3470)
- Alicja Wolk (ORCID: https://orcid.org/0000-0001-7387-6845)
- Alan Thompson (ORCID: https://orcid.org/0000-0003-1400-0098)
- Diana Keating
- Gail P. Risbridger (ORCID: https://orcid.org/0000-0003-3089-4028)
- Srilakshmi Srinivasan (ORCID: https://orcid.org/0000-0002-3900-1727)
- Ying Wang (ORCID: https://orcid.org/0000-0002-1241-6252)
- Weiqiang Li (ORCID: https://orcid.org/0000-0002-9941-4355)
- Göran Hallmans (ORCID: https://orcid.org/0000-0001-9581-3845)
- Christopher S. Foster (ORCID: https://orcid.org/0000-0003-4925-6800)
- Ying Dong (ORCID: https://orcid.org/0000-0003-4135-932X)
- David Nicol (ORCID: https://orcid.org/0000-0003-0107-6990)
- Niclas Håkansson (ORCID: https://orcid.org/0000-0001-7673-5554)
- Diana Eccles
- Michael Borre
- Melissa C. Southey
- Kim De Ruyck
- Amanda B. Spurdle (ORCID: https://orcid.org/0000-0003-1337-7897)
- Nawaid Usmani
- Jong Y. Park
- Chris Bangma
- David E. Neal
- Lisa F. Newcomb
- Sara Lindström
- Michael C. Perry
- Catherine M. Tangen
- Meir J. Stampfer
- Anne-Maree Haynes
- Kay-Tee Khaw
- Paul D.P. Pharoah
- Sarah Thomas
- A. Millner
- Christopher Woodhouse
- Paul Cathcart
- Robert J. Hamilton
- S. N. Thibodeau
- Jeremy Clark
- Sune F. Nielsen
- Elizabeth Page
- Bernd Holleczek
- Azad Razack
- Achala Fernando
- Colin Cooper
- Christiane Maier
- Stephen Chanock
- Kathryn L. Penney
- N. van As
- Hardev Pandha
- Jórunn E. Eyfjörd
- S.I. Berndt
- Óskar Þór Jóhannsson
- Denzil James
- Jenny L. Donovan
- Cezary Cybulski
- Natalie Taylor
- Declan J. Cahill (ORCID: https://orcid.org/0000-0001-8618-0724)
- Graham G. Giles
- Manuel R. Teixeira
- Pardeep Kumar (ORCID: https://orcid.org/0000-0002-9416-1723)
- Radka Kaneva
- Nandita de Souza
- Paul Ardern-Jones
- Frank Chingewundoh
- Christos Mikropolis
Institutions
- University of East Anglia (GB)
- University of Southern California (US)
- University of Hawaiʻi at Mānoa (US)
- Bond University (AU)
- University of Copenhagen (DK)
- Oslo University Hospital (NO)
- Cedars-Sinai Medical Center (US)
- Brigham and Women's Hospital (US)
- American Cancer Society (US)
- Guy's Hospital (GB)
- Translational Research Institute (AU)
- Universidad de Cantabria (ES)
- Royal Marsden NHS Foundation Trust (GB)
- University of Hawaii System (US)
- Memorial Sloan Kettering Cancer Center (US)
- Karolinska University Hospital (SE)
- University of Helsinki (FI)
- University College London Hospitals NHS Foundation Trust (GB)
- The University of Texas MD Anderson Cancer Center (US)
- Harvard University (US)
- Garvan Institute of Medical Research (AU)
- University Hospital Centre Zagreb (HR)
- Institute of Cancer Research (GB)
- Radboud University Nijmegen (NL)
- University of Liverpool (GB)
- Imperial College Healthcare NHS Trust (GB)
- University of Alberta (CA)
- Inserm (FR)
- University of Turku (FI)
- Universität Hamburg (DE)
- Queensland University of Technology (AU)
- The University of Queensland (AU)
- University of Iceland (IS)
- The University of Melbourne (AU)
- Queen Mary University of London (GB)
- Tampere University (FI)
- Universitat Pompeu Fabra (ES)
- German Cancer Research Center (DE)
- University of Zagreb (HR)
- Universidade do Porto (PT)
- University of Toronto (CA)
- Lund University (SE)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Cancer Council Victoria (AU)
- University of Washington (US)
- Aarhus University (DK)
- Washington University in St. Louis (US)
- QIMR Berghofer Medical Research Institute (AU)
- University of Utah (US)
- Heidelberg University (DE)
- Barts Health NHS Trust (GB)
- University of Cambridge (GB)
- Florey Institute of Neuroscience and Mental Health (AU)
- Université Paris-Saclay (FR)
- Discovery Institute (US)
- Manchester Academic Health Science Centre (GB)
- Helsinki University Hospital (FI)
- Peter MacCallum Cancer Centre (AU)
- St George’s University Hospitals NHS Foundation Trust (GB)
- Cancer Research UK (GB)
- Princess Alexandra Hospital (AU)
- Institut Gustave Roussy (FR)
- Erasmus MC (NL)
- Turku University Hospital (FI)
- Aarhus University Hospital (DK)
- University Hospital Complex Of Vigo (ES)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Copenhagen University Hospital (DK)
- Gentofte Hospital (DK)
- Innovate UK (GB)
- Princess Margaret Cancer Centre (CA)
- Rigshospitalet (DK)
- John Radcliffe Hospital (GB)
- Nottingham City Hospital (GB)
- Karolinska Institutet (SE)
- University of Surrey (GB)
- University of Manchester (GB)
- Medical University of Sofia (BG)
- Moffitt Cancer Center (US)
- Ghent University (BE)
- University of Malaya (MY)
- University of Bristol (GB)
- University of California San Diego (US)
- Sorbonne Université (FR)
- University of Oxford (GB)
- St Mary's Hospital (GB)
- Fred Hutch Cancer Center (US)
- Spanish National Cancer Research Centre (ES)
- Mater Research (AU)
- Chris O’Brien Lifehouse (AU)
- Cancer Center of Hawaii (US)
- Complejo Hospitalario Universitario de Santiago (ES)
- Assistance Publique – Hôpitaux de Paris (FR)
- Sunshine Coast University Hospital (AU)
- Instituto Português de Oncologia Francisco Gentil (PT)
- Centre de recherche en Epidémiologie et Santé des Populations (FR)
- National University Hospital of Iceland (IS)
- University Medical Center Hamburg-Eppendorf (DE)
- City of Hope (US)
- IPO Porto (PT)
- Centre for Biomedical Network Research on Rare Diseases (ES)
- Instituto de Investigación Marqués de Valdecilla (ES)
- Medway Maritime Hospital (GB)
- Praxis für Humangenetik Tübingen (DE)
- Christus Santa Rosa Health System (US)
- University Hospitals Seidman Cancer Center (US)
- Monash Health (AU)
- Fundación Pública Galega de Medicina Xenómica (ES)
- Mayo Clinic in Arizona (US)
- Tampere University Hospital (FI)
- Health Innovation Manchester (GB)
- Wessex Regional Genetics Laboratory (GB)
- Hospital Del Mar (ES)
- The Christie Hospital (GB)
- Tampere University (FI)
- The Christie NHS Foundation Trust (GB)
- Municipal Institute for Medical Research (ES)
- South Australian Health and Medical Research Institute (AU)
- Centro de Investigación del Cáncer (ES)
- Centre for Cancer Biology (AU)
- Complexo Hospitalario Universitario A Coruña (ES)
- National Cancer Institute (US)
- Krebsregister Saarland (DE)
- International Epidemiology Institute (US)
- Barcelona Institute for Global Health (ES)
- Instituto de Investigación Sanitaria de Santiago (ES)
- Melbourne Clinic (AU)
- The Kinghorn Cancer Centre (AU)
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (ES)
- University Hospital Ulm (DE)
- Addenbrooke's Hospital (GB)
- Freemasons Foundation Centre for Men's Health (AU)
- Servicio Gallego de Salud (ES)
- NIHR Manchester Biomedical Research Centre (GB)
- International Hereditary Cancer Center (PL)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Instituto de Investigación de Enfermedades Raras (ES)
- George E. Wahlen Department of VA Medical Center (US)
- Hôpital Tenon (FR)
- University of Southampton (GB)
- Beckman Research Institute
- Onco-Urologie Prédictive
- University of Hawaii Cancer Center
- Division of Cancer Epidemiology and Genetics
- University College London (GB)
- Monash University (AU)
- The University of Adelaide (AU)
- Case Western Reserve University (US)
- Universitat de Barcelona (ES)
- Pomeranian Medical University (PL)
- Vanderbilt University Medical Center (US)
- Umeå University (SE)
- Stanford University (US)
- Icahn School of Medicine at Mount Sinai (US)
- KU Leuven (BE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-06
- DOI
- https://doi.org/10.1038/s41467-024-52472-6
- Citations
- 7
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 2.93
Funders
- U.S. Department of Defense
- Prostate Cancer Foundation
- Fundación Mutua Madrileña
- Movember Foundation
- Royal Marsden NHS Foundation Trust
- Australian Prostate Cancer Research
- Mater Foundation
- Australian Government
- National Institute for Health and Care Research
- Prostate Cancer Foundation of Australia
- Cancerfonden
- Knut och Alice Wallenbergs Stiftelse
- Magnus Ehrnroothin Säätiö
- Vetenskapsrådet
- Umeå Universitet
- Vedecká Grantová Agentúra MŠVVaŠ SR a SAV
- Sigrid Juséliuksen Säätiö
- National Institutes of Health
- Medical Research Council
- National Health and Medical Research Council
- Cancer Council Queensland
- Instituto de Salud Carlos III
- Advance Queensland
- National Cancer Institute