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000294428 1001_ $$aSrinivasan, Srilakshmi$$b0
000294428 245__ $$aA PSA SNP associates with cellular function and clinical outcome in men with prostate cancer.
000294428 260__ $$a[London]$$bNature Publishing Group UK$$c2024
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000294428 520__ $$aGenetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility in men. The non-synonymous KLK3 single nucleotide polymorphism (SNP), rs17632542 (c.536 T > C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity mediates prostate cancer pathogenesis. The 'Thr' PSA variant leads to small subcutaneous tumours, supporting reduced prostate cancer risk. However, 'Thr' PSA also displays higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterisation of this PSA variant demonstrates markedly reduced proteolytic activity that correlates with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele have reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes.
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000294428 650_7 $$0EC 3.4.21.77$$2NLM Chemicals$$aProstate-Specific Antigen
000294428 650_7 $$0EC 3.4.21.-$$2NLM Chemicals$$aKallikreins
000294428 650_7 $$0EC 3.4.21.-$$2NLM Chemicals$$aKLK3 protein, human
000294428 650_2 $$2MeSH$$aMale
000294428 650_2 $$2MeSH$$aHumans
000294428 650_2 $$2MeSH$$aProstatic Neoplasms: genetics
000294428 650_2 $$2MeSH$$aProstatic Neoplasms: pathology
000294428 650_2 $$2MeSH$$aProstatic Neoplasms: metabolism
000294428 650_2 $$2MeSH$$aProstatic Neoplasms: mortality
000294428 650_2 $$2MeSH$$aPolymorphism, Single Nucleotide
000294428 650_2 $$2MeSH$$aProstate-Specific Antigen: blood
000294428 650_2 $$2MeSH$$aProstate-Specific Antigen: metabolism
000294428 650_2 $$2MeSH$$aKallikreins: genetics
000294428 650_2 $$2MeSH$$aKallikreins: metabolism
000294428 650_2 $$2MeSH$$aGenetic Predisposition to Disease
000294428 650_2 $$2MeSH$$aAged
000294428 650_2 $$2MeSH$$aAnimals
000294428 650_2 $$2MeSH$$aChromosomes, Human, Pair 19: genetics
000294428 650_2 $$2MeSH$$aMiddle Aged
000294428 650_2 $$2MeSH$$aMice
000294428 650_2 $$2MeSH$$aAlleles
000294428 650_2 $$2MeSH$$aCell Line, Tumor
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