Biochemical activity induced by a germline variation in KLK3 (PSA) associates with cellular function and clinical outcome in prostate cancer
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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.
In: Research square, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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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