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


CONCLUSIONS
Shortening of CAG repeat length was found in in situ lesions of PCA and its possible precursors.
Tsujimoto
Yuichi
Y
Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
Takakuwa
Tetsuya
T
Takayama
Hitoshi
H
Nishimura
Kazuo
K
Okuyama
Akihiko
A
Aozasa
Katsuyuki
K
Nonomura
Norio
N
D000368:Aged; D005787:Gene Frequency; D005973:Glutamine / Q000235:genetics; D006801:Humans; D007834:Lasers; D008297:Male; D042282:Microdissection; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D010455:Peptides / Q000235:genetics; D011468:Prostatectomy / Q000379:methods; D011470:Prostatic Hyperplasia / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D011944:Receptors, Androgen / Q000235:genetics*; D018911:Trinucleotide Repeats / Q000235:genetics*
D010455:Peptides; D011944:Receptors, Androgen; D005973:Glutamine; C011080:polyglycine