Low-Activity V89L Variant in SRD5A2 Is Associated with Aggressive Prostate Cancer Risk: An Explanation for the Adverse Effects Observed in Chemoprevention Trials Using 5-Alpha-Reductase Inhibitors

• Published in: European urology 2007-10, Vol.52 (4), p.1082-1089
• Main Authors: Cussenot, Olivier, Azzouzi, Abdel-Rahmène, Nicolaiew, Nathalie, Mangin, Philippe, Cormier, Luc, Fournier, Georges, Valeri, Antoine, Cancel-Tassin, Géraldine
• Format: Article
• Language: English
• Subjects: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase - genetics; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase - metabolism; Amino Acid Substitution; Chemoprevention; Cholestenone 5 alpha-Reductase - antagonists & inhibitors; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - therapeutic use; Genetic Variation; Genotype; Humans; Lysine; Male; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Treatment Failure; Urology; Valine
• ISSN: 0302-2838
• DOI: 10.1016/j.eururo.2007.04.008

Abstract Objective The 5-alpha-reductase type 2 ( 5A2 ) enzyme catalyses the irreversible conversion of testosterone to dihydrotestosterone, the most active androgen in the prostate. This key enzyme in prostate gland physiopathology has recently been targeted by using inhibitors for chemoprevention of prostate cancer. However, some controversies have arisen by the observation of greater than expected high-grade tumours in men diagnosed with prostate cancer in the finasteride chemoprevention trial. To help understand the impact of prolonged exposure to low 5A2 activity on prostate cancer risk, we analysed the rather common genetic V89L polymorphism, which has previously been well characterised functionally for determining low enzymatic activities. Methods The study was performed on 1605 white Caucasian French men categorised in 803 patients with prostate adenocarcinoma and 802 matched healthy male controls. The different alleles and genotypes were analysed according to case-control status and the aggressiveness pattern of the tumours. Results The V89L amino acid substitution leading to the homozygous genotype LL increased the risk of clinically significant disease (odds ratio [OR] = 1.89, 95% confidence interval (%95 CI), 1.07–2.74; p = 0.0017) and was also associated with the most aggressive patterns of the disease (OR = 2.56, 95%CI, 1.41–4.63; p = 0.002). Conclusions Our data confirm in a large and homogeneous Caucasian French population that the low-activity V89L variant is associated with an increased risk of aggressive prostate cancer. These results corroborate that long-term exposure to 5A2 inhibitors (chemoprevention) must be evaluated in terms of risk of prostate cancer adverse effects.