Polymorphic CAG repeats in the androgen receptor gene, prostate-specific antigen polymorphism and prostate cancer risk
Andrea Gsur1,5,
Martin Preyer1,
Gerald Haidinger2,
Thomas Zidek2,
Stephan Madersbacher3,4,
Georg Schatzl3,
Michael Marberger3,
Christian Vutuc2 and
Michael Micksche1
1 Division of Applied and Experimental Oncology, Institute of Cancer Research,
2 Division of Epidemiology, Institute of Cancer Research and
3 Department of Urology, University of Vienna, Austria
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Abstract
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As the development of prostate cancer is androgen-dependent, it has been hypothesized that variation in transcriptional activity by the androgen receptor (AR) related to polymorphic CAG repeats in exon 1, influences prostate cancer risk. The AR regulates gene transcription by binding to androgen-response elements (AREs) in target genes, such as the prostate-specific antigen (PSA). In the ARE-I sequence of the PSA gene an adenine to guanine polymorphism is described. It has been hypothesized that the AR binds the two PSA alleles (A and G) with differing affinities and may, thereby, differentially influence prostate cancer risk. To examine the role of the polymorphisms in the AR and PSA genes in prostate cancer susceptibility, we conducted a case-control study of Austrian Caucasians with 190 newly diagnosed prostate cancer patients and 190 age-matched control men with benign prostatic hyperplasia (BPH). The polymorphisms were determined by polymerase chain reaction (PCR)-based methods using DNA from peripheral white blood cells. Logistic regressions were performed to calculate odds ratios (OR) and confidence limits (CL) and to control for possible confounders. Our data provide no evidence for an association between prostate cancer and CAG repeat length. However, we found a significant influence of the ARE-I PSA polymorphism on prostate cancer risk, when calculating the combination of the A/G and G/G genotypes relative to subjects with the A/A genotype (OR = 0.63; 95% CL 0.390.99; P = 0.048), suggesting that the G allele has a protective effect. In a case analysis according to Gleason score, the PSA G/G genotype was significantly more frequent in patients with Gleason score >7 (35.1%) than in patients with Gleason score <7 (21.5%), providing evidence that the PSA G/G genotype is associated with more advanced disease at time of diagnosis. However, the ambivalent role of the PSA during prostate carcinogenesis needs further investigation.
Abbreviations: AR, androgen receptor; ARE, androgen response element; BPH, benign prostatic hyperplasia; CL, confidence limit; IQR, interquartile range; OR, odds ratio; PSA, prostate-specific antigen.
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Introduction
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Despite the substantial public health impact of prostate cancer little is known about its aetiology. The accepted risk factors for the development of prostate cancer are advanced age, familial predisposition and potentially ethnicity. Furthermore, the development and progression of prostate tumours are influenced by androgens (1). The action of androgens is mediated through the androgen receptor (AR), a ligand-dependent transcription factor. The human AR gene, located on chromosome Xq11-12 (2), has been considered to be a candidate prostate cancer gene. Several molecular epidemiological studies have provided evidence in support of X-linked prostate cancer susceptibility genes (35).
Functional organization of the AR is like other members of the steroid receptor family: an N-terminal transcriptionactivation domain, encoded by exon 1, a highly conserved DNA binding domain, consisting of two zinc finger elements and a C-terminal androgen binding domain (6,7). The exon 1 of the AR contains several polymorphic repeats; the most variable is a polymorphic CAG repeat, which encodes a polyglutamine chain (8). The number of CAG repeats ranges in ~75% of Caucasians from 19 to 25 with an average of 20 (9). Because the length of the polymorphic CAG trinucleotide repeat is inversely correlated with the transactivation function of the AR in vitro (10), it has been proposed that men with shorter repeats will be at higher risk for prostate cancer (11).
The AR binds to the androgen response elements (ARE) in the regulatory region of target genes, which are largely unknown. One candidate is the prostate-specific antigen gene (PSA), a kallikrein-like serine protease (12), which is synthesized by the luminal epithelial cells of the human prostate. Despite the wide use of serum levels measurement of PSA for early detection and monitoring of patients with prostate cancer, the role of PSA in prostate physiology is still unclear. PSA seems to have both pathogenic and also protective functions on prostate cancer. Data indicating a role of PSA as an IGFBP-3 protease, thereby increasing bioavailable IGF-I and IGF-II, which may have stimulatory effects on prostatic cell proliferation (13). But on the other hand, PSA may function in tumours as an anti-angiogenic protein (14).
The PSA expression is regulated by androgens, as mediated by the AR. At least three AREs have been identified in the PSA gene promoter, at positions -170 (ARE-I), -394 (ARE-II) and approximately -4200 (ARE-III) in a far upstream enhancer region, respectively. A single nucleotide polymorphism, an adenine to guanine substitution at position -158 in the ARE-I sequence of the PSA gene has been described (15). It has been hypothesized that the AR binds the two PSA alleles (A and G) with differing affinity and may, thereby, differently influence prostate cancer risk (16).
The purpose of this study was to examine the association between prostate cancer risk and polymorphisms in two genes involved in the androgen pathway, the CAG repeat length in the AR and ARE-I PSA polymorphism. Therefore, we conducted a case-control study of 190 newly diagnosed patients with histologically verified, previously untreated prostate cancer and 190 age-matched control patients with lower urinary tract symptoms due to benign prostatic hyperplasia (BPH)/benign prostatic enlargement, in whom the presence of prostate cancer was carefully excluded either clinically or histologically.
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Materials and methods
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Study population
This case-control study was conducted at the University of Vienna from October 1998 to January 2001. Cases were Caucasian patients (n = 190) with previously untreated, histologically verified prostate cancer. The diagnosis of prostate cancer was made by transrectal ultrasound (TRUS) guided biopsies in all patients. The indication for prostate biopsy was either a suspicious finding on digital rectal examination (DRE) and/or elevated serum levels of PSA. Further diagnostic work-up in these patients included a nuclear bone scan. The control group consisted of 190 men with lower urinary tract symptoms due to BPH. In BPH patients prostate cancer was excluded either clinically by negative DRE and negative serum PSA according to age-specific reference values (17) or histologically by ultrasound guided transrectal prostate biopsies or transurethral resection of the prostate. Serum total and free PSA concentrations were determined by the equimolar AxSYM PSA assay (Abbott Laboratories, Chicago) with calculation of the free/total PSA ratio. Prostate volume was assessed by TRUS in all prostate cancer patients and controls. Controls were matched to the cancer patients on the basis of age (±2 years) in a ratio of 1:1. Written consent was obtained from all participants, and research protocols were approved by the institutional review board at the University of Vienna.
Genotyping
Mononuclear cells were isolated by Ficoll-Paque (Amersham Pharmacia Biotech, Arlington Heights, IL) gradient centrifugation from heparinized blood. Genomic DNA was extracted from mononuclear cells, using QIAmp Blood Kit (Qiagen Hilden, Germany).
The PSA polymorphism was determined by PCRRFLP method. Briefly, a 300 bp fragment containing the A
G polymorphism was amplified by PCR as described by Xue et al. (16). A 7 µl aliquot of the PCR product was digested with 2 U of restriction enzyme NheI (New England Biolabs, Hitchin, UK) at 37°C for 4 h and separated on a 2% ethidium bromide-stained agarose gel. The three possible genotypes (A/A, A/G and G/G) were distinguished by three distinct banding patterns, depending on the presence or absence of the NheI restriction site.
The CAG repeat length was determined by analysing the size of a PCR product containing the polymorphic microsatellite. An ~290 bp fragment was amplified by PCR using a pair of primers as described by Giovanucci et al. (9), the forward primer was fluorescently labelled with FAM. A total volume of 50 µl reaction mixture contained 100 ng DNA, PCR buffer (Applied Biosystems, Norwalk, CT), 1.5 mM MgCl2 (Applied Biosystems), 200 µmol deoxynucleotide triphosphate (Roche Diagnostics, Vienna, Austria), 20 pmol of each primer, and 1.5 U Taq Polymerase (Applied Biosystems). PCR condition was an initial denaturation step for 5 min at 94°C, 33 cycles at 94°C for 30 s, 59°C for 30 s and 72°C for 30 s with a final elongation step at 72°C for 7 min. A 1 µl aliquot of the PCR product was dissolved in 15 µl formamide (Life Technologies, Gathersburg, MD) with 0.4 µl of Genescan-500 (ROX) standard (Applied Biosystems) and denaturated for 5 min at 94°C. The size of the PCR products was determined using an ABI Prism 310 Genetic Analyzer with Genescan software (Applied Biosystems). The denaturating capillary gel electrophoresis was performed using POP 4 polymer (Applied Biosystems). An allelic ladder was constructed from sequenced PCR products of varying size and run together with each batch. A standard curve of fragment size versus CAG repeat length could be constructed, which allowed the calculation of the CAG repeat length of an unknown sample.
Primers for PCR reactions were obtained from VBC-Genomics (VBC-Genomics Bioscience Research, Vienna, Austria). PCR reactions were run on a thermal cycler 2400 from Applied Biosystems. Sequencing was performed by VBC-Genomics (VBC-Genomics Bioscience Research). Genotyping was done blinded to case-control status and 20% of the samples were randomly repeated for quality control, where no discrepancies were observed.
Statistical analysis
Analysis of data was performed using the computer software SPSS for Windows (version 10.0). Statistical analyses included analysis of variance for age, prostate volume and PSA levels. Logistic regressions were performed to calculate odds ratios (OR) and confidence limits (CL) and to control for possible confounders. Confounders included were age and CAG repeats. OR given in the tables were adjusted only if the confounding variables had a statistically significant influence on the OR calculations. All P values are two-sided; P-values <0.05 are considered statistically significant.
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Results
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Principal characteristics of the study population are given in Table I
. The cases and controls did not differ significantly with respect to age and prostate volume. Mean age was 65.9 years for cases and 66.5 years for controls. Prostate volume was 42.5 ml in cases and 40.5 ml in controls. Mean serum PSA levels, measured at time of diagnosis, averaged 30.8 ng/ml in prostate cancer patients and 4.7 ng/ml in controls (P < 0.001).
The CAG repeat length distribution of prostate cancer patients and controls is shown in Figure 1
. The determination of the CAG repeat length was performed in 380 men. Mean CAG repeat length was 22 (range 631) for prostate cancer cases and 22 (range 1532) for the control group.

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Fig. 1. Frequency distribution of CAG repeat length in 190 prostate cancer patients and 190 control patients.
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The CAG repeat length was categorized in tertiles (Table 2
), defined as short alleles (620), intermediate alleles (2122) and long alleles (2332), respectively. We found no evidence for an association between prostate cancer and CAG repeat length. Relative to the lowest tertile of CAG repeat length, men in the intermediate and highest tertiles had an OR of 1.28 (95% CL 0.762.15) and of 1.07 (95% CL 0.671.73), respectively.
The association of AR repeats tertiles with Gleason score in 190 prostate cancer patients was analysed (Table III
). Seventy-nine cases (41.6%) had Gleason score <7, and 111 (58.4 %) had Gleason score
7. Relative to the lowest tertile and Gleason score <7, the OR for the intermediate tertile was 1.07 (95% CL 0.512.26), for the highest tertile 0.92 (95% CL 0.461.85).
Prevalence and ORs for the PSA gene polymorphism are given in Table IV
. The PSA genotype distribution for controls was in HardyWeinberg equilibrium. The OR, calculated relative to subjects with the A/A genotype, was for the A/G genotype 0.61 (95% CL 0.371.01; P = 0.055), and for the G/G genotype 0.65 (95% CL 0.381.11; P = 0.117), respectively. The OR for the combination of the genotypes A/G and G/G versus A/A was statistically significant (OR = 0.63; 95% CL 0.390.99; P = 0.048).
The association of the PSA genotypes with Gleason score in 190 prostate cancer patients was analysed (Table V
). Relative to genotype A/A, the OR for high grade (Gleason score
7) versus low grade (Gleason score <7) disease was 1.30 (95% CL 0.662.59; P = 0.45) for genotype A/G, and significantly increased for the G/G genotype 2.29 (95% CL 1.064.94; P = 0.034).
In Table VI
the combined analysis of the CAG repeat length and the PSA polymorphism is presented. The OR was calculated for the A/G and G/G genotypes relative to A/A. In the lowest tertile of CAG repeat length (620) the OR was 0.43 (95% CL 0.181.00; P = 0.049); in the intermediate (2122) and in the highest tertile (2332) of CAG repeat length the OR was 0.65 (95% CL 0.281.52; P = 0.317) and 0.84 (95% CL 0.401.75; P = 0.638), respectively.
PSA serum levels in the control group in relation to the PSA genotypes and CAG repeats are given in Table VII
. Neither the PSA genotypes (P = 0.984) nor the tertiles of CAG repeats (P = 0.424) showed statistically significant differences of PSA levels.
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Discussion
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As androgens are critical for the development and progression of prostate cancer, Coetzee and Ross (18) had hypothesized that variation in transcriptional activity by the AR related to polymorphic CAG repeats influences prostate carcinogenesis. They suggested that smaller CAG repeats might be associated with a higher level of receptor transactivation, thereby increasing the risk of prostate cancer.
Several case-control studies have investigated the relationship between CAG repeat length in the AR and prostate cancer risk with contradictory findings. Our results are in accordance with some of these studies in which no overall significant association between CAG repeat length and prostate cancer risk was found, whereas other studies found at least a moderate increase in risk with short CAG repeats.
Stanford et al. (19) analysed in a population-based case-control study of middle-aged Caucasian men the CAG repeat length of the AR in 301 cases and 277 controls. The overall age-adjusted relative odds of prostate cancer associated with the number of CAG repeats as a continuous variable was 0.97 (95% CL 0.951.03), suggesting a 3% decrease in prostate cancer risk for each additional CAG repeat. However, this result was not of statistical significance. In a small study by Ingles et al. (20) of 57 non-Hispanic white prostate cancer patients and 169 controls, an OR of 2.1 was found for men carrying an AR CAG allele with <20 repeats compared with men with
20 repeats. Giovannucci et al. (9) reported a significant association between fewer CAG repeats and prostate cancer only for advanced prostate cancer cases (OR = 2.14) using 587 predominantly Caucasian prostate cancer cases and 588 age-matched controls selected from participants in a Physicans Health Study.
A French-German study comprised of 105 controls, where prostate cancer was excluded by DRE and PSA serum level determination, 132 sporadic prostate cancer cases and a sample of prostate cancer families (85 affected and 46 not affected family members) reported no correlation between prostate cancer risk and CAG repeat length (21).
As previous studies have suggested that short CAG repeats may predispose to more aggressive forms of prostate cancer (9,22), we also performed a case analysis according to Gleason score. However, we failed to detect an association between CAG repeat length, Gleason score and prostate cancer risk.
Generally, the estimated effects of short CAG repeats on prostate cancer risk in most of these studies are relatively small and reached significance only in subgroups with higher grade or stage of disease. But different study designs and analyses make these studies difficult to compare. Additionally, the study populations of these studies are of varying size. Another point that must also be considered is the population heterogeneity, especially in studies on prostate cancer, where disease incidence varies with ethnic background. Most of the studies that found at least a modest influence on risk have been undertaken in North America, where it is possible that effects of genetic heterogeneity can have confounded these results (23). In this Austrian study this problem can be excluded, because the study population consisted exclusively of Caucasian men. Moreover, our finding is consistent with other studies conducted in Europe, which also failed to detect an association between CAG repeat length and prostate cancer risk (21,24).
Furthermore, the selection of a control group is a critical point for the final outcome of molecular epidemiological studies. Most of the studies mentioned above used a population-based study design, which would be hampered by the uncertainty of underlying prostate cancer as it occurs at high frequency in the seventh-eighth decade. In our study the control group consisted of men with lower urinary tract symptoms due to BPH, in whom the presence of prostate cancer was excluded either clinically or histologically. In addition, it is well accepted that BPH is neither a premalignant lesion nor a precursor carcinoma. Therefore, we believe that our control group is appropriate, as discussed elsewhere (25,26). Additionally, the incidence of histological evidence of BPH is in the range of 7080% in elderly men (27), so it is almost impossible to select controls in this age group without BPH.
One potential limitation of using a BPH control group is the fact that polymorphisms in AR and PSA genes may be related to prostate volume and BPH aetiology. However, the studies investigating the association between the CAG repeat length and development of BPH yielded controversial results. Whereas some studies (2830) found a relation between CAG repeat length and the risk of developing BPH or prostate enlargement another failed to detect an association (31).
The AR stimulates the transcription of genes by binding androgen-response elements in promoters of target genes. One of these androgen-regulated target genes is the PSA gene, where a single nucleotide polymorphism within the most proximal of the three AREs, ARE-I has been described (15). It has been hypothesized that the AR binds the two allelic variants AGAACAnnnAGTACT and AGAACAnnnAGTGCT with different affinities, leading to differences in PSA expression (16). However, functional differences between the two alleles A and G have not yet been clarified experimentally.
To our knowledge, only one case-control study concerning ARE-I PSA polymorphism and prostate cancer has been published. Xue et al. (16) reported in a study of non-Hispanic white men, comprising of 57 prostate cancer cases and 156 controls, that subjects with the G/G genotype were at significantly increased risk for advanced but not localized prostate cancer. After cross-classification by PSA and AR genotypes they found men having the PSA G/G genotype in combination with short CAG alleles, defined as <20 CAG repeats, have a >5-fold increase in prostate cancer risk. Because the sample size of their case-control study was rather small (57 cases), the authors suggested confirming these results in larger studies.
In our study we found a significant influence of the ARE-I PSA polymorphism on prostate cancer risk, when calculating the combination of the A/G and G/G genotypes versus the A/A genotype, suggesting that the G allele has a protective effect. Men having at least one G allele were at 63% decreased risk of prostate cancer. However, in a case analysis according to Gleason score, the G/G genotype was significantly more frequent in patients with Gleason score >7 than in patients with Gleason score
7, providing evidence that the G allele is associated with more advanced disease at the time of diagnosis. Furthermore, we found a significant trend in OR from the A/A towards the G/G genotype among low grade versus high-grade disease. This is in accordance with Xue et al. (16), as they found that subjects with the PSA G/G genotype had an increased risk for advanced prostate cancer. Recently, Xue et al. (32) reported in a multi-ethnic cohort study of 420 healthy men that the polymorphisms in the AR and PSA gene contribute to variation in serum PSA levels. Men with short CAG alleles and the PSA A/A genotype were found to have higher serum PSA levels. As they found in their case-control study (16) that the PSA G/G genotype associated with increased risk of advanced prostate cancer, they argued that the anti-angiogenic effect of PSA could prevent progression of localized prostate cancers to more advanced stages. In contrast, in our control group we found no association between PSA serum levels and the PSA and AR polymorphism. These finding argue against the hypothesis that the AR binds the two PSA alleles with differing affinity, leading to differences in PSA expression (16). However, in interpreting our results one has to consider that our controls are BPH patients, a condition which is also androgen-dependent.
In this case-control study of Austrian Caucasian men we investigated polymorphisms of two genes involved in the androgen pathway, the CAG repeat length in exon 1 of the AR gene and the ARE-I polymorphism of the androgen regulated PSA gene. Our data provides no evidence for an association between prostate cancer and CAG repeat length. However, men having at least one PSA G allele were at statistically significant decreased risk of developing prostate cancer. Otherwise, in a case analysis according to Gleason score, the G/G genotype was associated with more advanced disease. Our data support the hypothesis of an ambivalent role of PSA during prostate carcinogenesis (13,14). PSA seems to have both stimulatory effects on prostatic cell proliferation (13) as well as anti-angiogenic properties (14). As relatively little is known about the biological function of the PSA protein, it needs further investigation to clarify the role of PSA in prostate cancer aetiology.
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Notes
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4 Present address: Department of Urology, Inselspital, University of Berne, Switzerland 
5 To whom correspondence should be addressed Email: andrea.gsur{at}univie.ac.at 
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Acknowledgments
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This work was supported by `Medizinisch-wissenschaftlicher Fonds des Bürgermeisters der Bundeshauptstadt Wien #1995 and the `T. Fox Foundation.
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Received January 28, 2002;
accepted July 24, 2002.