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[Cancer Research 54, 2861-2864, June 1, 1994]
© 1994 American Association for Cancer Research
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Frequent Detection of Codon 877 Mutation in the Androgen Receptor Gene in Advanced Prostate Cancers1

Jaya P. Gaddipati, David G. McLeod, Howard B. Heidenberg, Isabell A. Sesterhenn, Michael J. Finger, Judd W. Moul2 and Shiv Srivastava2

Urology Service, Walter Reed Army Medical Center, Washington, DC 20307-5001 [J. P. G., D. G. M., H. B. H., M. J. F., J. W. M., S. S.]; Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, 20814-4799 [J. P. G., D. G. M., H. B. H., M. J. F., J. W. M., S. S.]; and Armed Forces Institute of Pathology Washington, DC 20306-6000 [I. A. S.]

Prostatic tissue specimens derived from transurethral resections of patients with metastatic prostate cancer were analyzed for genetic alterations in the hormone-binding domain of the androgen receptor (AR) gene. Direct sequencing of the polymerase chain reaction-derived DNAs of 6 of 24 specimens revealed a codon 877 mutation (ACT -> GCT, Thr -> Ala) in the hormone-binding domain of the AR gene. This same AR mutation has been reported previously in a metastatic prostate cancer cell line, LNCaP, where this mutation confers upon the AR an altered ligand-binding specificity which is stimulated by estrogens, progestagens, and antiandrogens. It is possible that analogous to an activated/altered growth factor receptor oncogene, codon 877 mutant AR with altered ligand binding may provide a selective growth advantage in the genesis of a subset of advanced prostate cancer. Although estrogens are used infrequently, antiandrogens are used increasingly in hormonal therapy for patients with advanced prostate cancer. The stimulatory effect of these therapeutic agents on the codon 877 mutant AR further suggests that this frequently observed AR mutation may contribute to the treatment refractory disease.

1 This work was supported by the Center for Prostate Disease Research Grant G190CM, a program of the Henry M. Jackson Foundation for the Advancement of Military Medicine. The assertions and opinions contained herein are the private views of the authors and should not be construed as reflecting views of the Department of Defense or the United States Army.

2 To whom requests for reprints should be addressed, at Uniformed Services University of the Health Sciences, F. Edward Harbert School of Medicine, 4301 Jones Bridge Road, Bethesda, MD 20814-4799.

Received 3/ 9/94. Accepted 4/21/94.




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Copyright © 1994 by the American Association for Cancer Research.