A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer
: 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; Gago-Dominguez, Manuela; 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; Clements, Judith; Batra, Jyotsna; The IMPACT Study; The PROFILE Study Steering Committee; The Practical Consortium; The Australian Prostate Cancer BioResource
Publisher: Nature Research
: 2024
: Nature Communications
: Nature Communications
: 9587
: 15
: 2041-1723
DOI: https://doi.org/10.1038/s41467-024-52472-6
: https://doi.org/10.1038/s41467-024-52472-6
: https://research.utu.fi/converis/portal/detail/Publication/470834967
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.
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Acknowledgements: We would particularly like to thank all the patients and control men who took part in all the studies involved in this work, as well as all the researchers, clinicians, technicians, and administrative staff who have enabled this work to be carried out, and the collaborators in the PRACTICAL consortium. We acknowledge support from the NIHR to the Biomedical Research Centre at The Institute of Cancer and The Royal Marsden NHS Foundation Trust. We thank (in consortia with other cohorts: NSHDS investigators thank) the Biobank Research Unit at Umeå University, Västerbotten Intervention Programme, the Northern Sweden MONICA study and the County Council of Västerbotten for providing data and samples and acknowledge the contribution from Biobank Sweden, supported by the Swedish Research Council (VR 2017-00650). The Australian Prostate Cancer BioResource funding was obtained from a National Health and Medical Research Council Enabling Grant and an infrastructure grant from the Prostate Cancer Foundation of Australia. The authors acknowledge TRI for providing an excellent research environment and core facilities that enabled this research, particularly Preclinical Imaging, Biological Resources Facility, Histology and Microscopy. The authors acknowledge the Australian Research Council for funding the Vevo 2100/LAZR through a LIEF grant (LE150100067), and the Lions Club of Australia and the Mater Foundation for funding the Skyscan 1272 microCT. The Translational Research Institute is supported by grants from the Australian Government. The authors would like to thank the Australian Prostate Cancer Research Centre-Queensland for their support. Also, thanks to Dr Sally Stephenson (QUT, Brisbane) for providing the mKO2 vector and Dr. Sunderajhan Sekar and Mr. Sanchit Seth for their contribution and help with spheroid assays. We also thank all current and former members of the Clements and Batra labs for their helpful discussions and insight. This work was supported by project grants from the NHMRC, Cancer Council Queensland and PCFA to J.C. and J.B., J.C. was supported by NHMRC Principal Research Fellowship. J.B. was supported by NHMRC Career Development Fellowship, Advance QLD MCR Research Fellowship (AQIRF175-2019RD2), Education and Research Committee (SERC) grant by Pathology Queensland, DoD Prostate Cancer Idea Development Grant (W81XWH-19-1-0343), PCFA research grant and Centre for Genomics and Personalised Health Collaboration and Innovation grants (2023 and 2024). S.S. was supported by a QUTPRA scholarship, Advance QLD ECR Research Fellowship, PCFA John Mills YI Award, SERC grant by Pathology Queensland and Centre for Genomics and Personalised Health Collaboration and Innovation grants (2023 and 2024). TK was supported by a Movember Revolutionary Team Award. N Bock acknowledges support from the NHMRC, PCFA and Movember through a Peter Doherty ECR Fellowship (APP1091734), John Mills YI Award, and MRT Award, respectively, as well as support via an Advance QLD ECR Research Fellowship (AQIRF066-2019RD2) and from the Max Planck Queensland Centre for the Materials Science of Extracellular Matrices. JP is supported by a QUTPRA scholarship. O.M. was supported by grants from The European Research Council, The Knut and Alice Wallenberg Foundation and the Swedish Research Council. Contract grant sponsor Ana Vega: supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds (PI22/00589, PI19/01424; INT20/00071); the ERAPerMed JTC2018 funding (AC18/00117); the Autonomous Government of Galicia (Consolidation and structuring program: IN607B), by the Fundación Mutua Madrileña (call 2018) and by the AECC (PRYES211091VEGA). H.K. is supported by grants from Sigrid Jusélius Foundation and Magnus Ehrnrooth Foundation. R.J.K. was supported by National Cancer Institute [R01 CA175491 and R01 CA244948]. H.L. is supported in part from NIH/NCI by a Cancer Center Support Grant (P30-CA008748), U01-CA199338, R01CA244948, the Swedish Cancer Society (Cancerfonden 23 3074 Pj 01 H), and the Swedish Prostate Cancer Foundation (Prostatacancerförbundet). ABS was supported by NHMRC Investigator Fellowship (APP1177524).
