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, Manuela Gago-Dominguez, 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, Judith Clements and Jyotsna Batra ()
Additional contact information
Srilakshmi Srinivasan: Queensland University of Technology
Thomas Kryza: Woolloongabba
Nathalie Bock: Queensland University of Technology
Brian W. C. Tse: Woolloongabba
Kamil A. Sokolowski: Woolloongabba
Panchadsaram Janaththani: Queensland University of Technology
Achala Fernando: Queensland University of Technology
Leire Moya: Queensland University of Technology
Carson Stephens: Queensland University of Technology
Ying Dong: Queensland University of Technology
Joan Röhl: Queensland University of Technology
Saeid Alinezhad: Queensland University of Technology
Ian Vela: Queensland University of Technology
Joanna L. Perry-Keene: Birtinya
Katie Buzacott: Birtinya
Robert Nica: TissueGnostics GmbH
Manuela Gago-Dominguez: Genomic Medicine Group
Johanna Schleutker: FI-20014 University of Turku
Christiane Maier: Humangenetik Tuebingen
Kenneth Muir: University of Manchester
Catherine M. Tangen: Fred Hutchinson Cancer Research Center
Henrik Gronberg: Karolinska Institute
Nora Pashayan: University College London
Demetrius Albanes: NIH
Alicja Wolk: Karolinska Institutet
Janet L. Stanford: Fred Hutchinson Cancer Research Center
Sonja I. Berndt: NIH
Lorelei A. Mucci: Harvard T. H. Chan School of Public Health
Stella Koutros: NIH
Olivier Cussenot: Tenon Hospital
Karina Dalsgaard Sorensen: Aarhus University Hospital
Eli Marie Grindedal: Oslo University Hospital
Ruth C. Travis: University of Oxford
Christopher A. Haiman: University of Southern California/Norris Comprehensive Cancer Center
Robert J. MacInnis: The University of Melbourne
Ana Vega: Fundación Pública Galega Medicina Xenómica
Fredrik Wiklund: Karolinska Institute
David E. Neal: University of Oxford
Manolis Kogevinas: Barcelona Institute for Global Health
Kathryn L. Penney: Brigham and Women’s Hospital/Harvard Medical School
Børge G. Nordestgaard: University of Copenhagen
Hermann Brenner: German Cancer Research Center (DKFZ)
Esther M. John: Stanford University School of Medicine
Marija Gamulin: University of Zagreb
Frank Claessens: Department of Cellular and Molecular Medicine
Olle Melander: Lund University
Anders Dahlin: Lund University
Pär Stattin: Karolinska Institutet
Göran Hallmans: Umeå University
Christel Häggström: Umeå University
Robert Johansson: Umeå University
Elin Thysell: Umeå University
Ann-Charlotte Rönn: Karolinska University Hospital
Weiqiang Li: Icahn School of Medicine at Mount Sinai
Nigel Brown: Woolloongabba
Goce Dimeski: Woolloongabba
Benjamin Shepherd: Woolloongabba
Tokhir Dadaev: The Institute of Cancer Research
Mark N. Brook: The Institute of Cancer Research
Amanda B. Spurdle: Herston
Ulf-Håkan Stenman: University of Helsinki
Hannu Koistinen: University of Helsinki
Zsofia Kote-Jarai: The Institute of Cancer Research
Robert J. Klein: Icahn School of Medicine at Mount Sinai
Hans Lilja: Memorial Sloan Kettering Cancer Center
Rupert C. Ecker: Queensland University of Technology
Rosalind Eeles: The Institute of Cancer Research
Judith Clements: Queensland University of Technology
Jyotsna Batra: Queensland University of Technology

Nature Communications, 2024, vol. 15, issue 1, 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.

Date: 2024
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DOI: 10.1038/s41467-024-52472-6

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