前列腺癌及其可能的癌前病变中雄激素受体基因内CAG重复序列长度的原位缩短

In situ shortening of CAG repeat length within the androgen receptor gene in prostatic cancer and its possible precursors.

作者信息

Tsujimoto Yuichi, Takakuwa Tetsuya, Takayama Hitoshi, Nishimura Kazuo, Okuyama Akihiko, Aozasa Katsuyuki, Nonomura Norio

机构信息

Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.

出版信息

Prostate. 2004 Feb 15;58(3):283-90. doi: 10.1002/pros.10333.

DOI:10.1002/pros.10333

PMID:14743468

Abstract

BACKGROUND

The amino-terminal transcriptional activation domain of the androgen receptor (AR) gene contains two polymorphic trinucleotide repeat segments that encode polyglutamine (CAG)n and polyglycine (GGC)n tracts. Shorter CAG repeat lengths are associated with higher transcriptional activity. The previous studies using peripheral blood leukocytes showed the relationship between shorter CAG repeat length and risk for prostate cancer (PCA).

METHODS

Prostatic cancer (PCA), its possible precursors [high grade prostatic intraepithelial neoplasia (HGPIN) and postatrophic hyperplasia (PAH)], and non-neoplastic epithelium were microdissected from a whole-mount prostatectomy specimen from 34 cases with PCA. DNA extracted from each lesion was processed for PCR-based electrophoresis on 6% denaturing polyacrylamide gels, followed by direct sequencing. To examine whether the in situ shortening of CAG repeat was confined to the CAG repeat or was a part of phenomenon induced by microsatelite instability (MSI), BAT-25 and BAT-26, effective markers for detection of MSI, were also examined.

RESULTS

All non-neoplastic epithelial lesions had identical numbers of CAG repeat in the same prostate. CAG repeat lengths were identical in lesions in 25 cases. Two distinct products were found in 9 of 34 cases (26.5%); one product identical to that of non-neoplastic epithelium and another smaller one. In situ shortening of CAG repeat lengths in PCA, HGPIN, and PAH was found in 3 of 34 (8.8%), 6 of 34 (17.6%), and 3 of 10 (30%) cases, respectively. Frequency of CAG shortening was significantly higher in PAH than in PCA lesions (P < 0.05). The length of GGC repeats, BAT-25 and -26 was identical among all lesions in the same case. There was no significant correlation between shortening of CAG repeat length and the clinicopathologic parameters.

CONCLUSION

Shortening of CAG repeat length was found in in situ lesions of PCA and its possible precursors.

摘要

背景

雄激素受体（AR）基因的氨基末端转录激活域包含两个多态性三核苷酸重复序列，分别编码聚谷氨酰胺（CAG）n和聚甘氨酸（GGC）n序列。较短的CAG重复长度与较高的转录活性相关。先前使用外周血白细胞的研究显示了较短的CAG重复长度与前列腺癌（PCA）风险之间的关系。

方法

从34例PCA患者的全前列腺切除标本中显微切割出前列腺癌（PCA）、其可能的前驱病变[高级别前列腺上皮内瘤变（HGPIN）和萎缩后增生（PAH）]以及非肿瘤性上皮。从每个病变中提取的DNA在6%变性聚丙烯酰胺凝胶上进行基于PCR的电泳处理，随后进行直接测序。为了检查CAG重复序列的原位缩短是否仅限于CAG重复序列，还是微卫星不稳定性（MSI）诱导现象的一部分，还检测了用于检测MSI的有效标志物BAT-25和BAT-26。

结果

同一前列腺中的所有非肿瘤性上皮病变具有相同数量的CAG重复序列。25例患者病变中的CAG重复长度相同。在34例中的9例（26.5%）中发现了两种不同的产物；一种产物与非肿瘤性上皮的产物相同，另一种较小。分别在34例中的3例（8.8%）、34例中的6例（17.6%）和10例中的3例（30%）的PCA、HGPIN和PAH中发现了CAG重复长度的原位缩短。PAH中CAG缩短的频率显著高于PCA病变（P<0.05）。同一病例的所有病变中GGC重复序列、BAT-25和-26的长度相同。CAG重复长度的缩短与临床病理参数之间无显著相关性。