Methylation of cytidine nucleotides in GSTP1 regulatory sequences constitutes the most common genomic alteration yet described for human prostate cancer.
Using nested primer sets, a sensitive PCR assay for extensive GSTP1 CG island methylation changes was developed that was capable of detecting 200 pg of prostate cancer cell DNA among 1 microgram of normal leukocyte DNA.
The Swedish subjects were also analysed for the CYP2C19 alleles *1 and *2, and the GSTP1 alleles *A, *B and *C. No association was found between prostate cancer and polymorphisms in NAT2, CYP2D6, CYP2C19 or GSTP1.
Loss of GSTP1 expression correlated with DNA methylation of the CpG island in both prostate cancer cell lines and cancer tissues whereas methylation outside the CpG island in normal prostate tissue appeared to have no effect on gene expression.
GSTP1 DNA methylation status is more sensitive than telomerase analysis for the detection of malignant cells in seminal ejaculates from patients with prostate cancer.
These separate methylation domains are lost in all prostate cancer where GSTP1 expression is silenced and methylation extends throughout the island and spans across both the 5'- and 3'-boundary regions.
Human prostate cancer (PCA) cells characteristically contain hypermethylated CpG island sequences encompassing the transcriptional regulatory region of GSTP1, the gene encoding the pi-class glutathione S-transferase (GSTP1), and fail to express GSTP1 as a consequence of transcriptional "silencing."
Larger studies focusing on carcinoma size, location in the prostate, and urine collection techniques, as well as more sensitive technology, may lead to the useful application of GSTP1 hypermethylation in prostate cancer diagnosis and management.
Quantitation of GSTP1 methylation accurately discriminates between normal hyperplastic tissue and prostatic carcinoma in small samples of prostate tissue and may augment the standard pathologic/histologic assessment of the prostate.
This hypothesized critical role for GSTP1 inactivation in the earliest steps of prostatic carcinogenesis provides several attractive opportunities for prostate cancer prevention strategies, including (1) restoration of GSTP1 function, (2) compensation for inadequate GSTP1 activity (via use of therapeutic inducers of other glutathione S-transferases (GST), and (3) abrogation or attenuation of genome-damaging stresses.
Population-based case-control studies have found relationships between risk of prostate cancer and genetic polymorphisms in the CAG repeat and GGC repeat of the X-linked androgen receptor gene (AR) as well as the autosomal gene coding for glutathione S-transferase pi (GSTP1).
The use of real-time quantitative polymerase chain reaction to detect hypermethylation of the CpG islands in the promoter region flanking the GSTP1 gene to diagnose prostate carcinoma.
We propose that the GSTP1 gene is initially silenced in the prostate cancer and random sites of methylation accumulate that result in subsequent hypermethylation and chromatin remodelling.
MDA PCa 2a and 2b appear to be useful models of human prostatic carcinoma in that they lack expression of GSTP1 due to gene silencing via promoter methylation.
No significant effect on prostate cancer risk was detectable for GSTP1 genotype compared with the control population (odds ratio, 1.02; 95% confidence interval, 0.59-1.75).