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

Area of Science:

• Genetics
• Biochemistry
• Oncology

Background:

• Genetic association studies link chromosome 19q13.3 SNPs to prostate cancer (PCa) risk.
• The rs61752561 SNP in the KLK3 gene (encoding PSA) shows strong association with PCa risk.
• The biological mechanisms of rs61752561 SNP's contribution to PCa risk remain unclear.

Purpose of the Study:

• To elucidate the biological contribution of the rs61752561 SNP to PCa pathogenesis.
• To assess SNP-mediated biochemical changes in PSA protein.
• To evaluate the SNP's effect on PCa cell behavior and clinical PSA measurements.

Main Methods:

• Generated recombinant PSA protein variants for stability and activity assays.
• Established PC3 cell-PSA overexpression models to study PCa pathogenesis.
• Correlated SNP genotypes with serum total PSA (tPSA) and free/total (F/T) PSA ratios.

Main Results:

• The rs61752561 SNP alters PSA stability, conformation, and glycosylation, creating an extra glycosylation site.
• The resulting PSA variant exhibits reduced enzymatic activity and affects PCa cell proliferation and migration.
• The minor allele is linked to lower tPSA and higher F/T PSA ratios, suggesting altered immunoreactivity.

Conclusions:

• The rs61752561 SNP influences PCa pathogenesis through altered PSA glycosylation, stability, and activity.
• This SNP may affect the clinically measured F/T PSA ratio, impacting diagnostic accuracy.
• Considering these effects could enhance the precision of current PSA tests for PCa detection.