A PSA SNP Associates with Cellular Function and Clinical Outcome in Men with Prostate Cancer

A KLK3 germline variant analysed in 52,900 PCa patients and 40,470 disease-free controls across three independent cohorts is associated with reduced PCa risk, but, paradoxically, with poor survival outcomes.
The variant exhibited a dual effect; it reduced tumour growth while significantly increasing metastatic potential.
The variant disrupts PSA proteolytic activity, driving distinct tumour phenotypes.
Men with this variant may be less likely to be referred for biopsies due to lower total PSA and higher free-to-total PSA ratios, potentially skewing risk assessment.

Prostate cancer (PCa) is a major global health issue, and the KLK3 gene, which encodes prostate-specific antigen (PSA), is the current clinical biomarker for PCa screening. A germline variant (or single nucleotide polymorphism [SNP]) near KLK3, leading to an amino acid substitution in PSA, was previously identified as a potential DNA change associated with PCa risk. This specific SNP was found to be associated with lower PSA levels and higher frequency in PCa patients compared to non-patient samples, this raises the question of whether its effects are due to the functional impact of PSA on tumour modulation or bias in PSA-based detection methods.

Experimental models show that the cancer cells expressing the variant PSA, display a dual effect: smaller tumour growth with heightened metastatic burden, especially in the bone microenvironment, suggesting that while the variant reduces tumour growth, it enhances metastatic potential.

This variant also disrupts the proteolytic activity of PSA, which has a known function in suppressing tumour progression in metastasis by regulating key signaling pathways, including anti-angiogenic effects.

Crucially, the SNP affects how PSA interacts with serum inhibitors, leading to altered clinical measurements of PSA. This underlines the importance of differentiating PSA levels driven by genetics from those related to disease progression. Clinically, fewer men harbouring this variant could have delayed referrals for prostate biopsies due to lower total PSA levels and a higher free-to-total PSA ratio, which could be misleading in perceiving a reduced risk during standard screening.

These findings have important implications for PCa diagnostics and treatment. Understanding how this PSA variant influences tumour behaviour and affects clinical measurements opens the door for more accurate risk prediction and personalised treatment strategies. Future research should explore the dual role of the variant in both early detection and metastatic disease, potentially leading to better management of PCa patients carrying this SNP.

In conclusion, this study sheds light on the intricate relationship between genetic variation in PSA aka KLK3 gene, and prostate cancer risk, providing valuable insights for improving diagnostic accuracy and therapeutic interventions. The variant not only affects disease progression but also challenges the reliability of PSA-based diagnostic methods, urging a re-evaluation of how such genetic factors are integrated into prostate cancer care.

Written by: Srilakshmi Srinivasan & Jyotsna Batra

School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
Translational Research Institute, Queensland University of Technology, Woolloongabba, Brisbane, Queensland, Australia

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