Is the androgen receptor CAG repeat length significant for prostate cancer?

In this issue, Chen et al. (1) report results from a nested case-control study that examines a CAG repeat region in exon 1 of the androgen receptor gene (AR) in relation to risk of prostate cancer. In contrast with most of the early reports (2–4), but consistent with several more recent reports (5–9), fewer AR CAG repeats were not associated with higher risk of prostate cancer. The study by Chen et al. (1), conducted within the Beta Carotene and Retinol Efficacy Trial, was based on 300 cases and 300 controls, and, thus, reasonably powered to observe a moderate-sized effect. The biological rationale to study this polymorphic region in relation to prostate cancer, an androgen-dependent disease in its initial stages, is strong. This CAG repeat encodes a polyglutamine chain in the transactivation region of the AR (10), and longer polyglutamine chains hinder the transactivation activity of the AR in vitro (11). Moreover, the number of repeats have been shown to correlate with a number of androgenrelated clinical conditions; specifically, a high number of repeats appears to adversely influence fertility and spermatogenesis (12), and bone density (13), and fewer repeats are associated with increased risk of baldness (14) and benign prostatic hyperplasia (15–18). The initial studies showing that fewer AR CAG repeats related to a higher risk of prostate cancer (2–4) supported the hypothesis that androgenicity influences the development of prostate cancer. These findings also offered some insight into racial differences in susceptibility for prostate cancer because high-risk groups such as AfricanAmericans tend to have fewer AR CAG repeats, and low-risk groups in Asia have more repeats (10). It is unclear why the earlier finding of an association between fewer AR CAG repeats and prostate cancer risk has been difficult to confirm. Because prostate cancer is a heterogeneous disease, it is important to seek explanations for the apparently discordant results. Twelve studies have provided some relevant data on the topic. Four studies reported a statistically significant inverse association between AR CAG repeat number and prostate cancer risk (2, 4, 19, 20). Two of these studies (2, 4), conducted in the United States, are notable in that they largely included cases diagnosed at relatively young ages, were conducted at least partly before widespread PSA screening, and found that the CAG association tended to be stronger for more aggressive or advanced prostate cancers. A study of mostly advanced, symptomatic prostate cancer cases conducted in China, where PSA screening is not conducted, found a statistically significant association for repeats 22 versus 22 (RR 1.65; Ref. 19). Finally, a small study of 40 cases and 40 controls conducted in South Africa found an inverse association between AR CAG repeat number and risk of prostate cancer (P 0.02), and among patients, those with aggressive disease had fewer CAG repeats (P 0.02; Ref. 20). Seven studies did not find an overall relationship between AR CAG repeats and risk of prostate cancer (1, 5–9, 21). A notable feature of these studies is that almost all of the cases were diagnosed during the era of PSA screening. Additionally, most of these studies examined various subgroups based on age, and a consistent finding was that AR CAG repeats appeared most relevant for prostate cancers diagnosed at younger ages. In all five of the studies that presented results stratified by age group, a modest association was suggested for the youngest age group, usually cases diagnosed before the age of 60 or 65. Comparing AR CAG repeats 22 versus 22 in the youngest age group, the RRs were: RR 1.47 (3); RR 1.72 (5); RR 1.36 (6); RR 1.48 (1); and RR 1.08 for each decrement in CAG repeats (7). In contrast, no associations were observed in older age groups in all of these studies. Two other studies, also with overall null results, did not present results stratified by age but did find that younger cases tended to have a statistically significant higher frequency of fewer AR CAG repeats (8, 9). In another study, which did not have controls, younger cases tend to have fewer AR CAG repeats than older cases (P 0.02; Ref. 22). Only one study did not show this pattern of an association among younger cases or age of diagnosis (21). In that study, only 10% of cases were 60 years. To summarize, some patterns emerge from the discordant results. First, the studies with the strongest support that AR CAG length repeat number influences prostate cancer are those conducted in populations with minimal PSA screening (2, 4, 8, 19, 20). Secondly, the cancers most strongly affected appear to have a relatively aggressive phenotype (2, 4, 7, 8, 19, 20). Thirdly, the prostate cancer cases that tend to occur at younger ages tend to be most strongly related to AR CAG repeat number (1, 2, 4, 6–9, 20, 22). The relation between fewer AR CAG repeats and higher risk of aggressive prostate cancer in younger men suggests that 1 To whom requests for reprints should be addressed, at Harvard Medical School, Harvard School of Public Health, 665 Huntington Avenue, Building 2, Room 331, Boston, MA 02115. Received 6/17/02; accepted 6/17/02. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 2 The abbreviations used are: AR, androgen receptor; PSA, prostate-specific antigen; RR, relative risk. 985 Vol. 11, 985–986, October 2002 Cancer Epidemiology, Biomarkers & Prevention