부산대학교 도서관

BackgroundProstate cancer is a very common disease in more-developed countries, but its cause is largely unknown. It is an androgen-dependent cancer, and androgens have been proposed as having a substantial role in predisposition to the disease. Thus, variations in androgen metabolism genes may affect risk of this disease.MethodsWe screened 216 African-American and 172 Hispanic men with prostate cancer, and 261 African-American and 200 Hispanic healthy men (controls), from a large prospective cohort study (the Hawaii-Los Angeles Multiethnic Cohort Study) for a mis-sense substitution in the human prostatic (or type II) steroid 5[alpha]-reductase (SRD5A2) gene, the product of which controls metabolic activation of testosterone to dihydrotestosterone. This mis-sense substitution results in an alanine residue at codon 49 being replaced with threonine (A49T). We also reconstructed this mutation in the SRD5A2 cDNA, and overexpressed the enzyme in mammalian tissue culture cells.FindingsThe A49T aminoacid substitution in the SRD5A2 gene increased the risk of clinically significant disease 7.2-fold in African-American men (95% CI=2.17-27.91; p=0.001) and 3.6-fold in Hispanic men (1.09-12.27; p=0.04). The mutant enzyme had a higher in-vitro V[sub max] than the normal enzyme (9.9 vs 1.9 nmol min[sup -1] mg-[sup 1]).InterpretationThe A49T variant of the SRD5A2 gene may be a significant contributor to the incidence of prostate cancer in African-American and Hispanic men in Los Angeles. We estimate that the population attributable risk due to this aminoacid substitution for clinically significant disease is about 8% in both populations. Increased conversion of testosterone to dihydrotestosterone catalysed by this variant steroid 5[alpha]-reductase enzyme may be the cause of the increased risk. [ABSTRACT FROM AUTHOR]