The relationship between the androgen receptor CAG repeat polymorphism length and the response to intermittent androgen suppression therapy for advanced prostate cancer

OBJECTIVE: To determine whether the duration of the off-treatment interval in patients being treated with intermittent androgen deprivation therapy can be predicted by the length of the CAG trinucleotide repeat polymorphism in the androgen receptor. METHODS: This is a companion study to a prospective randomized trial, NCIC CTG PR-7, comparing intermittent to continuous androgen deprivation therapy in men with PSA progression after radiation therapy. The duration of the first off-treatment interval was established for 76 participants randomized to the intermittent therapy arm of the trial. Androgen receptor CAG repeat polymorphism lengths were determined for these 76 participants. Statistical analysis was completed to determine a relationship between CAG repeat length and the duration of the off-treatment interval. RESULTS: A significant correlation was not established (P = 0.424) between androgen receptor CAG repeat length and the duration of the first off-treatment interval. Categorical analysis of CAG repeat lengths using 18 and 22 as cutoff points did not find any significant difference in the mean duration of the off-treatment interval between categories (P = 0.672 and 0.774, respectively). CONCLUSION: No relationship was established between the duration of the first off-treatment interval and the CAG repeat length.     

The relationship between anogenital distance and the androgen receptor CAG repeat length

Anogenital distance (AGD) is used to define degree of virilization of genital development, with shorter length being associated with feminization and male infertility. The first exon of the androgen receptor (AR) consists of a polymorphic sequence of cytosine–adenine–guanine (CAG) repeats, with longer CAG repeat lengths being associated with decreased receptor function. We sought to determine if there is an association between AGD and AR CAG repeat length. A cross-sectional, prospective cohort of men evaluated at a urology clinic at a single institution was recruited. AGD (the distance from the posterior scrotum to the anal verge) and penile length (PL) were measured. Sanger DNA sequence analysis was used to define CAG repeat length. AGD and CAG repeat lengths in 195 men were determined. On unadjusted analysis, there was no linear relationship between CAG repeat length and PL (P=0.17) or AGD (P=0.31). However, on sub-population analyses, those men with longer CAG repeat lengths (>26) had significantly shorter AGDs compared to men with shorter CAG repeat lengths. For example, the mean AGD was 41.9 vs. 32.4 mm with a CAG repeat length ≤26 vs. >26 (P=0.01). In addition, when stratifying the cohort based on AGD, those with AGD less than the median (i.e. 40 mm) had a longer CAG repeat length compared to men with an AGD >40 mm (P=0.02). In summary, no linear relationship was found between AGD and AR CAG repeat length overall.     

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.     

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.     

雄激素受体基因ＣＡＧ多态性与前列腺癌的关系

目的：进一步探讨雄激素受体（ＡＲ)基因ＣＡＧ多态性与前列腺癌的关系,方法：采用分子生物学方法对３５８例前列腺癌患者ＡＲ基因ＣＡＧ进行测试,分析ＣＡＧ长度与临床各种指标的关系,结果：经统计学分析显示ＡＲ基因ＣＡＧ与年龄之间呈高相关性（Ｐ＝０．００７,r＝０．１１４）,但与ＰＳＡ、肿瘤分级及分期无显著相关性,结论：ＡＲ基因ＣＡＧ的长度与患者年龄成正比,即前列腺癌患者年龄越轻,其ＣＡＧ长度越短。     

CAG repeat length in the androgen receptor gene affects the risk of male infertility

During recent years several studies have suggested that a slight increase in the number of CAG repeat sequences in exon 1 of the androgen receptor gene causes idiopathic oligozoospermia. We tested whether CAG repeats are more numerous in men with idiopathic infertility compared to those with known causes of oligozoospermia. CAG repeats were analysed in a consecutive sample of 217 infertile men covering a wide range of diagnoses and sperm counts. Data were compared with those of a control group of 131 normozoospermic men including 62 fathers. CAG repeats (x +/- SD) did not differ between idiopathically (21.4 +/- 2.9) and non-idiopathically infertile men (21.6 +/- 2.8) or normozoospermic men of unproven fertility (20.6 +/- 3.0). Only fathers had significantly fewer repeats (19.4 +/- 3.1; p < 0.001). Different from controls, no correlation between CAG repeats and any semen parameter existed in patients. Comparison of our and published studies showed that odds ratios for infertility in men with CAG repeat length in the upper quartile of the normal range increased when the controls were selected by proven fertility. We conclude that more numerous CAG repeats do not directly cause oligozoospermia and propose that men with longer CAG repeats might be more prone to develop infertility in response to any pathogen/epigenetic factors.     

CAG repeat length in androgen receptor gene and male infertility in Egyptian patients

The CAG repeat and its association with infertility has been debatable. Therefore, this study was planned to assess the distribution of CAG repeat expansion in Egyptian patients and to investigate its association with male infertility. Forty-five infertile men were eligible for the study in addition to 20 aged-matched fertile males as control. Semen analysis, scrotal sonography, assay of serum testosterone, follicle-stimulating hormone (FSH) and luteinising hormone (LH), and determination of the CAG repeat number within exon 1 of the androgen receptor (AR) gene were carried out. Statistically significant difference was found between infertile and control groups regarding sperm count, sperm motility, serum FSH level and CAG repeats (P < 0.05); statistically insignificant difference for the CAG repeats (P = 1.0) was found between oligozoospermic and asthenospermic groups; negative correlation was found between CAG repeat length and sperm count, and a positive correlation was found between CAG repeat length and serum FSH (P < 0.05). Our results validate the concept that long stretches of CAG repeat may be associated with lower AR function with derangement of sperm production, and this may contribute to male infertility in Egyptian men.     

An increased CAG repeat length in the androgen receptor gene in azoospermic ICSI candidates

The androgen receptor gene has a polymorphic trinucleotide repeat that encodes a polyglutamine tract in its N-terminal transactivation domain. We started this study in order to find out whether a correlation existed between the length of this polymorphic tract and the presence of azoospermia in candidates for intracytoplasmic sperm injection (ICSI). The CAG repeat length in exon 1 of the androgen receptor (AR) gene was directly sequenced in 102 patients with azoospermia and in 96 fertile controls. Hormone levels were also measured in patients with azoospermia. The mean AR gene CAG repeat length was significantly larger in azoospermic subjects than it was in control fertile men (23.25 +/- 2.7 versus 22.42 +/- 2.8; P =.033). A receiver operating characteristic analysis evidenced a cutoff point at 22/23 CAG repeats at which the probability of being azoospermic increased 2.2 times. Subsequent logistic regression analysis of the data showed that the odds for azoospermia increased with the number of CAG repeats. Men with more than 26 CAG repeats have a 4.09 greater risk of being azoospermic. Therefore, in our candidates for ICSI, a direct correlation exists between the CAG repeat length in the exon 1 of the AR gene and the risk of being azoospermic.     

CAG repeat length in the androgen receptor gene is enhanced in patients with idiopathic azoospermia

Objectives. To determine whether the number of CAG repeats in the androgen receptor gene is enhanced in patients with idiopathic azoospermia.Methods. Using the polymerase chain reaction, the number of CAG repeats was assayed in 41 patients with idiopathic azoospermia and in 48 normozoospermic fertile men.Results. In the control group, the CAG repeat length ranged from 17 to 30 (mean 23.9 ± 2.9); in the azoospermic group, the CAG repeat length ranged from 20 to 34 (mean 26.5 ± 3.5). The difference between the two groups was statistically significant (P = 0.0013). None of the men in the control group had a CAG repeat length greater than 31; four of the azoospermic men had 34 CAG repeats.Conclusions. Results suggest that an increase in the number of CAG repeats in the androgen receptor gene to 31 or greater may be associated with the etiology of at least some cases of idiopathic azoospermia.     

CAG polymorphic repeat length in androgen receptor gene combined with pretreatment serum testosterone level as prognostic factor in patients with metastatic prostate cancer

OBJECTIVE: Androgen ablation has been the initial treatment of choice for men with metastatic prostate cancer, but the disease generally relapses to an androgen-independent state thereafter. To understand which groups respond well or poorly to endocrine therapy is thus important. Several studies have shown that pretreatment serum testosterone (T) levels and the length of the CAG repeat at the N-terminal region of the androgen receptor are significant. However, the relevance of a combination of these factors has not been reported. We therefore investigated the clinical significance of CAG repeat length and pretreatment serum T levels among Japanese patients with metastatic prostate cancer (TxNxM1), and analyzed their relevance to survival. METHODS: Fifty-two Japanese patients with metastatic prostate cancer were enrolled in this study. We determined the length of the CAG repeat by both PCR sequencing and fragment analysis. Pretreatment serum T levels were measured using a radioimmunoassay. We examined the clinical significance of the CAG repeats and T levels individually and in combination with respect to several clinical factors. RESULTS: The pretreatment T level in the responder group was significantly higher than that in the non-responders (p=0.009) and the mean was 4.33+/-2.12 ng/ml. Kaplan-Meier analyses revealed that cause-specific survival was significantly enhanced in patients with higher levels of T (p=0.0489). The length of the CAG repeat was positively associated with age at diagnosis (p=0.032). The mean CAG repeat length was 22.5+/-3.0 and this value was significantly shorter in patients with poorly differentiated, than with well and moderately differentiated tumors (p=0.019). Kaplan-Meier analyses revealed a significantly better cause-specific survival rate as well as progression-free survival rate in patients with longer CAG repeats. Cause-specific survival curves were better in patients with higher T levels and longer CAG repeats than with lower T levels and shorter CAG repeats (p=0.0066). A multivariate analysis showed that the most significant prognostic factor was histological grade, followed by EOD grade, marker response and the combination of T and CAG. CONCLUSION: Pretreatment serum T levels together with the length of the N-terminal CAG repeat of the androgen receptor gene can distinguish responders from non-responders to androgen ablation. These parameters appear to be clinically useful, in that therapies appropriate to individual patients could be selected. Further studies are necessary to confirm these results.     

The magnitude of early castration-induced primary tumour regression in prostate cancer does not predict clinical outcome

INTRODUCTION: This study was designed to test whether early castration-induced short-term cellular changes in primary prostate tumours could predict clinical outcome in advanced disease. PATIENTS AND METHODS: Biopsies from 83 patients obtained before and within two weeks after surgical castration were investigated. Tumour epithelial cell apoptosis, proliferation, and prostate specific antigen (PSA) levels were quantified using immunohistochemistry, laser capture micro-dissection, and real time RT-PCR. Cellular effects were related to changes in serum PSA levels and clinical outcome. RESULTS: Decreased proliferation and PSA mRNA levels, and increased apoptosis were observed in most tumours. These early cellular responses were not correlated to each other and did not predict serum PSA response or cancer-specific survival. A nadir PSA level below 1 ng/ml predicted a longer cancer-specific survival after castration therapy. CONCLUSION: Castration therapy causes primary tumour regression in most patients with advanced prostate cancer, but these primary tumour effects are not predictive for systemic disease control. Studies of early changes in metastases during hormonal therapy will probably give more predictive information for clinical outcome than further studies in primary tumours.     

中国人群雄激素受体基因CAG多态性与前列腺癌关系的研究

目的　探讨国人雄激素受体 (AR)基因CAG多态性分布及与前列腺癌的关系。　方法　采用PCR、DHPLC和直接测序方法 ,对 10 5例前列腺癌和 190例健康老年男性外周血标本进行AR基因CAG重复长度测定 ,分析评价CAG重复长度与前列腺癌易感性的关系。　结果　前列腺癌和对照组ARCAG平均重复长度分别为 2 2 .7和 2 3 .3 ,差异无显著性意义 (P =0 .2 2 )。CAG重复长度<2 2与≥ 2 2相比 ,患前列腺癌的危险性增加 2 .3 9倍 ,差异有显著性意义 (P =0 .0 12 )。　结论　中国男性人群AR基因短的CAG重复长度 (<2 2 )与前列腺癌的危险性有关。与西方人群研究结果相比 ,中国男性有长的CAG重复     

CAG repeat expansion in the androgen receptor gene is not associated with male infertility in Indian populations

CAG repeat expansion in exon 1 of the androgen receptor (AR) gene has been reported to be associated with male infertility in some but not all populations. Until now, studies have not been carried out to examine this among Indian populations. For the first time, we have analyzed the CAG repeat motif in the AR gene in 280 men with azoospermia and in 201 men with normal fertility. The mean number of CAG repeats in the AR gene of men with azoospermia was 21.7 +/- 0.18, with a high incidence of repeat number 22. Among fertile-control men, the mean number of CAG repeats was 22.4 +/- 0.19, with a predominance of repeat number 23. The highest number of CAG repeats (32) was found with low frequency in both fertile and azoospermic groups. Comparison of fertile men and those with azoospermia on the basis of CAG repeats revealed that the number of CAG repeats in both groups were similar, as revealed with a paired t test (t = 0.04; P =.967). Expansion of the CAG repeat in the AR gene is therefore not associated with male infertility in Indian populations. This suggests that what is true for one population may not be true for other populations.     

Polymorphic forms of prostate specific antigen and their interaction with androgen receptor trinucleotide repeats in prostate cancer

BACKGROUND: Recent data has suggested that polymorphisms in the prostate specific antigen (PSA) may increase prostate cancer (PC) risk. The PSA gene contains a G/A substitution in the androgen response element (ARE) 1 region. The androgen receptor (AR) gene has polymorphic regions containing variable length glutamine and glycine repeats and these are believed to be associated with PC risk. The effect on PC risks from PSA polymorphisms alone and synergistically with the AR gene was examined in this report. METHODS: One hundred PC patients and an age matched cohort of 79 benign prostate hyperplasia and 67 population controls were entered in this study. DNA was extracted from blood and PSA/ARE promoter region amplified by PCR. PCR products were cut with Nhe 1 restriction enzyme to distinguish G/A alleles. AR/CAG and GGC repeat length was detected by automated fluorescence from PCR products. RESULTS: We found a significantly higher PSA/GG distribution in PC (30%) than either benign prostatic hyperplasia (BPH) (18%) or population controls (16%) (P = 0.025). Furthermore the GG distribution within cases was even greater in younger men (< 65 years; 42%; P = 0.012). Additionally, when PSA genotype was cross classified with CAG repeat, significantly more cases than both BPH and population controls were observed to have a short (< 22) CAG/GG genotype (P = 0.006). CONCLUSIONS: Our results indicate that the PSA/ARE GG genotype confers an increased risk of PC especially among younger men. Moreover, we confirm previous results that a short glutamine repeat in conjunction with GG genotype significantly increases the risk of malignant disease.