Brooks, J. D. et al. CG island methylation changes near the GSTP1 gene in prostatic intraepithelial neoplasia. Cancer Epidemiol. Biomark. Prev. 7, 531-536

Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-2101, USA.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.13). 07/1998; 7(6):531-6.
Source: PubMed


Prostate intraepithelial neoplasia (PIN) is a purported prostate cancer precursor lesion and a candidate biomarker for efficacy assessment in prostate cancer chemoprevention trials. Loss of expression of the pi-class glutathione S-transferase enzyme GSTP1, which is associated with the hypermethylation of deoxycytidine residues in the 5'-regulatory CG island region of the GSTP1 gene, is a near-universal finding in human prostate cancer. GSTP1 expression was assessed by immunohistochemistry in 60 high-grade PIN samples adjacent to and distant from prostate adenocarcinoma. Whereas abundant enzyme polypeptide expression was evident in all normal prostatic tissues, all samples of high-grade PIN and adenocarcinoma were completely devoid of GSTP1. DNA from 10 high-grade PIN lesions was analyzed for GSTP1 CG island methylation changes using a PCR technique targeting a polymorphic (ATAAA)n repeat sequence in the promoter region of the GSTP1 gene. Somatic GSTP1 CG island methylation changes were detected in DNA from 7 of the 10 PIN lesions. Allele discrimination was possible for 5 of the 10 DNA samples: 2 of the 5 samples exhibited DNA methylation changes at both alleles; whereas 3 samples displayed no DNA methylation changes at either allele. GSTP1 CG island methylation changes were present in each of the five homozygous samples. Hypermethylation of the 5'-regulatory region of the GSTP1 gene may serve as an important molecular genetic biomarker for both prostate cancer and PIN. The finding of frequent GSTP1 methylation changes in PIN and prostate cancer supports a role for PIN lesions as a prostate cancer precursor and may provide insight to the molecular pathogenesis of prostate cancer.

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Available from: James D Brooks, Oct 10, 2015
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    • "Promoter hypermethylation leading to epigenetic silencing of GSTP1 gene expression is frequently detected in prostate cancer cells, the most commonly diagnosed type of malignancy among men in Western European countries and the second cause of cancer-related deaths among men worldwide (Brooks et al., 1998; Cairns et al., 2001; Jeronimo et al., 2002; Henrique and Jeronimo, 2004; Dumache et al., 2010; Ferlay et al., 2010). Interestingly , GSTP1 hypermethylation is strictly restricted to malignant cells including prostate cancer cells (PCa) as well as prostatic intraepithelial neoplasia (PIN). "
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    ABSTRACT: Glutathione S-transferases (GSTs) are phase II drug detoxifying enzymes that play an essential role in the maintenance of cell integrity and protection against DNA damage by catalyzing the conjugation of glutathione to a wide variety of exo- and endogenous electrophilic substrates. Glutathione S-transferase P1 (GSTP1), the gene encoding the pi-class GST, is frequently inactivated by acquired somatic CpG island promoter hypermethylation in multiple cancer subtypes including prostate, breast, liver, and blood cancers. Epigenetically mediated GSTP1 silencing is associated with enhanced cancer susceptibility by decreasing its "caretaker" gene function, which tends to promote neoplastic transformation allowing cells to acquire additional alterations. Thus, this epigenetic alteration is now considered as a cancer biomarker but could as well play a driving role in multistep cancer development, especially well documented in prostate cancer development. The present review discusses applications of epigenetic alterations affecting GSTP1 in cancer medicine used alone or in combination with other biomarkers for cancer detection and diagnosis as well as for future targeted preventive and therapeutic interventions including by dietary agents.
    Frontiers in Pharmacology 07/2014; 5:170. DOI:10.3389/fphar.2014.00170 · 3.80 Impact Factor
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    • "For example, hypermethylation of GSTP1 (a glutathione S-transferase) is found in approximately 85% of prostate cancer, including prostate intraepithelial neoplasia.62 This is not the case in benign hyperplastic prostate tissue, and therefore its detection in blood or biopsied tissue can be used to detect the presence of prostate cancer cells.63,64 Similarly, MGMT and MLH1 (DNA mismatch-repair genes) have been demonstrated to undergo epigenetic inactivation in gliomas65 and ovarian cancers,66 respectively. "
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    ABSTRACT: The emergence of epigenetic mechanisms as key regulators of gene expression has led to dramatic advances in understanding cancer biology. Driven by complex layers that include aberrant DNA methylation and histone modification, epigenetic aberrations have emerged as critical processes that disrupt cellular machinery and homeostasis. Recent discoveries have already translated into successful clinical trials and improved patient care, with several agents approved for hematologic disease and others undergoing study. As the field matures, substantial challenges persist that will require resolution. These include the need to decipher more fully the interplay between the epigenetic and genetic machinery, patient selection and improving treatment efficacy in solid tumors, and optimizing combination therapies to counteract chemoresistance and minimize adverse effects. Here, we review recent progress in epigenetic treatments and consider their implications for future cancer therapy.
    OncoTargets and Therapy 03/2013; 6:223-32. DOI:10.2147/OTT.S34680 · 2.31 Impact Factor
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    • "DNA topoisomerase II-alpha staining by immunohistochemistry is intermediate between benign tissue and prostate cancer [30]. HGPIN also displays epigenetic changes, including hypermethylation [44]. "
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    ABSTRACT: High-grade prostatic intraepithelial neoplasia (HGPIN) has been established as a precursor to prostatic adenocarcinoma. HGPIN shares many morphological, genetic, and molecular signatures with prostate cancer. Its predictive value for the development of future adenocarcinoma during the prostate-specific antigen screening era has decreased, mostly owing to the increase in prostate biopsy cores. Nevertheless, a literature review supports that large-volume HGPIN and multiple cores of involvement at the initial biopsy should prompt a repeat biopsy of the prostate within 1 year. No treatment is recommended for HGPIN to slow its progression to cancer.
    Korean journal of urology 05/2012; 53(5):297-303. DOI:10.4111/kju.2012.53.5.297
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