Nm. Makridakis et al., Association of mis-sense substitution in SRD5A2 gene with prostate cancer in African-American and Hispanic men in Los Angeles, USA, LANCET, 354(9183), 1999, pp. 975-978
Citations number
24
Categorie Soggetti
General & Internal Medicine","Medical Research General Topics
Background Prostate cancer is a very common disease in more-developed count
ries, but its cause is largely unknown. It is an androgen-dependent cancer,
and androgens have been proposed as having a substantial role in predispos
ition to the disease. Thus, variations in androgen metabolism genes may aff
ect risk of this disease,
Methods We 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 C
ohort Study) for a mis-sense substitution in the human prostatic (or type I
I) steroid 5 alpha-reductase (SRD5A2) gene, the product of which controls m
etabolic 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, a
nd overexpressed the enzyme in mammalian tissue culture cells,
Findings The A49T aminoacid substitution in the SRD5A2 gene increased the r
isk 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-max than the normal enzyme (9.9
vs 1.9 nmol min(-1) mg(-1)).
Interpretation The A49T variant of the SRD5A2 gene may be a significant con
tributor to the incidence of prostate cancer in African-American and Hispan
ic men in Los Angeles. We estimate that the population attributable risk du
e to this aminoacid substitution for clinically significant disease is abou
t 8% in both populations. Increased conversion of testosterone to dihydrote
stosterone catalysed by this variant steroid 5 alpha-reductase enzyme may b
e the cause of the increased risk.