Absence of a correlation of androgen receptor gene CAG repeat length and prostate cancer risk in an African-American population

Shorter androgen receptor gene CAG repeat length has been associated with an increased risk of prostate cancer, an earlier age of onset, and more advanced stage of disease. Studies comparing the distribution of CAG repeat lengths within different populations have reported that racial groups with higher prostate cancer incidence also have shorter CAG repeat lengths. We evaluated CAG repeat length in 685 black men in Louisiana, South Carolina, and the District of Columbia who were participating in prostate cancer screening, comparing the 118 who were diagnosed with prostate cancer with 567 who had normal serum prostate-specific antigen levels and no evidence of cancer on digital rectal examination. The median CAG repeat length was 21 among cases and 19 among controls (P = 0.11). Cases were significantly older than controls, with a median age of 68 years compared with 54 years (P < 0.0001). After adjusting for age, we found no association between prostate cancer risk and CAG repeat length (odds ratio, 1.05; 95% CI, 0.98-1.13; P = 0.16). Dividing CAG repeat lengths into septiles and calculating the odds ratio for each revealed no specific repeat-length range with a significantly elevated or depressed risk of prostate cancer, but a trend test showed a significant association between longer CAG repeat lengths and an elevated risk of prostate cancer (P = 0.02). Neither grade nor stage was associated with CAG repeat length. This study confirms earlier reports that black men have shorter CAG repeat lengths than reported white and Asian populations. We did not find an increased risk of prostate cancer among black men with fewer CAG repeats.     

Association between androgen receptor gene CAG repeat polymorphism and breast cancer risk: a meta-analysis

Androgens have been hypothesized to influence risk of breast cancer through several possible mechanisms, including their conversion to estradiol and their binding to the estrogen receptor and/or androgen receptor (AR) in the breast. The CAG repeat polymorphism in AR exon 1 has been implicated in breast cancer risk; however, studies on the association between this polymorphism and breast cancer risk remain conflicting. In order to derive a more precise estimation of the relationship, a large population-based case–control study was performed. We found that a long CAG sequence has a protective effect on breast cancer using an a priori determined cutoff (<22 or ≥22) in a dominant model analysis [SL–LL vs. SS, odds ratio (OR) = 0.86, 95% confidence intervals (CI): 0.67–1.10]. A similar result was obtained by analyzing seven detailed genotyping case–control studies by allele comparison in dominant and recessive models. However, larger scale primary study is required to further evaluate the interaction of AR CAG polymorphism and breast cancer risk.     

Esophageal cancer risk in relation to GGC and CAG trinucleotide repeat lengths in the androgen receptor gene

The incidence of esophageal squamous cell cancer in African males in South Africa is one of the highest in the world. Because most patients present with advanced disease such that survival is poor, the identification of high-risk individuals will facilitate early disease detection. Two polymorphic triplet repeats-(CAG)(n) and (GGC)(n)-in the androgen receptor gene were evaluated as potential genetic susceptibility loci for esophageal squamous cell cancer. Shorter lengths of these alleles have been reported to be associated with increased risk for prostate cancer. Our study sample comprised African males (29 patients and 109 controls), African females (14 patients and 59 controls) and Colored males (15 patients and 58 controls) whose alleles were analyzed singly and in combination. As in prostate cancer, the short (GGC)(n) alleles were implicated in esophageal cancer in African males: the average allele length was significantly shorter in patients compared to controls (p = 0.018), and a short (GGC)(n) allele was associated with elevated risk for disease [(GGC)(21) (GGC)(16)] OR 0.26, 95% CI 0.11-0.65. Analysis using logistic regression led to narrower CIs for the ORs and enabled presentation of a risk profile.     

Polymorphic CAG and GGN repeat lengths in the androgen receptor gene and prostate cancer risk: a population-based case-control study in China

The length of the polymorphic CAG trinucleotide repeat in the polyglutamine region of the androgen receptor (AR) gene is inversely correlated with the transactivation function of the AR. Because increased androgenic activity has been linked to prostate cancer and because an ethnic variation exists in the CAG repeat length, this polymorphism has been suggested to explain part of the substantial racial difference in prostate cancer risk. We conducted a population-based case-control study in China to investigate whether CAG and other polymorphisms of the AR gene are associated with clinically significant prostate cancer in this low-risk population. Genomic DNA from 190 prostate cancer patients and 304 healthy controls was used for direct sequencing to evaluate the relationship of CAG and GGN (polyglycine) repeat length in the AR gene. Relative to western men, our study subjects had a longer CAG repeat length, with a median of 23 and only 10% of the subjects having a CAG repeat length shorter than 20. Men with a CAG repeat length shorter than 23 (median length) had a 65% increased risk of prostate cancer (odds ratio, 1.65; 95% confidence interval, 1.14-2.39), compared with men with a CAG repeat length of 23 or longer. For the GGN tract (GGT3GGG1GGT2GGCn), based on the sequencing results from 481 samples, we are the first to show that although GGC regions in the polyglycine tract are highly variable, there are no mutations or polymorphisms in the GGT and GGG regions. More than 72% of the subjects had a GGN repeat length of 23, and those with a GGN repeat length shorter than 23 had a 12% increased risk of prostate cancer (95% confidence interval, 0.71-1.78), compared with those with > or = 23 GGN repeats. Our study not only confirms that Chinese men do have a longer CAG repeat length than western men but also represents the first population-based study to show that even in a very low-risk population, a shorter CAG repeat length confers a higher risk of clinically significant prostate cancer. These results imply that CAG repeat length can potentially serve as a useful marker to identify a subset of individuals at higher risk of developing clinically significant prostate cancer. Larger studies are needed to evaluate the combined effect of CAG and GGN repeats. Because of the significance of AR in prostate cancer, investigation of factors that interact with the polyglutamine region of the AR gene to alter AR function and modulate prostate cancer risk is an important area for future research.     

Racial variation in CAG repeat lengths within the androgen receptor gene among prostate cancer patients of lower socioeconomic status.

PURPOSE: To evaluate (1) whether there were racial differences in the androgen receptor gene CAG repeat length and in clinical or laboratory attributes of prostate cancer at the time of diagnosis; (2) whether there were differences in race, Gleason score, prostate-specific antigen (PSA) level, and stage at diagnosis by androgen receptor gene CAG repeat length; and (3) whether sociodemographic, clinical, and laboratory based factors might be associated with advanced-stage prostate cancer. To our knowledge, our study is the first to report on CAG repeat lengths in a cohort of prostate cancer patients, which includes large numbers of African-American men. METHODS: CAG repeat lengths on the androgen receptor gene were evaluated for 151 African-American and 168 white veterans with prostate cancer. The chi(2) test, t test, and logistic regression analyses were used to evaluate the associations between CAG repeat lengths and race, stage, histologic grade, and PSA levels at diagnosis. RESULTS: The mean age of the cohort at the time of diagnosis was 68.7 years. At presentation, 42.0% had stage D prostate cancer, 26.5% had Gleason scores of 8 to 10, and 53.0% had PSA levels >/= 10 ng/dL. Mean androgen receptor gene CAG repeat length for white veterans was 21.9 (SD, 3.5) versus 19.8 (SD, 3.2) for African-American veterans (P =.001). Men with shorter CAG repeats were more likely to have stage D prostate cancer (P =.09) but were not more likely to have a higher PSA concentration or Gleason score. CONCLUSION: In this cohort of men with prostate cancer, short CAG repeat length on the androgen receptor gene was associated with African-American race and possibly with higher stage but not with other clinical or pathologic findings.     

Shorter CAG repeats in androgen receptor and non-GG genotypes in prostate-specific antigen loci are associated with decreased risk of benign prostatic hyperplasia and prostate cancer

The age-adjusted risk of prostate cancer (PC) has increased in Singapore since 1968. We investigated the relationship between polymorphisms in four genes, androgen receptor (AR), prostate-specific antigen (PSA), 5alpha-reductase type II (SRD5A2) and cytochrome P450c17alpha (CYP17) and PC and benign prostatic hyperplasia (BPH). Men with shorter CAG repeats in AR and above 69years at diagnosis showed a trend of decreased PC risk (OR=0.28, 95% CI=0.08-1.03; p=0.05). Shorter CAG repeats and non-GG genotypes in the AR and PSA loci, respectively, showed a trend of decreased PC risk (OR=0.25, 95% CI=0.06-1.03; p=0.06) and a significantly decreased BPH risk (OR=0.38, 95% CI=0.15-0.94; p=0.04). The results indicate that allelic variation in PSA promoter activity may be androgen dependent and interaction of genes in androgen pathway may influence the risk of BPH and PC in Singapore males.     

Involvement of different mechanisms for the association of CAG repeat length polymorphism in androgen receptor gene with prostate cancer

While androgen and androgen receptor (AR) activity have been strongly implicated in prostate cancer development and therapy, the influence of the CAG repeat, which is found within the first exon of the AR gene, on prostate carcinogenesis is still unclear. We investigated the differences in the length of the CAG repeat between prostate cancer patients and controls in the Chinese population as well as between TMPRSS2:ERG fusion positive and negative samples. A general association between prostate cancer and either longer or shorter AR CAG repeat length was not observed in the Chinese population. However, our data suggest that certain CAG repeat lengths may increase or decrease prostate cancer risk. Shorter CAG repeat length was also not shown to be associated with a higher induction rate of TMPRSS2 and ERG proximity, an essential step for TMPRSS2:ERG fusion formation. However, samples with a CAG repeat of 17 were found more frequently in the TMPRSS2:ERG fusion positive than negative prostate cancer cases and mediated a higher rate of androgen-induced TMPRSS2 and ERG co-localisation than AR with longer (24) and shorter (15) CAG repeats. This suggests that 17 CAG repeats may be associated with TMPRSS2:ERG fusion positive prostate cancer, but may have a preventive role for prostate cancer in the Chinese population, which has a low TMPRSS2:ERG fusion frequency. This study suggests that different mechanisms for the association of CAG repeat length polymorphism and prostate cancer exist in different ethnic populations.     

A case-control study of the androgen receptor gene CAG repeat polymorphism in Australian prostate carcinoma subjects

BACKGROUND: The development of prostate carcinoma is androgen-dependent. The coding sequence of the androgen receptor (AR) gene contains a CAG repeat polymorphism that has been shown to influence AR activity in vitro. Studies of this polymorphism as a prostate carcinoma risk factor have been conflicting. METHODS: A matched case-control design was used in a clinic-based multicenter study of Australian prostate carcinoma subjects. Cancer subjects were matched by age and locality with controls, all of whom had a serum prostate specific antigen (PSA) level of less than 4 mg/L. Conditional logistic regression was used to determine the relative risk of prostate carcinoma dependent on AR gene CAG number. The association of disease characteristics at diagnosis with the polymorphism also was assessed. RESULTS: Five hundred forty-five cases of prostate carcinoma and 456 matched case-control pairs were recruited. Association studies of disease characteristics at diagnosis showed age at diagnosis to be associated with AR CAG number by univariate (P = 0.004) and multivariate (adjusting for PSA, stage, and grade) linear regression (P = 0.018). No association was observed between the polymorphism and disease stage (TNM-based categories; P = 0.277), histologic grade (P = 0.41), or PSA level at diagnosis (P = 0.48). In the pairwise case-control analysis, the odds ratio of prostate carcinoma for a change of 5 CAG repeats gave an odds ratio of 0.9821 (95% confidence interval, 0.84-1.15). CONCLUSIONS: In this Australian study population, the AR CAG repeat polymorphism was not a risk factor for prostate carcinoma, but a shorter repeat sequence was associated with earlier age at diagnosis.     

CAG repeat length in the androgen receptor gene is related to age at diagnosis of prostate cancer and response to endocrine therapy, but not to prostate cancer risk

The length of the polymorphic CAG repeat in the N-terminal of the androgen receptor (AR) gene is inversely correlated with the transactivation function of the AR. Some studies have indicated that short CAG repeats are related to higher risk of prostate cancer. We performed a case-control study to investigate relations between CAG repeat length and prostate cancer risk, tumour grade, tumour stage, age at diagnosis and response to endocrine therapy. The study included 190 AR alleles from prostate cancer patients and 186 AR alleles from female control subjects. All were whites from southern Sweden. The frequency distribution of CAG repeat length was strikingly similar for cases and controls, and no significant correlation between CAG repeat length and prostate cancer risk was detected. However, for men with non-hereditary prostate cancer (n = 160), shorter CAG repeats correlated with younger age at diagnosis (P = 0.03). There were also trends toward associations between short CAG repeats and high grade (P = 0.07) and high stage (P = 0.07) disease. Furthermore, we found that patients with long CAG repeats responded better to endocrine therapy, even after adjusting for pretreatment level of prostate-specific antigen and tumour grade and stage (P = 0.05). We conclude that short CAG repeats in the AR gene correlate with young age at diagnosis of prostate cancer, but not with higher risk of the disease. Selection of patients with early onset prostate cancer in case-control studies could therefore lead to an over-estimation of the risk of prostate cancer for men with short CAG repeats. An association between long CAG repeats and good response to endocrine therapy was also found, but the mechanism and clinical relevance are unclear.     

The androgen receptor CAG repeat polymorphism and risk of breast cancer in the Nurses' Health Study

Shorter alleles of a polymorphic [CAG](n) repeat in exon 1 of the androgen receptor (AR) have been associated with increased risk of prostate cancer and decreased risk of breast cancer. We prospectively assessed the association between the [CAG](n) repeat polymorphism in the androgen receptor and breast cancer risk among Caucasian women in a case-control study nested within the Nurses' Health Study cohort (cases, n = 727; controls, n = 969). In addition, we assessed whether androgen receptor genotype influences endogenous steroid hormone levels in women and whether the associations between androgen receptor alleles and breast cancer risk differed according to established breast cancer risk factors. Women with one or more long AR [CAG](n) repeat alleles (>or=22 repeats) were not at increased risk of breast cancer [odds ratio (OR), 1.06; 95% confidence interval (CI), 0.83-1.35]. Significant associations were not observed between AR genotypes comprised of two short alleles ([CAG](n) or=22: OR, 0.92; 95% CI, 0.62-1.36) or two long alleles ([CAG](n) >or= 25 versus both alleles or=22; OR, 1.70; 95% CI, 1.20-2.40; P for interaction = 0.04). In summary, we observed no overall relation of AR genotype with breast cancer risk among mostly postmenopausal Caucasian women. However, these data suggest that longer AR [CAG](n) repeat alleles may increase breast cancer risk among women with a first-degree family history of breast cancer.     

Trinucleotide repeat polymorphisms in the androgen receptor gene and risk of ovarian cancer.

INTRODUCTION: Androgens may play a role in the development of ovarian cancers. Two trinucleotide repeat polymorphisms have been described in exon 1 of the androgen receptor (AR) gene that may affect its function. Previous studies of ovarian cancer and AR repeat polymorphisms have been inconsistent. METHODS: We analyzed CAG and GGC repeat length polymorphisms in the AR gene using data from a population-based case-control study of ovarian cancer that included 594 cases and 681 controls. Repeat lengths were determined by fluorescent DNA fragment analysis using ABI GeneScan software. Change point models were used to determine appropriate repeat length cutoff points by race (African American versus Caucasian) for both the shorter and longer CAG and GGC repeats. RESULTS: No relationship was observed between CAG repeat length and ovarian cancer among Caucasians. Among African Americans, having a short repeat length on either allele was associated with a 2-fold increase in ovarian cancer risk (age-adjusted odds ratio, 2.2; 95% confidence interval, 1.1-4.1). Having short CAG repeat lengths for both alleles was associated with a 5-fold increased risk for developing ovarian cancer (age-adjusted odds ratio, 5.4; 95% confidence interval, 1.4-1.7). No relationship with the GGC repeat length polymorphisms was observed. CONCLUSION: These results suggest that having a short CAG repeat length in AR increases ovarian cancer risk in African Americans. The failure to observe this relationship in Caucasians may be due to the rarity of such short CAG alleles in this population or could reflect racial differences in disease etiology.     

Circulating steroid hormones and the risk of prostate cancer.

Epidemiologic studies have failed to support the hypothesis that circulating androgens are positively associated with prostate cancer risk and some recent studies have even suggested that high testosterone levels might be protective particularly against aggressive cancer. We tested this hypothesis by measuring total testosterone, androstanediol glucuronide, androstenedione, DHEA sulfate, estradiol, and sex hormone-binding globulin in plasma collected at baseline in a prospective cohort study of 17,049 men. We used a case-cohort design, including 524 cases diagnosed during a mean 8.7 years follow-up and a randomly sampled sub-cohort of 1,859 men. The association between each hormone level and prostate cancer risk was tested using Cox models adjusted for country of birth. The risk of prostate cancer was approximately 30% lower for a doubling of the concentration of estradiol but the evidence was weak (P(trend)=0.07). None of the other hormones was associated with overall prostate cancer (P(trend) >or= 0.3). None of the hormones was associated with nonaggressive prostate cancer (all P(trend) >or= 0.2). The hazard ratio [HR; 95% confidence interval (95% CI)] for aggressive cancer almost halved for a doubling of the concentration of testosterone (HR, 0.55; 95% CI, 0.32-0.95) and androstenedione (HR, 0.51; 95% CI, 0.31-0.83), and was 37% lower for a doubling of the concentration of DHEA sulfate (HR, 0.63; 95% CI, 0.46-0.87). Similar negative but nonsignificant linear trends in risk for aggressive cancer were obtained for free testosterone, estradiol, and sex hormone-binding globulin (P(trend)=0.06, 0.2, and 0.1, respectively). High levels of testosterone and adrenal androgens are thus associated with reduced risk of aggressive prostate cancer but not with nonaggressive disease.     

雄激素受体基因微卫星CAG多态性与前列腺癌的分期分级

目的研究雄激素受体（AR）基因三核苷酸CAG微卫星多态性与前列腺癌（PC）分期和分级的关系,探讨其与肿瘤生物学特性的相关性。方法运用聚合酶链反应-单链构象多态性分析法（PCR-SSCP）,对37例PC标本的AR基因CAG微卫星数量进行测定,并进行不同病变期别、分化级别间的比较及统计学分析。结果AR基因CAG微卫星数量在病变B期与C～D期分别为25.04±1.88和22.14±2.64（P=0.002）;其短的AR基因CAG（数量＜22）的分布为B期13.0%(3/23),C～D期28.6%(4/14);其长的AR基因CAG（数量≥22）的分布为B期87.0%(20/23),C～D期71.4%(10/14),差异有显著性（P=0.029）。AR基因CAG微卫星数量随PC病变分化程度的增高而增加,低分化为23.64±2.56,中分化为24.29±3.45,高分化为25.6±1.67,在高分化与低分化间差异有显著性（P=0.047）。短组CAG微卫星的分布比例随病变分化程度的升高而降低,长组CAG微卫星的分布比例随病变分化程度的升高而增加。结论AR基因CAG微卫星数量的多少可能是构成前列腺癌不同生物学特性的因素之一,短的CAG微卫星的AR基因可能与恶性度较高的前列腺癌表型有关。     

The polymorphic exon 1 androgen receptor CAG repeat in men with a potential inherited predisposition to prostate cancer.

Recent studies have provided epidemiological evidence in support of a possible prostate cancer susceptibility locus on the X chromosome. The androgen receptor (AR) gene, located at Xq11-12, has been implicated as a risk factor for the development of prostate cancer. To examine the potential role of the AR locus in prostate cancer susceptibility, the AR CAG repeat length was measured in 270 Caucasian men with prostate cancer from 133 unrelated families. Each of these families has two or more confirmed cases of prostate cancer occurring in first- and/or second-degree relatives. No evidence for linkage of the AR gene to prostate cancer was observed. We tested for the previously reported association of short CAG alleles with prostate cancer using t tests, Pearson's chi2 tests, and logistic regression; analyses were subsequently repeated to incorporate only men with moderate- to high-grade prostate cancer. No association between AR CAG allele length and prostate cancer was detected when either a subset of unrelated patients or a subset of unrelated patients with moderate- to high-grade cancer was compared with a set of unrelated controls. We failed to detect an association between short AR CAG alleles and early age of prostate cancer diagnosis. Once specific hereditary prostate cancer genes have been identified, future studies can more carefully delineate the potential role of this AR polymorphism as a modifier locus in high-risk families.     

CAG repeat length polymorphism in the androgen receptor gene and breast cancer risk: data on Indian women and survey from the world

We analyzed the length of the CAG repeats of the androgen receptor gene in Indian women with breast cancer, and compared the data with that of other populations across the world in an attempt to find a potential pattern of association. The study was undertaken on 1,408 individuals comprising 747 breast cancer patients and 661 control individuals recruited from three southern states of India: Andhra Pradesh, Tamil Nadu, and Karnataka. The comparison revealed no difference in mean length of the repeat between cases and controls in any of the three groups or in the analysis of pooled data. No significant difference between pre- and post-menopausal cases in any of the three groups or in the analysis of pooled data was observed. Most of the studies to date support either positive association (longer repeats--increased disease risk) or no association, and only 2 out of 20 studies reported negative association (inverse correlation between repeat length and disease risk). Comparison of these data with those from other populations revealed several interesting facts. Particularly notable is that repeat length shows association with breast cancer risk in a population-specific manner with most of the studies on American and Canadian women showing positive association, whereas those on Australian and Israeli women showing no association. Only one study had been conducted on other populations including Asians/South Asians; this restricted us from finding any patterns of association in these populations.