Significance of the CAG repeat polymorphism of the androgen receptor gene in prostate cancer progression

Purpose: The CAG repeat polymorphism of the androgen receptor gene has been associated with an increased prostate cancer risk, and the repeat length correlated with cancer stage and grade at presentation. Men with an allele length of less than or equal to 18 CAG repeats have a 2-fold increase in risk for high-stage or high-grade prostate cancer, compared with patients with a longer CAG repeat. We examined the significance of the CAG repeat polymorphism of the androgen receptor gene for predicting prostate cancer progression among 318 patients treated by radical prostatectomy for clinically localized prostate cancer between 1987 and 1994. Materials and Methods: Leukocyte DNA was collected and genotyping of the CAG repeat polymorphism was performed using a PCR-based direct sequencing method. Risk ratios were calculated for developing biochemical recurrence for patients associated with an allele length of less than or equal to 18 CAG repeats, compared with patients with an allele length of >18 CAG repeats, controlling for grade, stage and serum PSA level at diagnosis using Cox proportional hazard modeling. Results: Overall, the CAG repeat allele was not predictive of recurrence; tumor grade, stage and PSA level at diagnosis were the only predictors of recurrence in a multivariate analysis. However, for patients at low risk for recurrence (Gleason score 2 to 6, stage pT2, and PSA less than or equal to 10 ng./ml.), the relative risk of recurrence associated with an allele of less than or equal to 18 CAG repeats was 8.07 (95% C.I., 2.02 to 32.2, p = 0.004), compared with patients with an allele length of >18 CAG repeats. In contrast, for patients at high risk of recurrence (Gleason score greater than or equal to 7, stage pT3/4, or PSA > 10 ng./ml.), the relative risk associated with the less than or equal to 18 CAG repeat allele was 0.72 (95% C.I., 0.33 to 1.57, p = 0.41), compared with patients with the >18 CAG repeat allele. Conclusions: The length of the CAG repeat polymorphism of the androgen receptor gene may be important for prostate cancer recurrence among patients who are otherwise at low risk for recurrence after radical prostatectomy. These findings have potential implications for patient selection for adjuvant treatment, and for the development of novel treatments.