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Gene Expression Silencing in PIN
Cancels the Detoxification Enzyme Glutathione (March 2003)
The question of whether HGPIN can be identified as a precursor to PC was
addressed by Dr. Sidransky, Professor of Urology and Director of Research
in Molecular Biology at the Johns Hopkins' Kimmel Cancer Center in the
article, "Quantification of GSTP1 [Glutathione S-Transferase] Methylation
in Non-neoplastic Prostatic Tissue and Organ Confined Prostate
Adenocarcinoma" (JNCI, November 2001). "Methylation" refers to the
presence of a methyl group attached to a member of the sequence of bases
in the DNA chain (in this case, specifically, the base cytidine in the
promoter region in the gene) thereby preventing the transcription
mechanism from "reading" the gene and thereby "silencing" it. Methylation
is one of nature's favored mechanisms for selecting which genes should and
should not be expressed and when that expression should take place in the
sequence of development. The polymerase chain reaction assay was employed
to identify the obstructing presence of methylation preventing the
expression of the GSTP1 gene thereby depriving the cell of the benefits of
the detoxifying enzyme glutathione. Glutathione provides an important
element of protection against oxidative damage to DNA, damage that can
lead to DNA strand breaks and unwanted mutations. The methylation of this
specific gene is the most common adverse alteration of DNA in prostate
neoplasia and develops very early in the disease process. In his study of
69 prostatectomy specimens with organ-confined adenocarcinoma 63 showed
this abnormality. Twenty eight of these specimens contained both PC and
HGPIN, and in 15 of these HGPIN showed methylation of the GSTP1 promoter.
In a separate study of TURP specimens 9 of 31 showed methylation. However,
when the extent of methylation in PC, HGPIN, and BPH was evaluated
quantitatively, significant separation of the results was found among the
three types of lesions. These results were compared to a control lesion
with no methylation to establish a ratio of expression, and the median
ratio of methylation in BPH (from the TURP study) compared to control was
0 (range 0-0.1); in HGPIN 1.4 (range 0-49.5); and in PC 250.8 (range
53.5-697.5), raising the intriguing issue of whether the extent of GSTP1
methylation in HGPIN lesions predicts progression to invasive cancer.
Since histologic identification of the suspected transition from HGPIN to
PC has been elusive, perhaps by evaluating the levels of methylation in
HGPIN lesions pathologists can establish persuasive evidence of this
transition. Perhaps by quantitating methylation in HGPIN it would also be
possible to place a specific instance of HGPIN at its appropriate position
along the suspected spectrum of progression toward recognizable prostate
cancer. Understanding of this sort would have an impact on the management
of this vexing lesion. The GSTP1 test can be performed on paraffin-embeded
tissue tissue from prostate biopsies and could be used in retrospective
studies. This issue is under active study at Johns Hopkins.
Bottom Line: Additional data will be
coming from Dr Sidransky on this important issue.
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