A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer
Authors: Srinivasan Srilakshmi , Kryza Thomas , Bock Nathalie , Tse Brian W. C. , Sokolowski Kamil A. , Janaththani Panchadsaram , Fernando Achala , Moya Leire , Stephens Carson , Dong Ying , Röhl Joan , Alinezhad Saeid , Vela Ian , Perry-Keene Joanna L. , Buzacott Katie , Nica Robert ,   The IMPACT Study, Bancroft Elizabeth , Page Elizabeth , Ardern-Jones Audrey , Bangma Chris , Castro Elena , Dearnaley David , Eccles Diana , Evans Gareth , Eyfjord Jorunn , Falconer Alison , Foster Christopher , Hamdy Freddie C. , Jóhannsson Óskar Þór , Khoo Vincent , Lindeman Geoffrey , Lubinski Jan , Maehle Lovise , Millner Alan , Mikropoulos Christos , Mitra Anita , Moynihan Clare , Offman Judith , Rennert Gad , Side Lucy , Suri Mohnish , Wilson Penny , Gago-Dominguez Manuela ,   The PROFILE Study Steering Committee, Kumar Pardeep , Antoniou Antonis , McHugh Jana , Raghallaigh Holly Ni , Hall Rose , Taylor Natalie , Thomas Sarah , Myhill Kathryn , Hogben Matthew , McGrowder Eva , Keating Diana , James Denzil , Merson Joe , Hussain Syed , Wood Angela , Dennis Nening , Ardern-Jones Paul , van As Nick , Hazell Steve , Lewis Sarah , Pharoah Paul , Schalken Jack , Sohaib Aslam , de Souza Nandita , Cathcart Paul , Chingewundoh Frank , Perry Mathew , Bamber Jeff , Dias Alexander , Mikropolis Christos , Saya Sibel , Chamberlain Antony , Da Silva Anne-Marie Borges , D’Mello Lucia , Moss Sue , Melia Jane , Kinsella Netty , Sobczak Justyna , Mcaddy Naami , Nicol David , Ogden Chris , Cahill Declan , Thompson Alan , Woodhouse Christopher , Gnanapragasam Vincent J. , Cooper Colin , Clark Jeremy , Schleutker Johanna , Maier Christiane , Muir Kenneth , Tangen Catherine M. , Gronberg Henrik , Pashayan Nora , Albanes Demetrius , Wolk Alicja , Stanford Janet L. , Berndt Sonja I. , Mucci Lorelei A. , Koutros Stella , Cussenot Olivier , Sorensen Karina Dalsgaard , Grindedal Eli Marie , Travis Ruth C. , Haiman Christopher A. , MacInnis Robert J. , Vega Ana , Wiklund Fredrik , Neal David E. , Kogevinas Manolis , Penney Kathryn L. , Nordestgaard Børge G. , Brenner Hermann , John Esther M. , Gamulin Marija , Claessens Frank , Melander Olle , Dahlin Anders , Stattin Pär , Hallmans Göran , Häggström Christel , Johansson Robert , Thysell Elin , Rönn Ann-Charlotte , Li Weiqiang , Brown Nigel , Dimeski Goce , Shepherd Benjamin , Dadaev Tokhir , Brook Mark N. , Spurdle Amanda B. , Stenman Ulf-Håkan , Koistinen Hannu , Kote-Jarai Zsofia , Klein Robert J. , Lilja Hans , Ecker Rupert C. , Eeles Rosalind ,   The Practical Consortium, Schumacher Fredrick R. , Benlloch Sara , Olama Ali Amin Al , Chanock Stephen , Wang Ying , Weinstein Stephanie J. , West Catharine M. L. , Cancel-Tassin Géraldine , Donovan Jenny L. , Hamilton Robert J. , Ingles Sue Ann , Rosenstein Barry S. , Lu Yong-Jie , Giles Graham G. , Kibel Adam S. , Park Jong Y. , Cybulski Cezary , Nielsen Sune F. , Kim Jeri , Teixeira Manuel R. , Neuhausen Susan L. , De Ruyck Kim , Razack Azad , Newcomb Lisa F. , Lessel Davor , Kaneva Radka , Usmani Nawaid , Townsend Paul A. , Castelao Jose Esteban , van Shaik Ron H. N. , Menegaux Florence , Khaw Kay-Tee , Cannon-Albright Lisa , Pandha Hardev , Thibodeau Stephen N. , Kraft Peter , Blot William J. , Lophatananon Artitaya , Goodman Phyllis J. , Thompson Ian M. , Nordström Tobias , Dunning Alison M. , Tammela Teuvo L. J. , Auvinen Anssi , Håkansson Niclas , Andriole Gerald L. , Hoover Robert N. , Machiela Mitchell J. , Giovannucci Edward , Freeman Laura E. Beane , Borre Michael , Key Tim J. , Le Marchand Loic , Sheng Xin , Southey Melissa C. , Milne Roger L. , Gómez-Caamaño Antonio , Fachal Laura , Eklund Martin , Dierssen-Sotos Trinidad , Castaño-Vinyals Gemma , Alcaraz Antonio , Lindström Sara , Stampfer Meir , Bojesen Stig E. , Stroomberg Hein V. , Røder Andreas , Gao Xin , Holleczek Bernd , Schöttker Ben , Hoegel Josef , Schnoeller Thomas , Kulis Tomislav , Joniau Steven , Martinez Maria Elena , Aly Markus ,   The Australian Prostate Cancer BioResource, Tilley Wayne , Risbridger Gail P. , Horvath Lisa , Taylor Renea , Butler Lisa , Haynes Anne-Maree , Papargiris Melissa , Vela Ian , Clements Judith , Batra Jyotsna 
Published: November 2024

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.