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N7 Trinucleotide repeat length polymorphisms of the androgen receptor gene – a step forward in understanding the pathogenesis of prostate cancer

      Introduction and Objectives

      The pathogenesis of prostate cancer (PC) and the mechanisms responsible for progression of this tumor are not fully understood. The fact of androgen dependence of PC is known since 1940s. Action of androgens in prostate gland is mediated through the cytoplasmic molecule of androgen receptor (AR), which in turn stimulates expression of target genes correlated with regulation of cell cycle. Three regions of trinucleotide repeats were identified in the sequence of exon 1 of AR gene, namely (CAG)n, (GGN)n and (CCN)n. Two former are characterized by repeat length polymorphisms, which influence the activity and protein yield of AR. Data from literature suggest that shorter (CAG)n and (GGN)n regions are associated with higher transactivation activity and higher protein yield of the AR and may therefore constitute a risk factor for PC. The aim of our study was to evaluate the correlation between (CAG)n, (GGN)n and (CCN)n repeat length polymorphism of the AR gene and prostate cancer risk in polish population.

      Material and Methods

      The study was approved by local ethics committee. Written informed consent was obtained from 120 consecutive patients with pathologically confirmed prostate cancer, hospitalized in department of urology in Szczecin between 2004 and 2006. Population control group comprised genomic DNA samples isolated from umbilical cord blood samples of 120 male newborns born in the neonatology unit between 2004 and 2005. Amplification of polymorphic regions (CAG)n, (GGN)n and (CCN)n was performed using PCR method with fluorochrome stained primers. Length of microsattelites was assessed by means of capillary electrophoresis and sequencing. Statistic analysis was performed with Statistica 7.0. software.

      Results

      There were repeat length polymorphisms identified in (CAG)n and (GGN)n regions. The number of CCN repeats remained constant in both groups. There was no significant correlation between number of CAG repeats and number of GGN repeats. In comparison with control group, patients with PC had a significantly (p < 0.05) higher frequency of shorter CAG (n ≤ 18 repeats) and GGN (n ≤ 19 repeats) regions.

      Conclusions

      Shorter variants of (CAG)n and (GGN)n microsatellites were already shown to be associated with higher biological activity of androgen receptor. Our current study demonstrated that they are more frequently found in patients with prostate cancer than in population control. These findings suggest their role in pathogenesis of prostate cancer, and make them candidates for future genetic models of PC risk assessment.