Identification and characterization of somatic steroid 5α-reductase (SRD5A2) mutations in human prostate cancer tissue

Abstract

Prostate cancer is a very common disease in industrialized countries and it is known to be androgen-dependent. The human SRD5A2 gene encodes the prostatic (or type II) steroid 5a-reductase, which catalyses the irreversible conversion of testosterone to dihydrotestosterone (DHT), the most active androgen in the prostate. We have sequenced the entire protein-coding region of this locus in 30 microdissected prostate adenocarcinomas. We identified a total of 17 de novo amino-acid substitutions in 13 of these tumors. We also identified six additional silent substitutions. In total, 18 out of 30 (60%) of the tumors examined had de novo somatic substitutions in the prostatic steroid 5a-reductase-coding region. We also characterized all of the SRD5A2 missense substitutions biochemically and pharmacologically, using three 5a-reductase inhibitors, including finasteride. The biochemical parameters of the distinct 5a-reductase missense substitutions varied substantially. We note that two out of the three recurrent SRD5A2 missense substitutions increased 5a-reductase in vitro activity, while the third one is essentially neutral. These findings are consistent with a role for increased DHT levels in the prostate through increased activity of the SRD5A2 locus in prostate cancer progression, in a subset of patients. Our pharmacologic studies also reveal substantial variability for each 5a-reductase inhibitor. These data, therefore, should be taken into account in both prevention as well as therapeutic trials of prostate cancer utilizing 5a-reductase inhibitors.

Novel compound heterozygous mutations in the SRD5A2 gene from 46,XY infants with ambiguous external genitalia

“…3), which strongly suggest a gain-of-function effect. This observation is supported by a previous study showing that some missense SRD5A2 mutations do not impair but increase the steroid 5a-reductase activity (Makridakis et al 2004). …”

Pharmacogenetic analysis of human steroid 5α reductase type II: comparison of finasteride and dutasteride

“…Some of these SRD5A2 mutations resulted in increased enzyme activity and lowered inhibition by finasteride (Makridakis et al 2000(Makridakis et al , 2004. These findings suggest that the presence of specific SRD5A2 mutants that are not efficiently inhibited by finasteride may, at least partially, explain the unexpected finding of an increase in high grade prostate cancer rate in the PCPT (reported by Thompson et al 2003) since these mutants might result in more aggressive growth of tumors.…”

“…We have reported significant genetic and pharmacogenetic variation for both finasteride and dutasteride at the SRD5A2 locus in both somatic prostate cancer tissue and constitutional DNA of prostate cancer patients (Makridakis et al 2000(Makridakis et al , 2004. Some of these SRD5A2 mutations resulted in increased enzyme activity and lowered inhibition by finasteride (Makridakis et al 2000(Makridakis et al , 2004.…”

“…We have reported evidence that increased intraprostatic androgen metabolism, particularly through genetic variants of the enzyme steroid 5 -reductase, may play an important role in both predisposition to prostate cancer (Makridakis et al 1999) as well as prostate cancer progression (Makridakis et al 2004). Human prostatic (type II) steroid 5 -reductase is encoded by the SRD5A2 gene located in chromosome band 2p23 (Russell & Wilson 1994).…”

“…The kinetics of steroid 5 -reductase inhibition that we reported previously (Makridakis et al 2000(Makridakis et al , 2004 were based on 10-min incubations for all enzyme variants. Finasteride, however, dissociates from the enzyme very slowly, and therefore is a time-dependent inhibitor of steroid 5 -reductase (Faller et al 1993, Tian et al 1994, 1995.…”