The SRD5A2 V89L polymorphism is associated with severity of disease in men with early onset prostate cancer.
BACKGROUND
Emerging evidence indicates that testosterone (T), and not dihydrotestosterone (DHT), is the most relevant androgen that promotes carcinogenesis in the prostate. Steroid 5-alpha reductase type II (SRD5A2) catalyzes the irreversible conversion of T to DHT in male reproductive organs. Because the SRD5A2 gene is highly polymorphic at codon 89, two SRD5A2 isoforms are expressed that differ in K(m) and V(max) values. The more common and rapid catalytic isoform contains a valine residue at position 89; the slower-catalytic variant contains leucine at this position.


METHODS
Thirty-three men with early onset prostate cancer (PCa) were genotyped for the SRD5A2 V89L substitution and other polymorphisms in genes encoding receptors or enzymes that play important roles in pathways of steroid metabolism to ascertain if they were associated with standard clinical measures of disease progression at the time of diagnosis.


RESULTS
The expression of at least one SRD5A2 leucine allele in young men with PCa was associated with more significant disease at the time of presentation, as was defined by pretreatment PSA level, clinical staging and Gleason score when compared with affected subjects harboring the more common SRD5A2 valine variant. A dosage effect of a single leucine allele was evident in heterozygotes, as values of their clinical and pathological variables were consistently situated between the extremes of the homozygous V or L phenotypes.


CONCLUSIONS
The SRD5A2 leucine isoform appears to be acting in a dose-dependent manner as a significant disease-modifying factor in young men diagnosed with PCa.
Scariano
John K
JK
Department of Pathology and Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131-0001, USA.
Treat
Eric
E
Alba
Frances
F
Nelson
Harold
H
Ness
Scott A
SA
Smith
Anthony Y
AY
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics*; D000230:Adenocarcinoma / Q000235:genetics*; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics*; D012307:Risk Factors; D012720:Severity of Illness Index
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase