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A Prevalent Missense Substitution That Modulates Activity of Prostatic Steroid 5-Reductase¹

Department of Biochemistry and Molecular Biology [N.M., J.K.V.R.], Institute for Genetic Medicine [N.M., B.E.H., J.K.V.R.], Department of Preventive Medicine [R.K.R., M.C.P., M.C.Y., B.E.H.], and Department of Obstetrics and Gynecology [L. C., F.Z.S.], University of Southern California School of Medicine, USC/Norris Comprehensive Cancer Center, HMR413, 2011 Zonal Avenue, Los Angeles, CA 90033-1034; Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, Hawaii 96813 [L.N.K.]; and Department of Community, Occupational and Family Medicine, National University of Singapore, Singapore 0511 [C-Y. S.]

Prostate cancer is the most common serious cancer diagnosed in men in the United States. This disease is also characterized by a striking racial/ethnic variation in incidence: highest in African-Americans, intermediate in Caucasians, slightly lower in Latinos, and lowest in Asians. Ample biochemical and epidemiological evidence suggests a role for androgens, particularly testosterone and dihydrotestosterone, in prostate cancer etiology. We have analyzed a candidate gene for prostate cancer, tSRD5A2, encoding prostatic steroid 5-reductase type II, which converts testosterone into the more bioactive dihydrotestosterone, for mutations. We report here one amino acid substitution, V89L, which replaces valine at codon 89 with leucine. This substitution is a "germline" (constitutional) DNA polymorphism, and it is common, panethnic, and reduces in vivo steroid 5-reductase activity. This substitution is particularly common among Asians and may explain the low risk for prostate cancer in this population.

¹ This work was supported by Grants CD 53890 (to M. C. Y.) and CA 68581 (to J. K. V. R.).

² To whom requests for reprints should be addressed, at USC-School of Medicine, Institute for Genetic Medicine, 2011 Zonal Avenue, HMR 413, Los Angeles, CA 90033. Phone: (213) 342-1529; Fax: (213) 342-2764; E-mail: reichard@zygote.hsc.usc.edu.

Received 12/ 2/96. Accepted 1/27/97.

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