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.     

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 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.     

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.     

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.     

CAG repeat length analysis and mutation screening of the androgen receptor gene in Japanese men with idiopathic azoospermia.

Because androgens are required for normal spermatogenesis, we are investigating abnormalities in the androgen receptor as a possible cause of impaired spermatogenesis in patients with idiopathic male infertility. The CAG repeat length in exon 1 and mutations of the androgen receptor gene were studied in 30 men with idiopathic azoospermia and in 51 fertile men. In men with azoospermia, plasma luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels were measured and testicular biopsies were performed. The CAG repeat length ranged from 19 to 30 (mean 23.4 +/- 2.9) and from 17 to 28 (mean 23.7 +/- 3.2) in men with azoospermia and in controls, respectively. There was no significant difference between the 2 groups. In men with azoospermia, the Johnsen testicular biopsy score negatively correlated with plasma FSH (P < .01). However, the Johnsen testicular biopsy score did not correlate with plasma LH and testosterone levels. The CAG repeat length did not correlate with the Johnsen testicular biopsy score, or with plasma concentrations of LH, FSH, and testosterone. No abnormalities in the androgen receptor gene were detected. These facts suggest that the CAG repeat length and alterations in the androgen receptor gene are not associated with the etiology of idiopathic azoospermia.     

The androgen receptor in hormone-refractory prostate cancer

Advanced prostate cancer is responsive to hormone therapy that interferes with androgen receptor （AR） signalling. However, the effect is short-lived, as nearly all tumours progress to a hormone-refractory （HR） state, a lethal stage of the disease. Intuitively, the AR should not be involved because hormone therapy that blocks or reduces AR activity is not effective in treating HR tumours. However, there is still a consensus that AR plays an essential role in HR prostate cancer （HRPC） because AR signalling is still functional in HR tumours. AR signalling can be activated in HR tumours through several mechanisms. First, activation of intracellular signal transduction pathways can sensitize the AR to castrate levels of androgens. Also, mutations in the AR can change AR ligand specificity, thereby allowing it to be activated by non-steroids or anti-androgens. Finally, overexpression of the wild-type AR sensitizes itself to low concentrations of androgens. Therefore, drugs targeting AR signalling could still be effective in treating HRPC.     

血清睾酮水平预测前列腺癌骨转移的临床研究

目的:本研究观察低血清睾酮水平是否能独立预测前列腺癌骨转移的风险。方法:本研究纳入标准为接受前列腺穿刺证实为前列腺癌,并进行骨扫描检测的患者165例,患者年龄58~78(66.6±5.3)岁。所有患者在诊断为前列腺癌之前未接受过雄激素剥夺治疗、化疗、放射治疗。我们收集患者的临床资料包括:年龄、前列腺穿刺Gleason评分、血清性激素、前列腺特异抗原(PSA)和碱性磷酸酶(ALP)水平,其中血清标本在前列腺穿刺之前的清晨收集。根据骨扫描结果,将前列腺癌分为骨扫描组和非骨扫描组,通过单因素分析筛选出有差异的因子,并进行了多因素非条件回归模型筛选出独立预测因子。结果:165例前列腺癌患者纳入本次研究,依据骨扫描结果分为前列腺癌骨转移组和非骨转移组。单因素分析结果显示年龄(P=0.126)、黄体生成素(P=0.930)、卵泡刺激素(P=0.763)和雌二醇(P=0.256)在两组之间并没有统计学差异,而血清PSA(P<0.001)、前列腺穿刺的Gleason评分(P<0.001)、血清睾酮(P=0.013)及血清碱性磷酸酶(P<0.001)在预测骨转移有统计学意义。多因素分析结果显示低血清睾酮(P=0.531)、前列腺穿刺Gleason评分(P=0.898)并不能作为独立因子预测前列腺癌骨转移的风险,而血清碱性磷酸酶(P<0.001,OR=1.018[1.011~1.026])和血清PSA(P<0.001,OR=1.029[1.015~1.044])是有效的预测前列腺癌骨转移的风险因子。结论:低血清睾酮水平与前列腺癌骨转移密切相关,但不能成为有效的预测前列腺癌骨转移的风险因子。     

雄激素受体在雄激素非依赖性前列腺癌的表达

目的探讨雄激素受体(AR)在国人雄激素非依赖性前列腺癌(AIPC)的表达及其临床意义。方法采用免疫组化两步法,检测AR在15例AIPC和20例雄激素依赖性前列腺癌(ADPC)组织标本的表达水平。结果1例AIPC无AR表达,其余14例AIPC及全部ADPC均有AR高表达,AIPC染色的光密值为0.31±0.04较ADPC0.28±0.03升高。结论大多数国人AIPC均高表达AR,AR的异常表达可能在前列腺癌的进展中发挥重要的作用。