Androgen Receptor Mutations in Prostate Cancer

Abstract

We analyzed the frequency and relevance of mutations in the coding region of the androgen receptor (AR) in genomic DNA extracted from 137 specimens of prostate cancer. The specimens were obtained from the primary tumors of patients 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 androgen resistance with known mutations in the AR. To control for genetic instability, 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 detected 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 in group 2B). Simultaneous analysis of exon 2 of the progesterone receptor was carried out, and no SSCP changes were 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 significant number of AR mutations in metastatic disease indicates that mutations of this molecule may play a role in the most advanced phases of the natural history of this disease, either by facilitating growth or acquisition of the metastatic phenotype.

Molecular Biology of the Androgen Receptor

“…Molecular analysis of prostate cancer tissues faces hurdles because of the heterogeneous nature of the tissue samples and of the tumor itself. 175,176 Microdissection of tumor tissue to enrich for cancer cell DNA has yielded a higher fraction of samples with detectable AR mutations. 166 Analysis of primary prostate tissues with epitope-specific AR antibodies and careful microdissection disclosed up to 44% AR mutations in prostate cancer samples.…”

“…Other reviews on AR, its coactivators, physiology, endocrinology, and its role in prostate cancer should also be consulted. [1][2][3][4][5][6][7][8][9][10] The AR gene is located on the X chromosome and therefore is single-copy in males, which allows for the phenotypic manifestation of mutations without the influence of a wild-type codominant allele. Medical geneticists have cataloged more spontaneous mutations of human AR than of any other gene in part because AR is not essential to the formation of a viable human organism.…”

Androgen receptor‐related diseases: what do we know?

“…As the NTD of the AR receptor is a highly conserved region, deleterious mutations are relatively rare (mutations have been found in only 8% of the codons in this domain). The majority of the mutations prematurely terminate the translational process through stop codons or frameshift mutations from nucleotide insertions/deletions (Gelmann, ). One study discovered a mutation in the fourth nucleotide which decreases the translational efficiency of the AR mRNA in a PAIS patient (Choong et al ., ,b).…”

“…The DNA‐binding domain (including the two prominent zinc fingers), on the other hand, contains a significantly higher percentage (27%) of codons that exhibit mutations (Gelmann, ). Mutations in this domain – which consist mainly of single nucleotide substitutions – cause the DNA‐binding/dimerization activity of the protein to be defective, leading to impaired or absent transcriptional activation by the AR (Gast et al ., ).…”

“…Only six mutations have been reported in the hinge region of the AR (only 8% of codons exhibited mutations) (Gelmann, ), possibly signifying that this region affords flexibility in its genetic makeup. Some variations in the gene sequence are not significantly detrimental to AR function (Greep, ).…”