Hardy D O, Scher H I, Bogenreider T, Sabbatini P, Zhang Z F, Nanus D M, Catterall J F
Center for Biomedical Research, Population Council, New York, New York 10021, USA.
J Clin Endocrinol Metab. 1996 Dec;81(12):4400-5. doi: 10.1210/jcem.81.12.8954049.
The androgen receptor (AR) is a structurally conserved member of the nuclear receptor superfamily. The amino-terminal domain is required for transcriptional activation and contains a region of polyglutamine encoded by CAG trinucleotide repeats. In humans, the number of CAG repeats is polymorphic; the average number is 22 in Caucasian males. Expansion of CAG repeats in the AR has clinical implications for human disease. As androgen influences prostate cancer growth, polymorphisms in CAG repeat length may affect the clinical course of patients with prostate cancer. To test for an association between clinical parameters of human prostate cancer and CAG repeat length, we analyzed normal lymphocyte DNA from 109 patients. The CAG region of the AR was amplified by the PCR. Reaction products were then amplified using end-labeled internal primers, cut at the internal PstI site and assayed on sequencing gels using a sequence ladder as a size standard. Sequence analysis of several samples validated this method for measurement of CAG repeat number. The median age of patients was 63 yr (range, 42-83), with 104 Caucasian, 2 African American, 1 Asian, and 2 other racial origin. The median repeat length was 25 for patients with stage A, 22 for patients with stage B, 22 for patients with stage C, and 23 for patients presenting with stage D disease. A significant correlation between CAG repeat length and age at onset was observed, whereas correlations with stage, level of prostate-specific antigen at diagnosis, and time to prostate-specific antigen relapse were not significant. Shorter CAG repeat lengths may be associated with the development of prostate cancer in men at a younger age. These data suggest that CAG repeat length can affect the risk of developing prostate cancer.
雄激素受体（AR）是核受体超家族中结构保守的成员。其氨基末端结构域对于转录激活是必需的，并且包含由CAG三核苷酸重复序列编码的多聚谷氨酰胺区域。在人类中，CAG重复序列的数量具有多态性；在白种男性中平均数量为22。AR中CAG重复序列的扩增对人类疾病具有临床意义。由于雄激素影响前列腺癌的生长，CAG重复长度的多态性可能会影响前列腺癌患者的临床病程。为了检测人类前列腺癌临床参数与CAG重复长度之间的关联，我们分析了109例患者的正常淋巴细胞DNA。通过PCR扩增AR的CAG区域。然后使用末端标记的内部引物扩增反应产物，在内部PstI位点切割，并以序列阶梯作为大小标准在测序凝胶上进行检测。对多个样本的序列分析验证了该方法用于测量CAG重复数。患者的中位年龄为63岁（范围42 - 83岁），其中104例为白种人，2例为非裔美国人，1例为亚洲人，2例为其他种族。A期患者的重复长度中位数为25，B期患者为22，C期患者为22，D期疾病患者为23。观察到CAG重复长度与发病年龄之间存在显著相关性，而与分期、诊断时前列腺特异性抗原水平以及前列腺特异性抗原复发时间之间的相关性不显著。较短的CAG重复长度可能与男性在较年轻时患前列腺癌有关。这些数据表明CAG重复长度会影响患前列腺癌的风险。
