FREQUENT DETECTION OF CODON-877 MUTATION IN THE ANDROGEN RECEPTOR GENE IN ADVANCED PROSTATE CANCERS

Prostatic tissue specimens derived from transurethral resections of pa tients with metastatic prostate cancer were analyzed for genetic alter ations in the hormone-binding domain of the androgen receptor (AR) gen e. 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 mutati on has been reported previously in a metastatic prostate cancer cell l ine, LNCaP, where this mutation confers upon the AR an altered ligand- binding specificity which is stimulated by estrogens, progestagens, an d antiandrogens. It is possible that analogous to an activated/altered growth factor receptor oncogene, codon 877 mutant AR with altered lig and binding may provide a selective growth advantage in the genesis of a subset of advanced prostate cancer. Although estrogens are used inf requently, antiandrogens are used increasingly in hormonal therapy for patients with advanced prostate cancer. The stimulatory effect of the se therapeutic agents on the codon 877 mutant AR further suggests that this frequently observed AR mutation may contribute to the treatment refractory disease.