Short alleles of both GGN and CAG repeats at the exon-1 of the androgen receptor gene are associated to increased PSA staining and a higher Gleason score in human prostatic cancer

Abstract

The exon 1 of the human androgen receptor (AR) gene contains two length polymorphisms of CAG (polyglutamine) and GGN (polyglycine). “In vitro” experiments suggest that the larger GGN repeats provide a lower AR-protein yield, whereas the larger CAG repeats decrease the AR transcriptional activity, both decreasing the AR signalling intensity. Here we have tested such possibilities in human prostatic cancer (CaP) specimens. We used 72 archival samples of radical prostatectomy. Parallel slides were used for AR protein or PSA immunohistochemistry, and for genotyping studies. Polymorphisms were genotyped by PCR, fragment length analysis and sequencing selected samples. The AR staining was positively correlated with the Gleason score ( r = 0.320; P = 0.005), but it was not correlated to CAG or GGN repeat length or PSA staining. The number of GGN repeats was negatively correlated to the intensity of PSA staining ( r = −0.243; P = 0.04). Combination of short alleles of both tracts was significantly higher in: the heavier stained tertiles for PSA ( P = 0.03) and AR ( P = 0.06); and in the subgroup of samples having a Gleason score of 7 or higher ( P = 0.021). The results support the hypothesis that the shorter alleles of CAG and GGN repeats in the AR gene are associated to an increased AR signalling intensity in human prostate cancer, and with more aggressive forms of the disease.