AR CAG Research Articles

Expression of Humoral Autoimmunity is Related to Androgen Receptor CAG Repeat Length in Men with Systemic Lupus Erythematosus

We sought to explore whether inherited differences in androgen sensitivity conferred by variation in the length of a CAG repeat in exon 1 of the androgen receptor gene could be correlated with differing manifestations of humoral autoimmunity in men with lupus. In a sample of 15 men with lupus, AR CAG repeat length was linearly correlated with levels of antibodies against extractable nuclear antigens and with the number of diagnostic criteria for lupus. Protein microarrays were used to assess levels of 86 different IgG and IgM autoantibodies in the sera of these patients. IgG autoantibodies were more frequently observed in male lupus patients with longer AR CAG repeat length (>23), while IgM autoantibodies were more prevalent in subjects with shorter CAG repeat length (≤23). These data support a potential role for androgen signaling in the modulation of immunoglobulin class switching processes, with consequent impact on the autoimmune phenotype in men with lupus.

Association of androgen receptor CAG repeat polymorphism with VO2max response to hypoxic training in North China Han men

The purposes of this study were to investigate the distribution characteristics of CAG repeat polymorphism in exon 1 of androgen receptor gene and the association of CAG polymorphism with VO₂max response to hypoxic training in North China Han men. Sixty-five healthy young men completed a 30-day HiHiLo training (living high, exercise high and training low) in a simulated normobaric hypoxic environment. All subjects slept in 14.3-14.8% O₂ concentration, and participated in hypoxic training three times a week in 15.4% O₂ concentration. VO₂max (peak oxygen consumption) and body weight were measured before and after hypoxic training. A total of 15 repeat alleles were observed by CAG genotype analyze, in which (CAG)22 was most common. When using 21 and 22 alleles, respectively, as cut-off points, we found that the baseline body weight of two shorter genotype groups was significantly lower than that of longer ones, and that the ΔVO₂max and ΔrVO₂max (Δrelative value of VO₂max) of two shorter genotype groups were significantly higher than those of longer ones after hypoxic training. These findings indicated that AR CAG repeat polymorphism was associated with the exercise performance after simulated normobaric hypoxic HiHiLo training in North China Han men, and that the shorter genotypes had a better individual response to hypoxic training.

Androgen Receptor CAG Repeat Length and Association With Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial

We investigated the association between the length of the polymorphic trinucleotide CAG microsatellite repeats in exon 1 of the AR gene and the risk of prostate cancer. This is a nested case-control study of 1,159 cases and 1,353 controls from the Prostate Cancer Prevention Trial, a randomized, placebo controlled trial testing whether the 5α-reductase inhibitor finasteride could decrease the 7-year prevalence of prostate cancer. During the course of the trial men underwent annual digital rectal examination and prostate specific antigen measurement. Prostate biopsy was recommended in all men with abnormal digital rectal examination or finasteride adjusted prostate specific antigen greater than 4.0 ng/ml. Cases were drawn from men with biopsy determined prostate cancer identified by for cause or end of study biopsy. Controls were selected from men who completed the end of study biopsy. Mean CAG repeat length did not differ between cases and controls. The frequency distribution of cases and controls for the AR CAG repeat length was similar. There were no significant associations of CAG repeat length with prostate cancer risk when stratified by treatment arm (finasteride or placebo), or when combined. There was also no significant association between CAG repeat length and the risk of low or high grade prostate cancer. There is no association of AR CAG repeat length with prostate cancer risk. Knowledge of AR CAG repeat length provides no clinically useful information to predict prostate cancer risk.

Selected estrogen receptor 1 and androgen receptor gene polymorphisms in relation to risk of breast cancer and fibrocystic breast conditions among Chinese women

Background: Polymorphisms in sex hormone receptor-encoding genes may alter the activity of sex hormone receptors and thereby affect susceptibility to breast cancer and related outcomes. Methods: In a case–control study of women from Shanghai, China, we examined the risk of breast cancer and fibrocystic breast conditions associated with the ESR1 PvuII (rs2234693) and XbaI (rs9340799) and AR CAG repeat ((CAG) n ) and GGC repeat ((GGC) n ) polymorphisms among 614 women with breast cancer, 467 women with fibrocystic conditions, and 879 women without breast disease. We also evaluated whether risk differed by the presence/absence of proliferative changes (in the extratumoral epithelium or fibrocystic lesion), menopausal status, or body mass index (BMI). Age-adjusted odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated using logistic regression. Results: Only associations with AR (CAG) n and (GGC) n genotypes were detected. Allocating AR (CAG) n genotypes into six categories, with the (CAG) 22–24/(CAG) 22–24 genotype category designated as the reference group, the (CAG) >24/(CAG) >24 genotype category was associated with an increased risk of fibrocystic breast conditions (OR, 1.8; 95% CI, 1.1–3.0). Relative to the AR (GGC) 17/(GGC) 17 genotype, the (GGC) 17/(GGC) 14 genotype was associated with elevated risks of incident breast cancer (OR, 2.6; 95% CI, 1.3–5.4) and fibrocystic conditions (OR, 2.3; 95% CI, 1.1–4.5). Results did not differ according to proliferation status, menopausal status, or BMI. Conclusion: Although these data lend support for a link between AR variation and breast disease development, given the low frequency of the putative risk-conferring genotypes and other constraints, further confirmation of our results is needed.

Androgen receptor status predicts response to chemotherapy, not risk of breast cancer in Indian women

BackgroundConsiderably little is known about the biological role and clinical significance of androgen receptor expression in breast cancer. The objectives of this study were to characterize AR-CAG repeat genotypes in a cohort of women with breast cancer and to determine the influence of AR on response to neoadjuvant chemotherapy and clinical outcome.Materials and methodsGenotyping of the AR CAG repeat region was done on 70 patients and 80 healthy aged- matched female controls. To assess response to NACT, tissue samples from 30 LABC cases were evaluated quantitatively by real time for AR mRNA expression. The clinical response was correlated with both the pre and post chemotherapy AR expression. The CAG alleles did not show differences between cases and controls when the mean of short, long and average length of both CAG alleles was considered. However, analysis when done defining short allele as CAGn < 20 (AR1) and the long as CAGn ≥ 20 (AR2), risk was found associated with AR2 allele with marginal significance (P = 0.09). Stratification by age of onset, FH, stage, grade ER and AR status failed to reveal any association with breast cancer risk. Genotype carriers with ≥20 CAGn showed decrease of AR mRNA expression although significance could not be established (P = 0.47). Tumours in responders had the higher AR mRNA expression levels in pre neo-adjuvant chemotherapy condition (p < 0.02) which got reduced after neoadjuvant chemotherapy and the difference was found to be significant (P = 0.014).ConclusionsAlthough, expansion of the CAGn in the AR gene doesn't show any major effect on breast cancer risk, patients with positive AR expression, pre neoadjuvant chemotherapy, were found to be good responders and a decrease in mRNA level of AR gene related to the chemotherapy-induced apoptosis could serve as an important independent predictor of response to NACT.

PSAand Androgen-Related Gene (AR,CYP17, andCYP19) Polymorphisms and the Risk of Adenocarcinoma at Prostate Biopsy

The aim of the present study was to examine the impact of polymorphisms in prostate-specific antigen (PSA) and androgen-related genes (AR, CYP17, and CYP19) on prostate cancer (PCa) risk in selected high-risk patients who underwent prostate biopsy. Blood samples and prostate tissues were obtained for DNA analysis. Single-nucleotide polymorphisms in the 50-untranslated regions (UTRs) of the PSA (substitution A>G at position-158) and CYP17 (substitution T>C at 50-UTR) genes were detected by polymerase chain reaction (PCR)-restriction fragment length polymorphism assays. The CAG and TTTA repeats in the AR and CYP19 genes, respectively, were genotyped by PCR-based GeneScan analysis. Patients with the GG genotype of the PSA gene had a higher risk of PCa than those with the AG or AA genotype (OR=3.79, p=0.00138). The AA genotype was associated with lower PSA levels (6.44 +/- 1.64 ng=mL) compared with genotypes having at least one G allele (10.44 +/- 10.06 ng=mL) ( p=0.0687, 95% CI=0.3146 to 8.315, unpaired t-test). The multivariate analysis confirmed the association between PSA levels and PSA genotypes (AA vs. AG+ GG; chi2=0.0482) and CYP19 (short alleles homozygous vs. at least one long allele; chi2=0.0110) genotypes. Genetic instability at the AR locus leading to somatic mosaicism was detected in one PCa patient by comparing the length of AR CAG repeats in matched peripheral blood and prostate biopsy cores. Taken together, these findings suggest that the PSA genotype should be a clinically relevant biomarker to predict the PCa risk.

Androgen receptor CAG repeat polymorphism is associated with serum testosterone levels, obesity and serum leptin in men with type 2 diabetes

To determine the relationships between androgen receptor CAG repeat polymorphism length (AR CAG), sex hormones and clinical variables in men with type 2 diabetes (DM2). Men with DM2 are known to have a high prevalence of low testosterone levels. Studies suggest that testosterone replacement therapy may improve insulin sensitivity and glycaemic control in men with DM2 and reduces central obesity and serum leptin. AR CAG is known to correlate negatively with AR sensitivity and positively with body fat, insulin levels, and leptin in healthy men. Cross-sectional study set in a district general hospital diabetes centre. Sex hormones, AR CAG and symptoms of hypogonadism were assessed in 233 men with DM2. Associations were sought between these variables and others such as obesity, leptin, glycaemic control, and blood pressure. Testosterone was negatively associated and AR CAG positively associated with obesity and leptin. The associations of AR CAG with leptin and obesity were independent of testosterone, estradiol, gonadotropins, and age. AR CAG was also independently associated with total, bioavailable and free testosterone, LH, waist circumference, body mass index, leptin, and systolic blood pressure. There was no association of AR CAG with sex hormone binding globulin, estradiol, HbA(1C) or the symptoms of hypogonadism. The association of longer AR CAG with obesity and leptin suggests that shorter AR CAG may have an influence in maintaining healthy anthropomorphics and metabolism in men with DM2. Testosterone and LH levels are higher in men with longer AR CAG, probably reflecting reduced negative feedback through a less sensitive receptor.

Somatic Mosaicism of Androgen Receptor CAG Repeats in Colorectal Carcinoma Epithelial Cells From Men

The X-linked human androgen receptor gene (AR) contains an exonic polymorphic trinucleotide CAG. The length of this encoded CAG tract inversely affects AR transcriptional activity. Colorectal carcinoma is known to express the androgen receptor, but data on somatic CAG repeat lengths variations in malignant and normal epithelial cells are still sporadic. Using laser capture microdissection (LCM), epithelial cells from colorectal carcinoma and normal-appearing mucosa were collected from the fresh tissue of eight consecutive male patients undergoing surgery (mean age, 70 y; range, 54-82). DNA isolated from each LCM sample underwent subsequent PCR and DNA sequencing to precisely determine AR CAG repeat lengths and the presence of microsatellite instability (MSI). Different AR CAG repeat lengths were observed in colorectal carcinoma (ranging from 0 to 36 CAG repeats), mainly in the form of multiple shorter repeat lengths. This genetic heterogeneity (somatic mosaicism) was also found in normal-appearing colorectal mucosa. Half of the carcinoma cases examined tended to have a higher number of AR CAG repeat lengths with a wider range of repeat size variation compared to normal mucosa. MSI carcinomas tended to have longer median AR CAG repeat lengths (n = 17) compared to microsatellite stable carcinomas (n = 14), although the difference was not significant (P = 0.31, Mann-Whitney test). Multiple unique somatic mutations of the AR CAG repeats occur in colorectal mucosa and in carcinoma, predominantly resulting in shorter alleles. Colorectal epithelial cells carrying AR alleles with shorter CAG repeat lengths may be more androgen-sensitive and therefore have a growth advantage.

Determination of ancestral allele for possible human cancer-associated polymorphisms

To determine ancestral allele in possible cancer-associated polymorphisms, DNA samples from 10 chimpanzees ( Pan troglodytes) were sequenced for alleles corresponding to 17 polymorphisms: 8 short tandem repeats [IL1RN (alias IL-1RA) variable number tandem repeat (VNTR); TYMS (previously TS) VNTR; AR CAG repeat; dinucleotide repeats of UGT1A1, IGF1, IFNG (alias IFN-γ), ESR1 (alias ER-α), and EGFR] and 9 single nucleotide polymorphisms ( MMP1-1607 1G/2G, MMP3-1171 5A/6A, OGG1 Ser326Cys, ALDH2 Gly487Lys, TP53 Arg72Pro, ABCG2 Gln141Lys, MGMT Leu84Phe, SOD2 Ala-9Val, and MTHFR Ala222Val). No chimpanzee polymorphism corresponded to human IL1RN VNTR; the ancestral allele was a repeat lost in humans. Dinucleotide repeat polymorphisms of IGF1, IFNG, ESR1, and EGFR were shared by chimpanzees, but the length of repeats tended to be longer in humans than in chimpanzees. This tendency was particularly evident for IGF1. All of the SNPs tested are human-specific nucleotide changes. The ancestral allele 7A was shown to be lost in MMP3-1171 5A/6A. Thus, all of the possible cancer-associated polymorphisms tested have human-specific alleles, and the ancestral allele is lost in three polymorphisms ( IL1RN VNTR, UGT1A1 CA repeat, and MMP3-1171 5A/6A), suggesting a possible involvement of human-specific alleles in cancer susceptibility.

Androgen receptor gene polymorphism may affect the risk of urothelial carcinoma

The study sought to explore if androgen receptor gene (AR) polymorphisms are associated with the risk of urothelial carcinoma (UC) which is male-predominant. AR CAG and GGN repeat lengths were analyzed in 277 UC cases and 280 age and sex-matched controls by direct sequencing of leukocyte DNA. Smoking habits were obtained using a structured questionnaire interview. Relative risks were compared between groups categorized by all possible cutoffs of AR CAG and GGN repeat lengths. Men and women who had 23 and 44 (cumulative) CAG repeats had a significantly greater risk of UC, respectively (OR 2.09, 95% CI: 1.05-4.17, p = 0.036 and OR 4.95, 95% CI: 1.56-15.73, p = 0.007). Amongst males who were medium-dose cigarette smokers, those who had 23 CAG and shorter GGN (<22) repeats, had an elevated risk than those with longer CAG and GGN (OR 4.32 and 4.57, p = 0.034 and 0.042, respectively). However, neither CAG nor GGN affected the UC risk in non-smokers or heavy smokers (> or =25 packs per day-years). AR CAG polymorphism may affect the risk of UC in both genders. In addition, AR polymorphisms may influence carcinogenic effect of medium-dose of cigarette smoking in men.

Increased risk of breast cancer in women bearing a combination of large CAG and GGN repeats in the exon 1 of the androgen receptor gene

The exon 1 of the human androgen receptor gene (AR) contains both CAG (polyglutamine) and GGN (polyglycine) repeat length polymorphisms. Large CAG repeats have been related to an increased risk of breast cancer (BC), whereas the influence of the GGN repeats is still unclear. Here, we have studied how the length of CAG and GGN repeats is associated with the risk of BC in a population from Tenerife (Canary Islands, Spain). The study was carried out on 257 woman diagnosed with BC and 393 controls, nesting in the ‘CDC of the Canary Islands’ cohort study. The AR CAG and GGN genotyping was performed by means of PCR amplification with specific fluorescently labelled primers followed by a capillary electrophoresis. The allelic distribution of CAG and GGN polymorphisms was similar in cases and controls. The mean of short and long CAG and GGN alleles did not show differences between cases and controls and the same was true when the average length of both CAG alleles (CAG n ) and GGN alleles (GGN n ) was considered. However, when CAG n and GGN n were categorised using 22 and 24 repeats as the cut-off point, respectively, significant differences between cases and controls were observed. The CAG n > 22 repeats were more frequent in cases than in controls, being associated with an increased risk of BC (OR = 1.49; CI 95% = 1.06–2.09; p = 0.021). No significant differences were found for categorised GGN n . For CAG n /GGN n combinations, the highest BC risk was found to be associated with the CAG n > 22/GGN n ⩾ 24 combination (OR = 2.47; CI 95% = 1.37–4.46; p = 0.003). In conclusion, our results indicate that longer CAG n /GGN n combinations increase the risk of BC and suggest that CAG and GGN AR polymorphisms should be considered in order to assess the BC risk.

Androgen receptor CAG repeat length contraction in diseased and non-diseased prostatic tissues

To investigate contraction of CAG repeats within the androgen receptor gene (AR) as shorter CAG repeats have been implicated as a possible risk factor in prostate cancer (PCa). AR CAG repeat lengths were analyzed in DNA from microdissected diseased prostates, leukocytes from matched peripheral blood, and control non-diseased prostates. Consistently, all prostatic tissues, whether from benign or cancerous areas of diseased prostates, or from control prostates, showed multiple AR CAG repeat contractions. Germline DNA from blood leukocytes had single CAG repeat lengths in the normal range. AR CAG repeat length contraction may be involved in prostate carcinogenesis and may precede the pathological process.

How valid is single nucleotide polymorphism (SNP) diagnosis for the individual risk assessment of breast cancer? / Welchen Stellenwert hat der diagnostische Einsatz von Einzelnukleotid-Polymorphismen (SNPs) bei der individuellen Risikoeinschätzung von Brustkrebs?

Abstract The number of reports investigating disease susceptibility based on the carriage of low-penetrance, high-frequency single nucleotide polymorphisms (SNPs) has increased over the last years. Evidence is accumulating defining specific individual variations in breast cancer susceptibility. Genetic variations of the estradiol and xenobiotic metabolisms, as well as genes involved in cell cycle control, have been described as significant contributors to breast cancer susceptibility with variations depending on ethnic background and co-factors such as smoking and family history of breast cancer. In sum, the highest level of evidence to date linking SNPs and breast cancer comes from nested case-control studies within the prospective Nurses' Health Study. These data establish seven SNPs – hPRB +331 G/A, AR CAG repeat, CYP 19 TTTA(10), CYP 1A1 Msp I, VDR FOK1, XRCC1 Arg194Trp, and XRCC2 Arg188His – as small, but significant risk factors for spontaneous, non-hereditary breast cancer. In addition, meta-analysis of data in the literature established the TGFBR1*6A, the HRAS1, GSTP Ile105Val, and the GSTM1 SNPs as low-penetrance genetic risk factors for sporadic breast cancer. The clinical consequences of such a risk elevation may be a detailed instruction of the patient as to general measures of breast cancer prevention such as a low-fat diet, optimization of the BMI, physical exercise, avoidance of alcohol and long-term hormone replacement therapy (HRT), and participation in a breast cancer screening program between the age of 50 and 70 years. Specific surgical or drug interventions such as prophylactic mastectomy and oophorectomy or prophylactic intake of tamoxifen are not indicated based on SNP analysis at this time.

How valid is single nucleotide polymorphism (SNP) diagnosis for the individual risk assessment of breast cancer?

The number of reports investigating disease susceptibility based on the carriage of low-penetrance, high-frequency single nucleotide polymorphisms (SNPs) has increased in recent years. Evidence is accumulating defining specific individual variations in breast cancer susceptibility. Genetic variations of estradiol and xenobiotics metabolisms as well as genes involved in cell-cycle control have been described as significant contributors to breast cancer susceptibility, with variations depending on ethnic background and co-factors such as smoking and family history of breast cancer. In sum, the highest level of evidence to date linking SNPs and breast cancer comes from nested case–control studies within the prospective Nurses' Health Study. These data establish seven SNPs – hPRB +331G/A, AR CAG repeat, CYP19 (TTTA)10, CYP1A1 MspI, VDR FOK1, XRCC1 Arg194Trp and XRCC2 Arg188His – as small but significant risk factors for spontaneous, non-hereditary breast cancer. In addition, meta-analysis of data in the literature establishes the TGFBR1*6A, HRAS1, GSTP Ile105Val and GSTM1 SNPs as low-penetrance genetic risk factors of sporadic breast cancer. The clinical consequences of such a risk elevation may be detailed instruction of the patient as to general measures of breast cancer prevention such as a low-fat diet, optimization of body mass index, physical exercise, avoidance of alcohol and long-term hormone replacement therapy, and participation in a breast cancer screening program between the ages of 50 and 70 years. Specific surgical or drug interventions such as prophylactic mastectomy and oophorectomy or prophylactic intake of tamoxifen are not indicated based on SNP analysis at this time.

Associations between ERα, ERβ, and AR Genotypes and Colon and Rectal Cancer

Estrogen and androgens are thought to be involved in the etiology of colorectal cancer. We evaluate genetic variants of the estrogen receptor genes (ERalpha and ERbeta) and the androgen receptor gene (AR). We use data from two large case-control studies of colon (n = 1,580 cases and 1,968 controls) and rectal (n = 797 cases and 1,016 controls) cancer. We evaluated the 351A >G XbaI polymorphism of ERalpha, the 1,082 G >A and CA repeat polymorphisms of ERbeta, and the CAG repeat of AR. Having two 25 or more CA repeats in ERbeta was associated with an increased relative risk of colon cancer in women [odds ratio (OR), 2.13; 95% confidence interval (95% CI), 1.24-3.64] but not in men (P(interaction) relative excess risk from interaction < 0.01; multiplicative = 0.03). Increasing number of AR CAG repeats was directly associated with colon cancer among men (OR, 1.28; 95% CI, 1.06-1.54), but not women (OR, 0.83; 95% CI, 0.68-1.02); the interaction P value for AR gene x sex was <0.01. Taking hormone replacement therapy (HRT) was associated with a reduced risk of colon cancer in the presence of the R allele of the ERbeta gene, whereas an R allele was associated with increased risk among postmenopausal women who did not take HRT. Postmenopausal women not using HRT who had > or =25 CA repeats of the ERbeta gene had over a 6-fold increased risk of colon cancer (OR, 6.71; 95% CI, 2.89-15.6). Our results suggest that the ERbeta gene is more important than ERalpha in the etiology of colorectal cancer.

Androgen Receptor Gene Methylation and Exon One CAG Repeat Length in Ovarian Cancer: Differences from Breast Cancer

More than one neoplastic founder clone can exist in benign epithelial tumours. Although theories of clonal selection make pluriclonality appear unlikely in carcinomas, published data do not exclude this possibility. This study looked for evidence of multiclonal X inactivation in ovarian carcinoma using AR methylation as a marker. Fifteen unifocal ovarian carcinomas and 14 multifocal carcinomas all in Scottish patients were studied. One representative formalin-fixed paraffin-embedded tumour block was chosen for each of the former and two for the latter. From each of these 43 tumour blocks three samples each of approximately 10(4) carcinoma cells were obtained by microdissection (129 in all). DNA released by proteinase K digestion was subjected to PCR amplification of the androgen receptor gene AR exon I CAG repeat polymorphism with and without prior digestion with methylation-sensitive restriction enzymes HpaII and HhaI. Complex amplification patterns were consistent with mosaic X inactivation in some ovarian carcinomas but acquired anomalies of AR methylation cannot be excluded. Parallel analysis of other X-linked polymorphic loci would strengthen the inference of clonality status from DNA methylation data in tumour X studies. Strikingly, the number of CAG repeats in the 29 ovarian tumour patients (median 16, range 11 - 20) was substantially fewer than in 34 previously studied breast cancer patients from the same scottish population (median 21, range 14 - 26; P < 0.0001), and women homozygous for the AR CAG repeat were over-represented in the ovarian cancer patients but not in the breast cancer series. These findings reinforce recent suggestions that AR may have a role in ovarian carcinogenesis.