Androgen receptor CAG polymorphism and the risk of benign prostatic hyperplasia in a Brazilian population

Benign prostatic hyperplasia (BPH) is a very frequent age-related proliferative abnormality in men. Polymorphic CAG repeat in the androgen receptor (AR) can alter transactivation of androgen-responsive genes and potentially influence BPH risk. We investigated the association between CAG repeat length and risk of BPH in a case-control study of a Brazilian population. We evaluated 214 patients; 126 with BPH and 88 healthy controls. DNA was extracted from peripheral leucocytes and the AR gene was analyzed using fragment analysis. Hazard ratio (HR) and 95% confidence interval were estimated using logistic regression models. Mean CAG length was not different between patients with BPH and controls. The CAG repeat length was examined as a categorical variable (CAG ≤ 21 vs. CAG > 21 and CAG ≤ 22 vs. CAG > 22) and did not differ between the control vs. the BPH group. We found no evidence for an association between AR CAG repeat length in BPH risk in a population-based sample of Brazilians.     

Association of polymorphisms within androgen receptor, 5alpha-reductase,and PSA genes with prostate volume,clinical parameters,and endocrine status in elderly men

BACKGROUND: The aim of this study was to assess the impact of polymorphisms of three genes within the androgen pathway on prostate volume, clinical parameters, and endocrine status. METHODS: Elderly men with lower urinary tract symptoms underwent clinical and endocrine work-up. In parallel, polymorphisms within the 5alpha-reductase gene (SRD5A2 V89L and A49T), the androgen receptor gene (AR; number of CAG repeats), and the prostate specific antigen (PSA) gene (A --> G substitution at position-158) were determined by polymerase chain reaction and restriction-length polymorphism analysis by using DNA from peripheral blood. RESULTS: A total of 190 men (66.5 +/- 9.2 yr) were analyzed. The number of CAG repeats within the AR and the PSA polymorphism revealed no associations to clinical and endocrine parameters. Individuals carrying the mutated SRD5A2 A49T allele (5.3% of the total population) had larger prostates (54.1 vs. 39.3 ml), higher PSA levels (12.2 vs. 4.3 ng/ml), and a 35% reduction in prostatic stroma/epithelial cell ratio. Men with the mutated SRD5A2 V89L gene had lower testosterone levels. CONCLUSIONS: In contrast to prostate cancer, polymorphisms within AR and PSA genes do not seem to be of importance for benign prostatic hyperplasia. Polymorphisms within the 5alpha-reductase gene are interesting biomarkers for the development of benign prostatic hyperplasia and benign prostatic enlargement.     

Polymorphisms in the vitamin D receptor gene and the androgen receptor gene and the risk of benign prostatic hyperplasia

OBJECTIVE: Little is known about risk factors for the development of benign prostatic hyperplasia (BPH). Recently, associations were observed between prostate cancer (CaP) risk and polymorphisms in the vitamin D receptor (VDR) gene and the androgen receptor (AR) gene. Since both receptors are relevant for prostate growth, the VDR and AR are also expected to be involved in the development of BPH. The objective of this study is to establish the relationship between the risk of BPH and a polymorphism in the number of CAG repeats in the AR gene and a TaqI restriction enzyme polymorphism in the VDR gene. METHODS: For this study, 98 patients who had been treated for BPH-related complaints and 61 convenience controls (predominantly bladder cancer patients) were recruited from the outpatient clinic. DNA was isolated from peripheral blood, and genotyping was performed with PCR-based methods. Means as well as odds ratios (ORs) with 95% confidence intervals (CI) were calculated using SPSS software. RESULTS: The mean number of CAG repeats in the AR gene in patients and controls was found to be similar: 21.8 (SD = 2.8) and 21.9 (SD = 2.9), respectively. In the subgroup of patients with a prostate volume of at least 50 cm(3), the mean number of repeats was 21.5 (SD = 2.6). The OR for BPH for individuals with homozygous presence of the VDR TaqI restriction fragment length polymorphism (RFLP) (tt) versus individuals with homozygous absence (TT) or heterozygotes (Tt) was found to be 1.0 (95% CI 0.4-2.4). For individuals with a prostate volume of at least 50 cm(3), the OR was 1.2 (95% CI 0.5-3. 2). CONCLUSION: Unlike earlier observations in prostate cancer, we did not find an association between the CAG repeat polymorphism in the AR gene and the TaqI RFLP polymorphism in the VDR gene and the risk of BPH.     

Androgen receptor CAG repeat length polymorphism in benign prostatic hyperplasia (BPH): correlation with adenoma growth.

BACKGROUND: The androgen receptor (AR) gene has a polymorphic CAG microsatellite encoding variable-length glutamine repeats in the AR protein. The purpose of this study was to evaluate the association between the growth of benign prostatic hyperplasia (BPH) and the AR gene CAG repeat length. METHODS: We determined CAG repeat lengths in 176 BPH patients who underwent simple prostatectomy and in 41 control subjects without benign prostatic enlargement (non-BPE group). RESULTS: A statistically significant (P < 0.02) trend for large adenoma size with short CAG repeat length was found among the adenoma quartiles. CAG repeat length in the fourth quartile (large adenoma, 21.5 +/- 2.7) was significantly shorter than in the first quartile (small adenoma, 23.3 +/- 2.1, P < 0.02). It tended to be shorter than in the non-BPE group (23.1 +/- 2.4), but CAG repeat lengths in the entire BPH (22.4 +/- 2.5) and non-BPE groups did not significantly differ. The relative risk of large BPH (the fourth quartile) was 2.75 (95% confidence interval, 1.05-7.24; P < 0.05) on comparing CAG repeats of < or = 22-> or = 23. CONCLUSIONS: Shorter CAG alleles may be a genetic factor that promotes the growth of BPH.     

Association of V89L SRD5A2 polymorphism with prostate cancer development in a Japanese population

PURPOSE: The SRD5A2 gene codes the steroid 5-reductase type II, a critical mediator of androgen action, and the V89L and A49T polymorphisms of this gene may be associated with a distinct enzyme activity. We explored the association among these polymorphisms and the risk of prostate cancer or benign prostatic hyperplasia (BPH) in a Japanese population. MATERIALS AND METHODS: This study included 302 patients with prostate cancer, 228 with BPH and 243 male controls. V89L and A49T polymorphisms were analyzed by the polymerase chain reaction restriction fragment length polymorphism method. Genotypes were evaluated by electrophoresis on agarose gel. RESULTS: For the V89L polymorphism there were no significant differences in genotype frequencies in patients with prostate cancer and controls (p = 0.071) or in patients with BPH and male controls (p = 0.219). However, males with the VV or VL genotype were at significantly increased risk for prostate cancer compared with those with the LL genotype (adjusted OR 1.69, 95% CI 1.07 to 2.65, p = 0.024). The risk of BPH in males with the VV or VL genotype was not significantly elevated in comparison with those with the LL genotype (adjusted OR 1.37, 95% CI 0.85 to 2.20, p = 0.194). The V89L variant was not associated with the grade or stage of prostate cancer, or with patient age. For the A49T polymorphism all subjects had the AA genotype. CONCLUSIONS: The V allele of the V89L polymorphism in the SRD5A2 gene may dominantly increase the risk of prostate cancer.     

Germline CAG repeat length of the androgen receptor and time to progression in patients with prostate cancer treated with androgen deprivation therapy

Study Type – Prognosis (retrospective cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Germline CAG repeat polymorphisms in the androgen receptor (AR‐CAG) have been shown to influence the activity of the androgen receptor, but there has been conflicting data from small retrospective studies evaluating the effect of CAG repeat polymorphisms on response to ADT. This is the largest published study to date investigating the association of germline AR‐CAG repeat lengths and efficacy of ADT in prostate cancer. Germline AR‐CAG repeat lengths do not predict response to ADT.

OBJECTIVES

? Germline CAG repeat polymorphisms in the androgen receptor (AR‐CAG) have been shown to influence the activity of the AR. ? The purpose of the present study was to determine if AR‐CAG repeat length correlates with time to progression on androgen deprivation therapy (ADT).

PATIENTS AND METHODS

? Germline AR‐CAG repeat lengths were determined in a cohort of 480 patients with recurrent or metastatic prostate cancer treated at a single tertiary care institution and correlated to time to progression (TTP) and overall survival.

RESULTS

? There was no significant correlation between differences in the AR‐CAG repeat lengths and TTP or overall survival in patients with prostate cancer receiving ADT. ? AR‐CAG repeat lengths did not significantly correlate with age, prostate‐specific antigen (PSA), Gleason score or clinical stage at diagnosis. ? In patients with metastatic disease, longer AR‐CAG repeat lengths (>23 vs ≤23) were associated with a longer TTP on ADT, but this finding was of borderline significance (median TTP 18.3 vs 15.5 months, P= 0.09; adjusted HR = 0.76, 95% confidence interval = 0.54–1.09).

CONCLUSIONS

? This is the largest published study to date investigating the association of germline AR‐CAG repeat lengths and efficacy of ADT in prostate cancer. ? Germline AR‐CAG repeat lengths do not predict response to ADT.     

The impact of polymorphism on prostate specific antigen gene on the risk, tumor volume and pathological stage of prostate cancer

PURPOSE: A single nucleotide polymorphism with adenine (A) to guanine (G) substitution is identified at position -158 in the androgen response elements region of the prostate specific antigen (PSA) gene. We evaluated the relationship between the PSA -158A/G polymorphism and the risk, tumor volume and pathological stage of prostate cancer. MATERIALS AND METHODS: Peripheral venous blood samples were obtained from 122 patients with prostate cancer and 84 controls with benign prostatic hyperplasia. The diagnosis, tumor volume and pathological stage of prostate cancer were all determined according to the pathological reports of transrectal ultrasound guided prostate biopsy, transurethral prostate resection and radical prostatectomy. The PSA -158A/G polymorphism was determined by polymerase chain reaction based restriction fragment length polymorphism methods. RESULTS: Patients with prostate cancer had significantly greater frequencies of the G allele (87.3% vs 77.4%) and GG genotype (78.7% vs 61.9%) than the control group (p = 0.008 and 0.028, respectively). The OR of GG to AG and AA was 2.27 (p = 0.008). In the prostate cancer group the GG genotype was also associated with larger tumor volume (2.34 vs 0.82 ml) and higher pathological stage (organ confined cancer 68.2% vs 31.8% and extracapsular extension 100% vs 0%) than the GA and AA genotypes (p = 0.013 and 0.036, respectively). CONCLUSIONS: The PSA -158A/G polymorphism is associated with prostate cancer. The G allele increases the risk of prostate cancer and the GG genotype is associated with larger tumor volume and higher pathological stage.     

Effect of a short CAG (glutamine) repeat on human androgen receptor function

BACKGROUND: The human androgen receptor (AR) gene contains an uninterrupted CAG repeat that is polymorphic in length in the general population (range, 11-31 CAG's; median, 21). The CAG repeat encodes a glutamine repeat in the N-terminal transactivation domain of the AR protein. We previously reported that a 17-CAG AR gene was much more common in a cohort of men with prostate cancer (8.5%) than in the general European American population (1.3%). This suggested that a 17-CAG repeat may have pathophysiological consequences. The goal of the present study was to directly test the hypothesis that a 17-CAG repeat might uniquely affect androgen action in human prostate cancer cells. METHODS: DU145 cells, lacking endogenous AR, were transiently transfected with an AR expression plasmid (with a CAG repeat ranging in length from 14 to 25) and an androgen-responsive reporter plasmid (PSA-luciferase). RESULTS: We found a significant effect of CAG repeat length on AR protein levels per unit amount of DNA transfected (one-way ANOVA, P = 0.02), indicating the need to express transactivation data per unit amount of AR protein. CAG17 AR had 40% more transactivation activity per unit amount of AR protein than CAG21 AR (P < 0.01). CONCLUSIONS: Thus, an AR with a 17-CAG repeat may mediate more efficacious growth stimulation of androgen-dependent prostate epithelial cells, and thereby increase the risk that prostate cancer cells develop more efficiently into a clinically significant cancer.     

Associations between polymorphisms in the steroid 5-alpha reductase type II (SRD5A2) gene and benign prostatic hyperplasia and prostate cancer

The prostate gland is an androgen-dependent, and polymorphisms in androgen synthesis gene steroid 5-alpha reductase type II (SRD5A2) may be associated with benign prostatic hyperplasia (BPH) and prostate cancer. We evaluated the association between 3 polymorphisms in the SRD5A2 gene (2 single nucleotide polymorphism: alanine-49 to threonine [A49T] and valine-89 to leucine [V89L], and a (TA)n dinucleotide repeat in the 3' untranslated region), and BPH and prostate cancer within a multiethnic population. Men between 60 and 86 years of age were recruited from annual prostate cancer screening programs and from a large urology clinic. Unconditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (95% CI). We genotyped 606 men (412 Hispanic, 98 Caucasian, 73 African-American, and 23 Asian), of whom 100 had prostate cancer, 393 had BPH (280 symptomatic and 113 asymptomatic), and 113 had normal prostates. Overall, the V89L variant was associated with prostate cancer; the OR for men with the leucine-leucine (LL) genotype compared to men with the valine-valine (VV) genotype was 4.47 (95% CI, 1.24-16.18). This association was stronger in Hispanics (OR=7.26; 95% CI: 1.49-35.47). Although V89L was nonsignificantly associated with BPH in overall population, BPH risk increased significantly with the number of L alleles in Hispanics (P for trend=0.03). Prostate cancer and BPH were not associated with the alanine-49 to threonine single nucleotide polymorphism and the (TA)n repeat. These results suggest that the SRD5A2 gene may play an important role in both BPH and prostate cancer.     

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 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 18 CAG repeats. In contrast, for patients at high risk of recurrence (Gleason score >/= 7, stage pT3/4, or PSA >10 ng./ml.), the relative risk associated 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.     

Genetic polymorphisms in the androgen receptor and type II 5 alpha-reductase genes in prostate enlargement

PURPOSE: We examined the association of androgen receptor gene cytosine-adenine-guanine (CAG) repeat length and the 2 single nucleotide polymorphisms A49T and V89L in the type II 5 alpha-reductase gene with prostate enlargement measured as the weight of the surgically removed prostate. MATERIALS AND METHODS: A total of 68 men with a prostate weighing 80 gm. or greater were compared with 197 controls with a prostate weighing less than 80 gm. These men had undergone radical prostatectomy between 1992 and 1996. DNA was extracted from archival prostate tissue uninvolved with cancer and genotyped for 3 polymorphic markers. The effects of genetic variants and clinicopathological variables on prostate enlargement risk were estimated by logistic regression. RESULTS: The age adjusted odds ratio estimate of prostate enlargement risk in men with 23 or greater versus 20 or fewer CAG repeats was 0.41 (95% confidence interval 0.19 to 0.89). This risk reduction was consistently found when an alternative prostate enlargement definition and subject restriction were used. No consistent association with prostate enlargement risk was observed for A49T or V89L polymorphisms. CONCLUSIONS: Our finding further supports the hypothesis that the shorter CAG repeat length of the androgen receptor gene is related to prostate enlargement.     

The role of an androgen receptor polymorphism in the clinical outcome of patients with metastatic prostate cancer

The androgen receptor plays a major role in the development and function of normal and malignant prostate cells. Due to the relationship of the androgen receptor and prostatic growth, it has been proposed that polymorphisms within the androgen receptor may play a role in an individual's susceptibility to developing prostate cancer. An inverse relationship has been established between a highly polymorphic trinucleotide repeat located in the first exon of the androgen receptor and the transactivaton function of the receptor. Serum samples were collected from 131 patients with histologically confirmed adenocarcinoma of the prostate, DNA was isolated, and the polymorphic CAG repeat was amplified by PCR and sequenced. The CAG repeat lengths were then compared with age at diagnosis, age at time of study, baseline log(10) PSA, Gleason score, time from diagnosis to initiation of hormonal therapy, time to progression after androgen ablation, and overall survival time. No correlation was found between CAG length and time to progression or overall survival time, but a significant correlation was found between Gleason score and CAG length suggesting that shorter CAG lengths may predict a higher histological grade of prostate cancer.     

Effect of GGC (glycine) repeat length polymorphism in the human androgen receptor on androgen action

BACKGROUND: The human androgen receptor (AR) contains glutamine (CAG) and glycine (GGC) repeat length polymorphisms. Normal glutamine repeat length affects androgen action, but an effect of normal glycine repeat length has not been studied. METHODS: To determine whether glycine/GGC repeat length affects AR function, we constructed AR cDNA expression vectors with different GGC repeat lengths in the physiological range (13-17 GGCs). AR constructs were transfected into AR-negative DU145 human prostate cancer cells along with an androgen-responsive reporter plasmid (PSA-firefly luciferase) and a transfection efficiency control plasmid (Renilla luciferase). RESULTS: Glycine repeat length had no significant effect on androgen-dependent AR transactivation activity expressed as firefly luciferase per unit amount of AR protein. However, AR protein levels (normalized for transfection efficiency) were inversely affected by glycine repeat length (P < 0.001; r = -0.9; e.g., GGC13 yielded 2.7 times more AR protein than did GGC17). Therefore, the net amount of AR activity per cell would be higher in cells expressing AR with a short glycine repeat. Based on programs that predict structure from RNA sequence, the GGC repeat can form a hairpin structure, the free energy of which decreases (i.e., hairpin stability increases) as a function of increasing repeat length. This suggests that hairpin stability may interfere with translation, accounting for the inverse effect of GGC repeat length on AR protein yields. CONCLUSIONS: The ability of a short GGC repeat to enhance androgen action provides a biologically plausible mechanism to account for reports that a short GGC repeat in the AR gene is a risk factor for prostate cancer.     

Linkage between polymorphisms in the prostate specific antigen ARE1 gene region,prostate cancer risk,and circulating tumor cells

BACKGROUND: The prostate specific antigen (PSA) gene has a polymorphic androgen response element (ARE) sequence with two alleles, A and G. PSA A-allele carriers have higher serum PSA levels in healthy men (HM). METHODS: We analysed DNA samples from 278 (556 alleles) unrelated individuals, 127 HM and 151 prostate cancer (PC) patients, for PSA ARE1 genotypes. RESULTS: The analysis of the frequencies from the 556 alleles indicates a significant overrepresentation of A-allele in the PC group under the age of 67 compared with the HM group (63.3% vs. 48.8%; P = 0.009). We found that men carrying two A-alleles have increased risk for PC onset under the age of 67 (odds ratio [OR] = 2.92; 95% confidence interval [CI], 1.10-7.86; P = 0.013). Multivariate logistic regression analysis confirmed this association (OR = 1.82; 95% CI, 1.03-3.22; P = 0.037). Furthermore, the homozygosity for the A-allele was associated with higher serum PSA levels (P = 0.027) and with the presence of circulating tumor cells in the blood of PC patients (P = 0.018). CONCLUSION: Our results indicate that polymorphism in the PSA gene promoter may be an important biomarker for prostate cancer risk, especially for an earlier onset of PC.     

Systematic replication study of reported genetic associations in prostate cancer: Strong support for genetic variation in the androgen pathway

BACKGROUND: Association studies have become a common and popular method to identify genetic variants predisposing to complex diseases. Despite considerable efforts and initial promising findings, the field of prostate cancer genetics is characterized by inconclusive reports and no prostate cancer gene has yet been established. METHODS: We performed a literature review and identified 79 different polymorphisms reported to influence prostate cancer risk. Of these, 46 were selected and tested for association in a large Swedish population-based case-control prostate cancer population. RESULTS: We observed significant (P < 0.05) confirmation for six polymorphisms located in five different genes. Three of them coded for key enzymes in the androgen biosynthesis and response pathway; the CAG repeat in the androgen receptor (AR) gene (P = 0.03), one SNP in the CYP17 gene (P = 0.04), two SNPs in the SRD5A2 gene (P = 0.02 and 0.02, respectively), a deletion of the GSTT1 gene (P = 0.006), and one SNP in the MSR1 gene, IVS5-59C > A, (P = 0.009). CONCLUSIONS: Notwithstanding the difficulties to replicate findings in genetic association studies, our results strongly support the importance of androgen pathway genes in prostate cancer etiology.