Shorter CAG repeat length in the androgen receptor gene is associated with more aggressive forms of breast cancer.

The androgen receptor (AR) is a transcription factor mediating the action of androgens. The AR gene is localized on chromosome X and it contains a series of CAG trinucleotide repeats. The length of the CAG repeats varies among individuals and this polymorphism is believed to be related to AR transcriptional activity. Studies have shown that fewer CAG repeats are associated with an increased risk as well as more aggressive forms of prostate cancer. Although AR is expressed in breast cancer and the impact of androgen and AR on breast cancer has been recognized, the role of the CAG repeats in breast cancer remains unknown. In this study, we measured the CAG repeats in breast cancer tissue using a PCR-based method. Of the 133 patients with primary breast cancer, 102 were heterozygous and 31 were homozygous. The mean CAG repeat number for homozygous women was 21; for heterozygous women the repeat number mean was 20 for the short allele and 24 for the long allele. The length of CAG repeats either in one allele or in both alleles was inversely correlated with the histological grade of breast cancer (r = -0.23 or -0.26, respectively, p < 0.05). An association between positive lymph nodes and fewer CAG repeats in both alleles was also suggested (p = 0.06). Furthermore, survival analysis indicated that the total number of CAG repeats in both alleles was associated with patient overall survival. With every CAG repeat increase, there was a 6% reduction in the risk of death (RR = 0.94, p = 0.03). The association remained significant after controlling for the homozygous and heterozygous status (RR = 0.92, p = 0.01). The association became no longer significant when clinical and pathological variables were adjusted in the analysis but this could be due to the reduction of sample size in the multivariate analysis. CAG heterozygosity and difference in number of CAG repeats between the two alleles were not associated with either disease features or patient survival. Our results suggest that longer CAG repeats may occur more frequently in less aggressive cancer and that the CAG repeats may play a role in breast cancer progression.

Relapse and cure rates of prostate cancer patients after radical prostatectomy and 5 years of follow-up.

OBJECTIVES: We have compared the ability of an ultrasensitive prostate specific antigen assay and a regular PSA assay to identify relapse and cure rates of prostate cancer patients after radical prostatectomy, during a 5-year follow-up period. DESIGN AND METHODS: We measured PSA by an ultrasensitive assay (detection limit 0.001 ng/mL) and a conventional PSA assay (detection limit 0.1 ng/mL) in serial serum samples obtained from 197 patients who have undergone radical prostatectomy. RESULTS: Based on ultrasensitive PSA analysis, we have identified three groups of patients: 62% of patients did not show any significant changes in serum PSA; 15% of patients demonstrated slow PSA increases over time but none of the measurements exceeded 0.1 ng/mL within 4 years; and 23% of the patients had relatively significant increases of serum PSA and were classified as having 'fast relapse'. The vast majority of these patients were subsequently identified to have relapse by the regular PSA assay. The ultrasensitive PSA assay detected relapse by an average of eighteen months earlier than the conventional PSA method. Fast relapsing patients were associated with other prognostic indicators of the disease including pre-operative PSA, tumor volume, Gleason score, clinical stage, surgical margin positivity, periprostatic tissue involvement, capsular invasion and seminal vesicle invasion. The group with slowly rising PSA had prognosis which was between the patients in remission and fast relapsing patients. CONCLUSIONS: The use of ultrasensitive PSA analysis for monitoring patients after radical prostatectomy provides earlier detection of relapse (by 18 months) and identifies three distinct groups of patients. Fast relapsing patients should be good candidates for early therapeutic interventions.

Rapid and accurate determination of (CAG)n repeats in the androgen receptor gene using polymerase chain reaction and automated fragment analysis.

OBJECTIVES: To develop and evaluate a new method for determination of the CAG repeat length in Exon 1 of the androgen receptor gene. DESIGN AND METHODS: The method is based on PCR amplification of a DNA region encompassing the repeats and analysis of the length of the PCR product on a sequencing gel. One of the PCR primers was labeled with Cy5.5 fluorescent dye to facilitate detection after laser excitation. We used a fully automated system for electrophoretic separation of the PCR product and accurate sizing of the length of the PCR product using fragment analysis. RESULTS: The major advantages of the new technique are its simplicity, speed, accuracy, and reproducibility. Analysis of the CAG repeats in genomic DNAs from 18 males indicated that they were all hemizygous with a mean CAG repeat number of 22 (range 20-30 repeats). Among 60 DNAs from females, 16 were homozygous and 44 were heterozygous. The repeat length ranged from 17-30 with a mean of 22. In both males and females, the distribution of CAG repeats was bimodal. CONCLUSION: We anticipate that this improved method for CAG repeat analysis will find applications in clinical studies involving prostate and breast cancer patients.