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...
| Authors | Srinivasan, S; Kryza, T; Bock, N; Tse, BWC; Sokolowski, KA; Janaththani, P; Fernando, A; Moya, L; Stephens, C; Dong, Y; Röhl, J; Alinezhad, S; Vela, I; Perry-Keene, JL; Buzacott, K; Nica, R; IMPACT Study; Gago-Dominguez, M; PROFILE Study Steering Committee; Schleutker, J; Maier, C; Muir, K; Tangen, CM; Gronberg, H; Pashayan, N; Albanes, D; Wolk, A; Stanford, JL; Berndt, SI; Mucci, LA; Koutros, S; Cussenot, O; Sorensen, KD; Grindedal, EM; Travis, RC; Haiman, CA; MacInnis, RJ; Vega, A; Wiklund, F; Neal, DE; Kogevinas, M; Penney, KL; Nordestgaard, BG; Brenner, H; John, EM; Gamulin, M; Claessens, F; Melander, O; Dahlin, A; Stattin, P; Hallmans, G; Häggström, C; Johansson, R; Thysell, E; Rönn, AC; Li, W; Brown, N; Dimeski, G; Shepherd, B; Dadaev, T; Brook, MN; Spurdle, AB; Stenman, UH; Koistinen, H; Kote-Jarai, Z; Klein, RJ; Lilja, H; Ecker, RC; Eeles, R; Practical Consortium; Australian Prostate Cancer BioResource; Clements, J; Batra, J |
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| Journal | Nature Communications |
| Pages | 9587 |
| Volume | 15 |
| Date | 6/12/2024 |
| Grant ID | AQIRF175-2019RD2 | State of Queensland | Advance Queensland; R01 CA244948 | NCI NIH HHS [CA] (United States); P30 CA008748 | NCI NIH HHS [CA] (United States); U01 CA199338 | NCI NIH HHS [CA] (United States); R01 CA175491 | NCI NIH HHS [CA] (United States); W81XWH-19-1-0343 | U.S. Department of Defense (United States Department of Defense) |
| Funding Body | |
| URL | http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1038/s41467-024-52472-6 |