The role of the human steroid 5-alpha-reductase type II gene in the molecular genetic predisposition to prostate cancer

rostate cancer is a very common disease in older men. Even though distinct US groups exhibit very different risk for the disease, suggesting that there is a genetic basis for the etiology of prostate cancer, the molecular predisposition of this disease is not presently understood.;I utilized the "candidate gene" approach, that is I screened the SRD5A2 gene for mutations, with single strand conformation polymorphism analysis. I report seven missense substitutions and seven polymorphisms in the SRD5A2 gene, with the V89L substitution being the most common. Then, I re-constructed those naturally occurring mutations with site-directed mutagenesis. and I tested the effect of each of the mutations on ;The finding that the A49T mutation is 4-11 times (depending on the race) more frequent in advanced prostate cancer cases than in controls correlates well with its increased in vitro activity. The discovery that the V89L mutation is much more common in low prostate cancer risk Asians than any other group correlates well with its decreased in vivo and in vitro activity. Finally, the finding that the R227Q mutation is only present in Chinese or Chinese Americans (which have very low prostate cancer risk) correlates well with the substantial reduction in the in vitro activity caused by this mutation. Therefore, distinct SRD5A2 alleles predispose people either to or against prostate cancer through altered androgen metabolism. The pharmacological (and other) implications of these discoveries are also discussed.;This work identifies a missense mutation (A49T), in the prostate specific steroid...