Biochemical activity induced by a germline variation in KLK3 (PSA) associates with cellular function and clinical outcome in prostate cancer

Srilakshmi Srinivasan; Thomas Kryza; Nathalie Bock; Brian Wc Tse; Kamil A Sokolowski; Janaththani Panchadsaram; Leire Moya; Carson Stephens; Ying Dong; Joan Röhl; Saeid Alinezhad; Ian Vela; Joanna L Perry-Keene; Katie Buzacott; Manuela Gago-Dominguez; Johanna Schleutker; Christiane Maier; Kenneth Muir; Catherine M Tangen; Henrik Gronberg; Nora Pashayan; Demetrius Albanes; Alicja Wolk; Janet L Stanford; Sonja I Berndt; Lorelei A Mucci; Stella Koutros; Olivier Cussenot; Karina Dalsgaard Sorensen; Eli Marie Grindedal; Timothy J Key; Christopher A Haiman; Graham G Giles; Ana Vega; Fredrik Wiklund; David E Neal; Manolis Kogevinas; Meir J Stampfer; Børge G Nordestgaard; Hermann Brenner; Marija Gamulin; Frank Claessens; Olle Melander; Anders Dahlin; Pär Stattin; Göran Hallmans; Christel Häggström; Robert Johansson; Elin Thysell; Ann-Charlotte Rönn; IMPACT Study

doi:10.21203/rs.3.rs-2650312/v1

Biochemical activity induced by a germline variation in KLK3 (PSA) associates with cellular function and clinical outcome in prostate cancer

Srilakshmi Srinivasan, Thomas Kryza, Nathalie Bock, Brian Wc Tse, Kamil A Sokolowski, Janaththani Panchadsaram, Leire Moya, Carson Stephens, Ying Dong, Joan Röhl, Saeid Alinezhad, Ian Vela, Joanna L Perry-Keene, Katie Buzacott, Manuela Gago-Dominguez, Johanna Schleutker, Christiane Maier, Kenneth Muir, Catherine M Tangen, Henrik GronbergNora Pashayan, Demetrius Albanes, Alicja Wolk, Janet L Stanford, Sonja I Berndt, Lorelei A Mucci, Stella Koutros, Olivier Cussenot, Karina Dalsgaard Sorensen, Eli Marie Grindedal, Timothy J Key, Christopher A Haiman, Graham G Giles, Ana Vega, Fredrik Wiklund, David E Neal, Manolis Kogevinas, Meir J Stampfer, Børge G Nordestgaard, Hermann Brenner, Marija Gamulin, Frank Claessens, Olle Melander, Anders Dahlin, Pär Stattin, Göran Hallmans, Christel Häggström, Robert Johansson, Elin Thysell, Ann-Charlotte Rönn, IMPACT Study

Publikation: Working paper › Preprint

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Abstract

Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility. The non-synonymous KLK3 SNP, rs17632542 (c.536T>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 as a previously undescribed function mediating prostate cancer pathogenesis. The ‘Thr’ PSA variant led to small subcutaneous tumours, supporting reduced prostate cancer risk. However, ‘Thr’ PSA also displayed higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterization of this PSA variant demonstrated markedly reduced proteolytic activity that correlated 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 had 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.

Originalsprog	Engelsk
Antal sider	41
DOI	https://doi.org/10.21203/rs.3.rs-2650312/v1
Status	Udgivet - 2024

Navn	Research square

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10.21203/rs.3.rs-2650312/v1Licens: CC BY

FulltextForlagets udgivne version, 1 MBLicens: CC BY

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Srinivasan, S., Kryza, T., Bock, N., Tse, B. W., Sokolowski, K. A., Panchadsaram, J., Moya, L., Stephens, C., Dong, Y., Röhl, J., Alinezhad, S., Vela, I., Perry-Keene, J. L., Buzacott, K., Gago-Dominguez, M., Schleutker, J., Maier, C., Muir, K., Tangen, C. M., ... IMPACT Study (2024). Biochemical activity induced by a germline variation in KLK3 (PSA) associates with cellular function and clinical outcome in prostate cancer. Research square https://doi.org/10.21203/rs.3.rs-2650312/v1

Srinivasan, S, Kryza, T, Bock, N, Tse, BW, Sokolowski, KA, Panchadsaram, J, Moya, L, Stephens, C, Dong, Y, Röhl, J, Alinezhad, S, Vela, I, Perry-Keene, JL, Buzacott, K, Gago-Dominguez, M, 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, Key, TJ, Haiman, CA, Giles, GG, Vega, A, Wiklund, F, Neal, DE, Kogevinas, M, Stampfer, MJ, Nordestgaard, BG, Brenner, H, Gamulin, M, Claessens, F, Melander, O, Dahlin, A, Stattin, P, Hallmans, G, Häggström, C, Johansson, R, Thysell, E, Rönn, A-C & IMPACT Study 2024 'Biochemical activity induced by a germline variation in KLK3 (PSA) associates with cellular function and clinical outcome in prostate cancer' Research square. https://doi.org/10.21203/rs.3.rs-2650312/v1

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abstract = "Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility. The non-synonymous KLK3 SNP, rs17632542 (c.536T>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 as a previously undescribed function mediating prostate cancer pathogenesis. The 'Thr' PSA variant led to small subcutaneous tumours, supporting reduced prostate cancer risk. However, 'Thr' PSA also displayed higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterization of this PSA variant demonstrated markedly reduced proteolytic activity that correlated 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 had 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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T1 - Biochemical activity induced by a germline variation in KLK3 (PSA) associates with cellular function and clinical outcome in prostate cancer

AU - Srinivasan, Srilakshmi

AU - Kryza, Thomas

AU - Bock, Nathalie

AU - Tse, Brian Wc

AU - Sokolowski, Kamil A

AU - Panchadsaram, Janaththani

AU - Moya, Leire

AU - Stephens, Carson

AU - Dong, Ying

AU - Röhl, Joan

AU - Alinezhad, Saeid

AU - Vela, Ian

AU - Perry-Keene, Joanna L

AU - Buzacott, Katie

AU - Gago-Dominguez, Manuela

AU - Schleutker, Johanna

AU - Maier, Christiane

AU - Muir, Kenneth

AU - Tangen, Catherine M

AU - Gronberg, Henrik

AU - Pashayan, Nora

AU - Albanes, Demetrius

AU - Wolk, Alicja

AU - Stanford, Janet L

AU - Berndt, Sonja I

AU - Mucci, Lorelei A

AU - Koutros, Stella

AU - Cussenot, Olivier

AU - Sorensen, Karina Dalsgaard

AU - Grindedal, Eli Marie

AU - Key, Timothy J

AU - Haiman, Christopher A

AU - Giles, Graham G

AU - Vega, Ana

AU - Wiklund, Fredrik

AU - Neal, David E

AU - Kogevinas, Manolis

AU - Stampfer, Meir J

AU - Nordestgaard, Børge G

AU - Brenner, Hermann

AU - Gamulin, Marija

AU - Claessens, Frank

AU - Melander, Olle

AU - Dahlin, Anders

AU - Stattin, Pär

AU - Hallmans, Göran

AU - Häggström, Christel

AU - Johansson, Robert

AU - Thysell, Elin

AU - Rönn, Ann-Charlotte

AU - IMPACT Study

PY - 2024

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N2 - Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility. The non-synonymous KLK3 SNP, rs17632542 (c.536T>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 as a previously undescribed function mediating prostate cancer pathogenesis. The 'Thr' PSA variant led to small subcutaneous tumours, supporting reduced prostate cancer risk. However, 'Thr' PSA also displayed higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterization of this PSA variant demonstrated markedly reduced proteolytic activity that correlated 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 had 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.

AB - Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility. The non-synonymous KLK3 SNP, rs17632542 (c.536T>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 as a previously undescribed function mediating prostate cancer pathogenesis. The 'Thr' PSA variant led to small subcutaneous tumours, supporting reduced prostate cancer risk. However, 'Thr' PSA also displayed higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterization of this PSA variant demonstrated markedly reduced proteolytic activity that correlated 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 had 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.

U2 - 10.21203/rs.3.rs-2650312/v1

DO - 10.21203/rs.3.rs-2650312/v1

M3 - Preprint

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BT - Biochemical activity induced by a germline variation in KLK3 (PSA) associates with cellular function and clinical outcome in prostate cancer

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