Advanced

Prostate cancer risk-associated single-nucleotide polymorphism affects prostate-specific antigen glycosylation and its function

Srinivasan, Srilakshmi; Stephens, Carson; Wilson, Emily; Panchadsaram, Janaththani; DeVoss, Kerry; Koistinen, Hannu; Stenman, Ulf Håkan; Brook, Mark N.; Buckle, Ashley M. and Klein, Robert J., et al. (2019) In Clinical Chemistry 65(1). p.1-9
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 2.3 108). 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.... (More)

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 2.3 108). 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.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Clinical Chemistry
volume
65
issue
1
pages
1 - 9
publisher
American Association for Clinical Chemistry
external identifiers
  • scopus:85059503148
ISSN
0009-9147
DOI
10.1373/clinchem.2018.295790
language
English
LU publication?
yes
id
fe87050f-7dea-4b49-98f2-d878f3ace6f2
date added to LUP
2019-01-22 08:45:35
date last changed
2019-06-19 04:07:48
@article{fe87050f-7dea-4b49-98f2-d878f3ace6f2,
  abstract     = {<p>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<sup>8</sup>). 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.</p>},
  author       = {Srinivasan, Srilakshmi and Stephens, Carson and Wilson, Emily and Panchadsaram, Janaththani and DeVoss, Kerry and Koistinen, Hannu and Stenman, Ulf Håkan and Brook, Mark N. and Buckle, Ashley M. and Klein, Robert J. and Lilja, Hans and Clements, Judith and Batra, Jyotsna},
  issn         = {0009-9147},
  language     = {eng},
  number       = {1},
  pages        = {1--9},
  publisher    = {American Association for Clinical Chemistry},
  series       = {Clinical Chemistry},
  title        = {Prostate cancer risk-associated single-nucleotide polymorphism affects prostate-specific antigen glycosylation and its function},
  url          = {http://dx.doi.org/10.1373/clinchem.2018.295790},
  volume       = {65},
  year         = {2019},
}