A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer

作者：Srilakshmi Srinivasan, Thomas Kryza, Nathalie Bock, Brian Wan-Chi Tse, Kamil A. Sokolowski, Janaththani Panchadsaram, Achala Fernando, Leire Moya, Carson Stephens, Ying Dong, Joan Röhl, Saeid Alinezhad, Ian Vela, Joanna Perry‐Keene, Katie Buzacott, Robert Nica, The IMPACT Study, Elizabeth Bancroft, Elizabeth Page, Audrey Ardern‐Jones, Chris Bangma, Elena Castro, David P. Dearnaley, Diana Eccles, D. Gareth Evans, Jórunn E. Eyfjörd, Alison Falconer, Christopher S. Foster, Freddie C. Hamdy, Óskar Þór Jóhannsson, Vincent Khoo, Geoffrey J. Lindeman, Jan Lubiński, Lovise Mæhle, Alan Millner, Christos Mikropoulos, Anita Mitra, Clare Moynihan, Judith Offman, Gad Rennert, Lucy Side, Mohnish Suri, Penny Wilson, Manuela Gago-Domínguez, Pardeep Kumar, Antonis C. Antoniou, Jana McHugh, Holly Ní Raghallaigh, R. R. Hall, Natalie Taylor, Sarah Thomas, Kathryn Myhill, Matthew Hogben, Eva McGrowder, Diana Keating, Denzil James, Joe Merson, Syed Arshad Hussain, Angela Wood, Nening M. Dennis, Paul Ardern-Jones, N. van As, Steve Hazell, Sarah J. Lewis, Paul D.P. Pharoah, J. Schalken, Aslam Sohaib, Nandita de Souza, Paul Cathcart, Frank Chingewundoh, Mathew Perry, Jeff Bamber, Alexander Dias, Christos Mikropolis, Sibel Saya, Antony Chamberlain, Anne-Marie Borges Da Silva, Lucia D’Mello, Sue Moss, J Melia, Netty Kinsella, Justyna Sobczak, Naami Mcaddy, David Nicol, Chris Ogden, Declan Cahill, Alan Thompson, Christopher Woodhouse, Vincent J. Gnanapragasam, Colin Cooper, Jeremy Clark, Johanna Schleutker, Christiane Maier, Kenneth Muir, Catherine M. Tangen, Henrik Grönberg, Nora Pashayan, Demetrius Albanes, Alicja Wolk, Janet L. Stanford, S.I. Berndt, Lorelei A. Mucci, Stella Koutros, Olivier Cussenot, Karina D. Sørensen, 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 N. 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 Ecker, Rosalind A. Eeles, Fredrick R. Schumacher, Sara Benlloch, Ali Amin Al Olama, Stephen Chanock, Ying Wang, Stephanie J. Weinstein, Catharine West, Géraldine Cancel‐Tassin, Jenny L. Donovan, Robert J. Hamilton, Sue A. Ingles, Barry S. Rosenstein, Yong‐Jie Lu, Graham G. Giles, Adam S. Kibel, Jong Y. Park, Cezary Cybulski, Sune F. Nielsen, Jeri Kim, Manuel R. Teixeira, Susan L. Neuhausen, Kim De Ruyck, Azad Razack, Lisa F. Newcomb, Davor Lessel, Radka Kaneva, Nawaid Usmani, Paul A. Townsend, Jose E. Castelao, Ron H. N. van Shaik, F. Ménégaux, Kay-Tee Khaw, Lisa Cannon‐Albright, Hardev Pandha, S. N. Thibodeau, Peter Kraft, William J. Blot, Artitaya Lophatananon, Phyllis J. Goodman, Ian M. Thompson, Tobias Nordström, Alison M. Dunning, Teuvo L.J. Tammela, Anssi Auvinen, Niclas Håkansson, Gerald L. Andriole, Robert N. Hoover, Mitchell J. Machiela, Edward L. Giovannucci, Laura E. Beane Freeman, Michael Borre, Timothy J. Key, Loı̈c Le Marchand, Xin Sheng, Melissa C. Southey, Roger L. Milne, Antonio Gómez‐Caamaño, Laura Fachal, Martin Eklund, Trinidad Dierssen‐Sotos, Gemma Castaño‐Vinyals, Antonio Alcaraz, Sara Lindström, Meir J. Stampfer, Stig E. Bojesen, Hein Vincent Stroomberg, Martin Andreas Røder, Xin Gao, Bernd Holleczek, Ben Schöttker, Josef Hoegel, Thomas Schnoeller, Tomislav Kuliš, Steven Joniau, Maria Elena Martinez, Markus Aly, The Australian Prostate Cancer BioResource, Wayne D. Tilley, Gail P. Risbridger, Lisa G. Horvath, Renea A. Taylor, Lisa M. Butler, Anne-Maree Haynes, Melissa Papargiris, Ian Vela, Judith A. Clements, Jyotsna Batra · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-52472-6 · 被引用次数：14 · 研究领域：Prostate Cancer Treatment and Research、Prostate Cancer Diagnosis and Treatment、Cancer-related molecular mechanisms research

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.