The prostate is an androgen-regulated organ and androgen receptor co-activators such as ARA24 and p160 are expressed in prostate tissue (see Chapter 12). Binding of these co-activators to the CAG repeat tract, which represents the androgen receptor's co-activator binding site, is reduced with increasing length of triplet numbers. Hence, the prostate should be an organ, in which effects of the CAG repeat polymorphism are visible. In general, there is a substantial difference in the incidence of prostate cancer between ethnic groups, with African Americans having a 20-to 30-fold higher incidence than East Asians (Hsing et al. 2000b). Such disparity cannot be explained entirely by screening bias in different populations. Also after multiple adjustments for ethnic and screening differences a significant contrast in incidence rates between African Americans, Caucasians and Asians is found (Platz etal. 2000; Ross etal. 1998).
It can be assumed that a polymorphism of the AR with the capacity to modulate androgen effects has an influence on the fate of malignant cells in the prostate. Thus, with shorter CAG repeats, an earlier onset of the disease would be observed, as well as an association with aggressiveness of the tumor. Investigation of a younger study group would then lead to the supposition of an increased risk to develop prostate cancer. While this would hold true for a specific younger age group, it is likely that the effect cannot be observed when older men are also involved since the overall incidence of prostate cancer is high. Stratification for life style factors and multidimensional matching of controls in a sufficient number of subjects is a prerequisite for respective investigations: this is best met by eight studies (Balic et al. 2002; Beilin et al. 2001; Correa-Cerro et al. 1999; Giovannucci et al. 1997; Hsing etal. 2000a; Latil etal. 2001; Platz etal. 2000; Stanford etal. 1997). Seven of these described an independent contribution of the CAG repeat polymorphism to prostate cancer, either to the age of onset or to the general risk of development. The age of the study group, timepoint and intensity of diagnostic performance varying with the location of the study most likely influence the result as to whether it is seen as earlier onset or higher risk. The putative association with disease stage is also likely to be influenced by such factors. Each triplet may hence account for a 3 to 14% risk for prostate cancer (Stanford etal. 1997). In conclusion, it is likely that the genesis of prostate cancer cells is not induced by androgens, but that stronger androgenicity induced by ARs with shorter polyglutamine stretches contributes to a faster development of these cells and this might be seen either as earlier onset of or as higher risk for prostate cancer, depending on the age of the study group.
Another aspect is the putative relation between benign hyperplasia of the prostate (BPH) and the CAG repeat polymorphism of the AR gene. BPH consists of the overgrowth of tissue within the transition zone and periurethral area of the prostate. This is histologically defined as epithelial and fibromuscular hyperplasia (Price etal. 1984). One factor modulating androgenic exposure is the cellular level of androgens, particularly dihydrotestoterone. The influence of the CAG repeat polymorphism causes variations in such effects as demonstrated by several studies. The two largest studies comparing matched healthy controls (n = 1041 and n = 499) and BPH patients (n = 310 and n = 449) described the odds ratio for BPH surgery or an enlarged prostate gland to be 1.92 (p = 0.0002) when comparing CAG repeat length of 19 or less to 25 or more. For a six-repeat decrement in CAG repeat length, the odds ratio for moderate or severe urinary obstructive symptoms from an enlarged prostate gland was 3.62 (p = 0.004) (Giovannucci etal. 1999a; 1999b). Similarly, adenoma size was found to be inversely associated with the number of CAG repeats in 176 patients vs. 41 controls (Mitsumori et al. 1999). Prostate growth during androgen substitution is also significantly modified by the CAG repeat polymorphism (see below).
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