Karina Dalsgaard Sørensen

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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Srilakshmi Srinivasan, Translational Research Institute, Woolloongabba, Queensland, Australia.
  • ,
  • Carson Stephens, Translational Research Institute, Woolloongabba, Queensland, Australia.
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  • Emily Wilson, Infection and Immunity Program and the Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
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  • Janaththani Panchadsaram, Translational Research Institute, Woolloongabba, Queensland, Australia.
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  • Kerry DeVoss, Endocrinology, QML Pathology, Mansfield, Queensland, Australia.
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  • Hannu Koistinen, Department of Clinical Chemistry, Biomedicum Helsinki, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
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  • Ulf-Håkan Stenman, Department of Clinical Chemistry, Biomedicum Helsinki, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
  • ,
  • Mark N Brook
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  • Ashley M Buckle, Infection and Immunity Program and the Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
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  • Robert J Klein, Icahn Institute for Genomics and Multiscale Biology and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
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  • Hans Lilja, Department of Translational Medicine, Clinical Virology, Lund University, Malmö, Sweden.
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  • Judith Clements, Translational Research Institute, Woolloongabba, Queensland, Australia.
  • ,
  • Jyotsna Batra, Translational Research Institute, Woolloongabba, Queensland, Australia.
  • ,
  • The PRACTICAL Consortium

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.

Original languageEnglish
JournalClinical Chemistry
Volume65
Issue1
Pages (from-to)e1-e9
ISSN0009-9147
DOIs
Publication statusPublished - Jan 2019

    Research areas

  • Aged, Cell Movement, Cell Proliferation, Genetic Predisposition to Disease, Glycosylation, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Prostate-Specific Antigen/genetics, Prostatic Neoplasms/genetics, Proteolysis

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