Androgen receptor polymorphisms: Association with prostate cancer risk, relapse and overall survival

Several reports have suggested that one or both of the trinucleotide repeat polymorphisms in the human androgen receptor (hAR) gene, (CAG)(n) coding f or polyglutamine and (GGC)(n) coding for polyglycine, may be associated wit h prostate cancer risk; but no study has investigated their association wit h disease progression. We present here a study of both hAR trinucleotide re peat polymorphisms not only as they relate to the initial diagnosis but als o as they are associated with disease progression after therapy. Lymphocyte DNA samples from 178 British Caucasian prostate cancer patients and 195 co ntrol individuals were genotyped by PCR for the (CAG)(n) and (GGC)(n) polym orphisms in hAR. Univariate Cox proportional hazard analysis indicated that stage, grade and GGC repeat length were individually significant factors a ssociated with disease-free survival (DFS) and overall survival (OS). The r elative risk (RR) of relapse for men with more than 16 GGC repeats was 1.74 (95% CI 1.08-2.79) and of dying from any cause, 1.98 (1.13-3.45). Adjustin g for stage and grade, GGC effects remained but were not significant (RRDFS = 1.60, p = 0.052; RROS = 1.65, p = 0.088). The greatest effects were in s tage T1-T2 (RRDFS = 3.56, 95% CI 1.13-11.21) and grade I (RRDFS = 6.47, 95% CI 0.57-72.8) tumours. No differences between patient and control allele d istributions were found by odds-ratio analysis, nor were trends with stage or grade evident in the proportion of short CAG alleles. Non-significant tr ends with stage and grade were found in the proportion of short GGC alleles . The (GGC), polymorphism in this population is a significant predictor of disease outcome. Since the (GGC)(n) effect is strongest in early-stage tumo urs, this marker may help forecast aggressive behaviour and could be used t o identify those patients meriting more radical treatment. Int. J. Cancer ( Pred. Oncol.) 84:458-465, 1999. (C) 1999 Wiley-Liss, Inc.