Microsatellite polymorphism of steroid hormone synthesis gene CYP11A1 is associated with advanced prostate cancer

Abstract

It is widely recognized that androgen biosynthesis and metabolism are associated with the development and progression of prostate cancer. The human CYP11A1 gene (CYP11A1) encodes the P450scc enzyme, which mediates the first step in sex steroid hormone synthesis. The gene contains a (tttta)n-5 bp tandem repeat microsatellite polymorphism located at 528 bp upstream of the translation initiation site and the CYP11A1 mRNA level may be modulated by the polymorphism. Recent studies suggested that the absence of the shortest (tttta)4 allele of the CYP11A1 polymorphism was associated with a risk of polycystic ovary syndrome and with a hyperandrogenic state in polycystic ovary syndrome patients. In our study which included 278 prostate cancer patients, 213 benign prostatic hyperplasia (BPH) patients and 299 male controls, we explored the association between the CYP11A1 polymorphism and prostate cancer on the hypothesis that the presence of the (tttta)4 allele may increase the risk of the development or progression of prostate cancer. In addition, we measured the serum levels of 6 steroid hormones or their metabolite (i.e., testosterone, free-testosterone, estrone, estradiol, dehydroepiandrosterone and androstendione) in 156 control males subjects and compared those with and without the (tttta)4 allele. The polymorphism was evaluated by PCR amplification of a 145-170 bp fragment followed by polyacrylamid gel electrophoresis. The CYP11A1 allele consisted of 4, 6, 7, 8 and 9 (tttta)-5 bp repeats. There was no significant difference in the genotype frequency as for the presence of the (tttta)4 allele between prostate cancer patients and male controls, and between prostate cancer patients and BPH patients. However, there was a significant difference in the genotype frequency in relation to the disease status. Prostate cancer patients without the (tttta)4 allele had an increased risk of metastatic disease (stage D) compared to those with the (tttta)4 allele [adjusted odds ratio (aOR)=1.76, 95% confidence interval (Cl)=1.07-2.90 and p =0.026]. Patients without the (tttta)4 allele had an increased risk of high grade prostate cancer (Gleason score 8 or more, or poorly differentiated cancer) compared to those with the (tttta)4 allele (aOR=1.79, 95% Cl=1.08-2.97 and p =0.025). No significant difference in the serum levels of 6 steroid hormones or their metabolites was found in the presence or absence of the (tttta)4 allele. Our results suggest that the CYP11A1 polymorphism may have a significant influence on the development of advanced and/or high grade prostate cancer and the absence of the CYP11A1 (tttta)4 allele, i.e., the homozygosity for the (tttta)6 or longer allele, could be a useful marker for the prediction of disease progression of prostate cancer.