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

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

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Biochemical activity induced by a germline variation in KLK3 (PSA) associates with cellular function and clinical outcome in prostate cancer. / Srinivasan, Srilakshmi; Kryza, Thomas; Bock, Nathalie; Tse, Brian Wc; Sokolowski, Kamil A; Panchadsaram, Janaththani; Moya, Leire; Stephens, Carson; Dong, Ying; Röhl, Joan; Alinezhad, Saeid; Vela, Ian; Perry-Keene, Joanna L; Buzacott, Katie; 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; Key, Timothy J; Haiman, Christopher A; Giles, Graham G; Vega, Ana; Wiklund, Fredrik; Neal, David E; Kogevinas, Manolis; Stampfer, Meir J; Nordestgaard, Børge G; Brenner, Hermann; Gamulin, Marija; Claessens, Frank; Melander, Olle; Dahlin, Anders; Stattin, Pär; Hallmans, Göran; Häggström, Christel; Johansson, Robert; Thysell, Elin; Rönn, Ann-Charlotte; IMPACT Study.

I: Research square, 2024.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

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

APA

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

Vancouver

Srinivasan S, Kryza T, Bock N, Tse BW, Sokolowski KA, Panchadsaram J o.a. Biochemical activity induced by a germline variation in KLK3 (PSA) associates with cellular function and clinical outcome in prostate cancer. Research square. 2024. https://doi.org/10.21203/rs.3.rs-2650312/v1

Author

Srinivasan, Srilakshmi ; Kryza, Thomas ; Bock, Nathalie ; Tse, Brian Wc ; Sokolowski, Kamil A ; Panchadsaram, Janaththani ; Moya, Leire ; Stephens, Carson ; Dong, Ying ; Röhl, Joan ; Alinezhad, Saeid ; Vela, Ian ; Perry-Keene, Joanna L ; Buzacott, Katie ; 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 ; Key, Timothy J ; Haiman, Christopher A ; Giles, Graham G ; Vega, Ana ; Wiklund, Fredrik ; Neal, David E ; Kogevinas, Manolis ; Stampfer, Meir J ; Nordestgaard, Børge G ; Brenner, Hermann ; Gamulin, Marija ; Claessens, Frank ; Melander, Olle ; Dahlin, Anders ; Stattin, Pär ; Hallmans, Göran ; Häggström, Christel ; Johansson, Robert ; Thysell, Elin ; Rönn, Ann-Charlotte ; IMPACT Study. / Biochemical activity induced by a germline variation in KLK3 (PSA) associates with cellular function and clinical outcome in prostate cancer. I: Research square. 2024.

Bibtex

@article{287d24aa72334b6ebd14b6b30c9bbac5,

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

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.",

author = "Srilakshmi Srinivasan and Thomas Kryza and Nathalie Bock and Tse, {Brian Wc} and Sokolowski, {Kamil A} and Janaththani Panchadsaram and Leire Moya and Carson Stephens and Ying Dong and Joan R{\"o}hl and Saeid Alinezhad and Ian Vela and Perry-Keene, {Joanna L} and Katie Buzacott and Manuela Gago-Dominguez and Johanna Schleutker and Christiane Maier and Kenneth Muir and Tangen, {Catherine M} and Henrik Gronberg and Nora Pashayan and Demetrius Albanes and Alicja Wolk and Stanford, {Janet L} and Berndt, {Sonja I} and Mucci, {Lorelei A} and Stella Koutros and Olivier Cussenot and Sorensen, {Karina Dalsgaard} and Grindedal, {Eli Marie} and Key, {Timothy J} and Haiman, {Christopher A} and Giles, {Graham G} and Ana Vega and Fredrik Wiklund and Neal, {David E} and Manolis Kogevinas and Stampfer, {Meir J} and Nordestgaard, {B{\o}rge G} and Hermann Brenner and Marija Gamulin and Frank Claessens and Olle Melander and Anders Dahlin and P{\"a}r Stattin and G{\"o}ran Hallmans and Christel H{\"a}ggstr{\"o}m and Robert Johansson and Elin Thysell and Ann-Charlotte R{\"o}nn and {IMPACT Study}",

year = "2024",

doi = "10.21203/rs.3.rs-2650312/v1",

language = "English",

journal = "Research square",

}

RIS

TY - JOUR

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

Y1 - 2024

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 - Journal article

C2 - 37034758

JO - Research square

JF - Research square

ER -

ID: 396407633