A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer Journal Article
| Authors: | Srinivasan, S.; Kryza, T.; Bock, N.; Tse, B. W. C.; Sokolowski, K. A.; Janaththani, P.; Fernando, A.; Moya, L.; Stephens, C.; Dong, Y.; Röhl, J.; Alinezhad, S.; Vela, I.; Perry-Keene, J. L.; Buzacott, K.; Nica, R.; The IMPACT Study; Gago-Dominguez, M.; The PROFILE Study Steering Committee; Schleutker, J.; Maier, C.; Muir, K.; Tangen, C. M.; Gronberg, H.; Pashayan, N.; Albanes, D.; Wolk, A.; Stanford, J. L.; Berndt, S. I.; Mucci, L. A.; Koutros, S.; Cussenot, O.; Sorensen, K. D.; Grindedal, E. M.; Travis, R. C.; Haiman, C. A.; MacInnis, R. J.; Vega, A.; Wiklund, F.; Neal, D. E.; Kogevinas, M.; Penney, K. L.; Nordestgaard, B. G.; Brenner, H.; John, E. M.; Gamulin, M.; Claessens, F.; Melander, O.; Dahlin, A.; Stattin, P.; Hallmans, G.; Häggström, C.; Johansson, R.; Thysell, E.; Rönn, A. C.; Li, W.; Brown, N.; Dimeski, G.; Shepherd, B.; Dadaev, T.; Brook, M. N.; Spurdle, A. B.; Stenman, U. H.; Koistinen, H.; Kote-Jarai, Z.; Klein, R. J.; Lilja, H.; Ecker, R. C.; Eeles, R.; The Practical Consortium; The Australian Prostate Cancer BioResource; Clements, J.; Batra, J. |
| Article Title: | A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer |
| 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. © The Author(s) 2024. |
| Keywords: | cancer survival; controlled study; aged; middle aged; osteolysis; human cell; single nucleotide polymorphism; genetics; polymorphism, single nucleotide; mortality; cancer risk; nonhuman; bone metastasis; cell proliferation; prostate specific antigen; animal cell; chromosome 19; mouse; animal; metabolism; animals; mice; allele; cell function; cancer susceptibility; genetic predisposition to disease; protein degradation; animal experiment; animal model; alleles; genetic variation; pathology; cell line, tumor; carcinogenesis; prostate cancer; prostate-specific antigen; prostatic neoplasms; blood; tumor burden; prostate tumor; tumor cell line; kallikrein; chromosomes, human, pair 19; tumor; genetic predisposition; biochemistry; antiangiogenic activity; cell invasion; serum; genetic marker; kallikreins; polymorphism; clinical outcome; subcutaneous tissue; cancer; humans; human; male; article; experimental metastasis; neoplastic cell transformation; klk3 protein, human |
| Journal Title: | Nature Communications |
| Volume: | 15 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-11-06 |
| Start Page: | 9587 |
| Language: | English |
| DOI: | 10.1038/s41467-024-52472-6 |
| PUBMED: | 39505858 |
| PROVIDER: | scopus |
| PMCID: | PMC11541583 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- Source: Scopus |
