Functional annotation of prostate cancer risk associated PSA germline variants

S Srinivasan1, C Stephens1, A Spurdle2, H Koistinen3,  The Practical Consortium4,  Australian Prostate Cancer BioResource1, J Clements1 and J Batra1,2

  1. Australia Prostate Cancer Research Centre - Queensland, Queensland University of Technology, Australia
  2. Molecular Cancer Epidemiology Laboratory, Queensland Institute of Medical Research, Australia
  3. University of Helsinki, Finland
  4. Centre for Cancer Genetic Epidemiology, UK

Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men. Genome-wide association studies have identified two non-synonymous single nucleotide polymorphisms (SNPs), rs61752561:G>A (D84N) and rs17632542:T>C (I161T), within the prostate-specific antigen (PSA)/Kallikrein-3 (KLK3), the current diagnostic marker for PCa. PSA has a role in PCa onset and metastasis. The two SNPs are associated with lower serum-PSA levels and reduced PCa risk. It is unclear if their association with PCa risk is due to lower serum-PSA levels in individuals with susceptibility alleles or have a biological role in prostate pathogenesis. Cell-based studies suggested that the two SNPs reduce the proliferative and migratory capabilities of PC3 cells and in HUVEC cell angiogenesis models, compared to the wild-type PSA expressing cells which may underpin the reduced risk in patients harbouring the susceptibility alleles. Biochemical-assays suggested that the SNP isoforms have a lower proteolytic activity and the T161-PSA variant has a lower protein stability that may also correlate to low serum-PSA levels while the N84-PSA leads to an extra-glycosylation site. Gene expression data from tumour tissues, verified the lower expression of KLK3 mRNA and a KLK3 splice variant for C-allele of the rs17632542 SNP. In conclusion, we have comprehensively investigated the molecular consequences of the two PSA germline variants which may contribute to a potential role in PCa pathogenesis. Further, utilisation of this information into current PSA diagnostic practice may improve the predictive accuracy of the test.