Androgen receptor mutations in prostate cancer

We analyzed the frequency and relevance of mutations in the coding region o f the androgen receptor (AR) in genomic DNA extracted from 137 specimens of prostate cancer. The specimens were obtained from the primary tumors of pa tients affected by stage B disease [15 nonmicrodissected (group 1A) and 84 microdissected (group 1B)] and from the metastatic deposits of individuals with stage D1 disease [8 nonmicrodissected (group 2A) and 30 microdissected (group 2B)] who had not undergone androgen ablation therapy. The study was conducted by PCR-single strand conformational polymorphism (SSCP) analysis of exons 2-8 in the four groups and direct sequence analysis of exon 1 in group 1B. As positive and negative controls, we used genomic DNA extracted from genital skin fibroblasts of patients affected by various forms of andr ogen resistance with known mutations in the AR. To control for genetic inst ability, PCR-SSCP analysis of exon 2 of the human progesterone receptor was carried out on each specimen. The overall number of mutations detected was 11 (8%), No mutations were det ected in any of the 99 patients with stage B disease. Eleven mutations were detected in exons 2-8 in 8 of the 38 patients with stage D1 disease (all i n group 2B). Simultaneous analysis of exon 2 of the progesterone receptor w as carried out, and no SSCP changes mere identified. These data suggest that AR mutations are rare and presumably do not play a role in the initial phase of prostatic carcinogenesis. The presence of a si gnificant number of AR mutations in metastatic disease indicates that mutat ions of this molecule may play a role in the most advanced phases of the na tural history of this disease, either by facilitating growth or acquisition of the metastatic phenotype.