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Clin Chem. 2019 Jan;65(1):e1-e9. doi: 10.1373/clinchem.2018.295790. Epub 2018 Dec 11.

Prostate Cancer Risk-Associated Single-Nucleotide Polymorphism Affects Prostate-Specific Antigen Glycosylation and Its Function.

Author information

1
Australian Prostate Cancer Research Centre-Queensland and Cancer Program, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.
2
Translational Research Institute, Woolloongabba, Queensland, Australia.
3
Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
4
Endocrinology, QML Pathology, Mansfield, Queensland, Australia.
5
Department of Clinical Chemistry, Biomedicum Helsinki, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
6
Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY.
7
Departments of Laboratory Medicine, Surgery (Urology Service) and Medicine (Genitourinary Oncology), Memorial Sloan Kettering Cancer Center, New York, NY.
8
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
9
Department of Translational Medicine, Lund University, Malmö, Sweden.
10
Australian Prostate Cancer Research Centre-Queensland and Cancer Program, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia; jyotsna.batra@qut.edu.au.

Abstract

BACKGROUND:

Genetic association studies have reported single-nucleotide polymorphisms (SNPs) at chromosome 19q13.3 to be associated with prostate cancer (PCa) risk. Recently, the rs61752561 SNP (Asp84Asn substitution) in exon 3 of the kallikrein-related peptidase 3 (KLK3) gene encoding prostate-specific antigen (PSA) was reported to be strongly associated with PCa risk (P = 2.3 × 10-8). However, the biological contribution of the rs61752561 SNP to PCa risk has not been elucidated.

METHODS:

Recombinant PSA protein variants were generated to assess the SNP-mediated biochemical changes by stability and substrate activity assays. PC3 cell-PSA overexpression models were established to evaluate the effect of the SNP on PCa pathogenesis. Genotype-specific correlation of the SNP with total PSA (tPSA) concentrations and free/total (F/T) PSA ratio were determined from serum samples.

RESULTS:

Functional analysis showed that the rs61752561 SNP affects PSA stability and structural conformation and creates an extra glycosylation site. This PSA variant had reduced enzymatic activity and the ability to stimulate proliferation and migration of PCa cells. Interestingly, the minor allele is associated with lower tPSA concentrations and high F/T PSA ratio in serum samples, indicating that the amino acid substitution may affect PSA immunoreactivity to the antibodies used in the clinical immunoassays.

CONCLUSIONS:

The rs61752561 SNP appears to have a potential role in PCa pathogenesis by changing the glycosylation, protein stability, and PSA activity and may also affect the clinically measured F/T PSA ratio. Accounting for these effects on tPSA concentration and F/T PSA ratio may help to improve the accuracy of the current PSA test.

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