Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypermethylation of regulatory sequences at the locus of the pi-class glutathione S-transferase gene GSTP1 was detected in 20 of 20 human prostatic carcinoma tissue specimens studied but not in normal tissues or prostatic tissues exhibiting benign hyperplasia. In addition, a striking decrease in GSTP1 expression was found to accompany human prostatic carcinogenesis. Immunohistochemical staining with anti-GSTP1 antibodies failed to detect the enzyme in 88 of 91 prostatic carcinomas analyzed. In vitro, GSTP1 expression was limited to human prostatic cancer cell lines containing GSTP1 alleles with hypomethylated promoter sequences; a human prostatic cancer cell line containing only hypermethylated GSTP1 promoter sequences did not express GSTP1 mRNA or polypeptides. Methylation of cytidine nucleotides in GSTP1 regulatory sequences constitutes the most common genomic alteration yet described for human prostate cancer.
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PMID:Cytidine methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic carcinogenesis. 797 32

Two variant glutathione S-transferase cDNAs have been described at the GSTP1 locus, which differ by a single base pair (A-G) substitution at nucleotide 313 of the GSTP1 cDNA. This results in an amino acid substitution which alters the function of the enzyme. In this study, a novel PCR assay has been developed which demonstrates that these two variant cDNAs represent distinct GSTP1 alleles (GSTP1a and GSTP1b). In a study of individuals with different forms of cancer, the GSTP1b allele is found to be strongly associated with bladder cancer and testicular cancer. In controls 6.5% of individuals were homozygous for the GSTP1b allele. In bladder cancer cases, this rose to 19.7% [n = 71, odds ratio 3.6 (1.4-9.2), P = 0.006] and in testicular cancer to 18.7% [n = 155, odds ratio 3.3 (1.5-7.7), P = 0.002]. In addition, in prostate cancer a highly significant decrease in the frequency of the GSTP1a homozygotes was observed [control 51.0% versus 27.8% cancer cases, n = 36, odds ratio 0.4 (0.02-3.3), P = 0.008]. Increases in the frequency of GSTP1b homozygotes was also observed in lung cancer and chronic obstructive pulmonary disease. However, these were not statistically significant. No change in breast or colon cancer allele frequencies was observed.
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PMID:Identification of genetic polymorphisms at the glutathione S-transferase Pi locus and association with susceptibility to bladder, testicular and prostate cancer. 911 Nov 93

Cancer-associated somatic genome alterations offer great promise as cancer biomarkers. Here we describe a new biomarker for human prostate cancer: extensive methylation of deoxycytidine nucleotides distributed throughout a 5' "CG island" region of the pi-class glutathione S-transferase gene (GSTP1). Using the PCR to amplify a GSTP1 promoter sequence fragment containing 12 recognition sites for HpaII and MspI, 52 of 57 (91%) prostatic carcinoma DNA specimens demonstrated extensive somatic increases in deoxycytidine methylation, detected as amplification of target GSTP1 promoter sequences following HpaII digestion, but not following MspI treatment. 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. This GSTP1 CG island DNA methylation assay, which targets a somatic genome change present in most prostate cancer cells but not in normal cells, may serve as a new molecular diagnosis and staging tool to aid in prostate cancer detection and treatment.
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PMID:CG island methylation changes near the GSTP1 gene in prostatic carcinoma cells detected using the polymerase chain reaction: a new prostate cancer biomarker. 918 79

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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PMID:CG island methylation changes near the GSTP1 gene in prostatic intraepithelial neoplasia. 964 98

Our laboratory has been involved in the study of Glutathione S-transferase pi (GST pi) for many years, both in terms of regulation of gene expression and in trying to understand the endogenous function(s) of this enzyme and also what role it may play in the carcinogenic process [1]. Over-expression of GST pi has been associated with carcinogenesis and the development of many different human tumours, for example testis [2], ovarian [3] and colorectal [4] and is often inversely correlated with prognosis or patient survival [5,6]. In addition, GST Pi has been implicated in the acquisition of antineoplastic drug resistance [7-9]. In order to study the transcriptional regulation of this gene, we have utilised a multi-drug resistant derivative (VCREMS) of the human mammary carcinoma cell line, MCF7, in which GST P1 mRNA and protein are significantly elevated in the absence of gene amplification [10-13]. Interestingly, we have recently reported the discovery of polymorphisms at the GSTP1 locus, resulting in two alleles GSTP1a and GSTP1b. In the study, the GSTP1b allele was found with increased frequency in bladder and testicular cancer, while the GSTP1a allele was significantly decreased in cases of prostate cancer [14]. In an attempt to elucidate the endogenous role(s) of GST pi, we have used homologous recombination in embryonic stem (ES) cells to inactivate both murine GST Pi genes and create a mouse strain completely deficient in the expression of this enzyme. This provides us with a unique animal model with which to study the effects of the absence of GST pi expression on the metabolism and pharmacokinetics of xenobiotics.
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PMID:Pi-class glutathione S-transferase: regulation and function. 967 44

Glutathione-S-Transferases (GSTs) comprise a family of isoenzymes that provide protection to mammalian cells against electrophilic metabolites of carcinogens and reactive oxygen species. Previous studies have shown that the CpG-rich promoter region of the pi-class gene GSTP1 is methylated at single restriction sites in the majority of prostate cancers. In order to understand the nature of abnormal methylation of the GSTP1 gene in prostate cancer we undertook a detailed analysis of methylation at 131 CpG sites spanning the promoter and body of the gene. Our results show that DNA methylation is not confined to specific CpG sites in the promoter region of the GSTP1 gene but is extensive throughout the CpG island in prostate cancer cells. Furthermore we found that both alleles are abnormally methylated in this region. In normal prostate tissue, the entire CpG island was unmethylated, but extensive methylation was found outside the island in the body of the gene. 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.
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PMID:Detailed methylation analysis of the glutathione S-transferase pi (GSTP1) gene in prostate cancer. 1002 13

The development of prostate cancer is dependent on heredity, androgenic influences, and exposure to environmental agents. A high intake of dietary fat is associated with an increased risk of prostate cancer, either through influence on steroid hormone profiles or through production of carcinogenic compounds that require biotransformation by enzymes. The polymorphic glutathione S-transferase (GST), N-acetyltransferase (NAT), and cytochrome P450 (CYP) enzymes are of particular interest in prostate cancer susceptibility because of their ability to metabolize both endogenous and exogenous compounds, including dietary constituents. Association between different NAT2, CYP2D6, CYP2C19 and GSTP1 genotypes and prostate cancer was studied in a Swedish and Danish case-control study comprising 850 individuals. The combined Swedish and Danish study population was analysed by polymerase chain reaction for the NAT2 alleles *4, *5A, *5B, *5C, *6 and *7, and for the CYP2D6 alleles *l, *3 and *4. 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. An association between CYP2D6 poor metabolism and prostate cancer was seen among smoking Danes; odds ratio 3.10 (95% confidence interval 1.07; 8.93), P = 0.03, but not among smoking Swedes; odds ratio 1.19 (95% confidence interval 0.41; 3.42), P = 0.75. Smoking is not a known risk factor for prostate cancer, and the association between CYP2D6 poor metabolism and prostate cancer in Danish smokers may have arisen by chance.
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PMID:Polymorphisms in NAT2, CYP2D6, CYP2C19 and GSTP1 and their association with prostate cancer. 1047 Oct 65

Glutathione S-transferases are enzymes involved in the metabolism of carcinogens and in the defence against reactive oxygen species. Genetic polymorphisms have been detected in glutathione S-transferases M1, T1 and P1, and some of these polymorphisms have been associated with an increased risk of cancer. In a case-control study (153 cases and 288 controls) the effect of these genetic polymorphisms on the risk of prostate cancer was investigated. Homozygote deletion of either GSTM1 or GSTT1 was not associated with a statistically significant increased risk, odds ratio (OR) 1.3; 95% confidence intervals (CI) 0.9-1.9 and 1.3; 0.8-2.2, respectively. Deletion of both GSTM1 and GSTT1 gave a near-significant increased risk (OR 1.7; 95% CI 0.9-3.4). Two allelic variants of GSTP1 (codon 105) have been reported. This polymorphism was not linked to an increased risk (OR 0.8; 95% CI 0.5-1.1). Smokers that lack either GSTM1 or GSTT1 activity had a slightly higher risk of prostatic cancer than smokers expressing the genes, OR 1.4 (95% CI 0.6-3.3) and 1.6 (0.6-3.9), respectively. Our results show that differences in enzymes involved in the metabolism of carcinogens slightly modify prostate cancer risk, especially in people exposed to carcinogens that are detoxified by these enzymes.
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PMID:Glutathione S-transferases as risk factors in prostate cancer. 1064 42

What defines the boundaries between methylated and unmethylated domains in the genome is unclear. In this study we used bisulfite genomic sequencing to map the boundaries of methylation that flank the 5'- and 3'-ends of the CpG island spanning the promoter region of the glutathione S-transferase (GSTP1) gene. We show that GSTP1 is expressed in a wide range of tissues including brain, lung, skeletal muscle, spleen, pancreas, bone marrow, prostate, heart, and blood and that this expression is associated with the CpG island being unmethylated. In these normal tissues a marked boundary was found to separate the methylated and unmethylated regions of the gene at the 5'-flank of the CpG island, and this boundary correlated with an (ATAAA)(19-24) repeated sequence. In contrast, the 3'-end of the CpG island was not marked by a sharp transition in methylation but by a gradual change in methylation density over about 500 base pairs. In normal tissue the sequences on either side of the 5'-boundary appear to lie in separate domains in which CpG methylation is independently controlled. 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.
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PMID:A distinct sequence (ATAAA)n separates methylated and unmethylated domains at the 5'-end of the GSTP1 CpG island. 1077 22

New diagnostic tools are needed for the early detection of prostatic cancer. The molecular detection of prostate cancer cells in ejaculates was evaluated using complementary PCR-based methods. LNCaP cells, a cell line derived from prostatic carcinoma, were spiked into normal seminal ejaculates and the prostatic epithelial component of the specimens was isolated by immunomagnetic bead sorting, using a monoclonal antibody to prostate-specific membrane antigen (PSMA). Ejaculates from nine patients with a recent diagnosis of prostate cancer were processed in a similar fashion, using LNCaP-spiked aliquots as an internal positive control. Telomerase expression was evaluated by the telomeric repeat amplification protocol (TRAP) and glutathione S-transferase gene promoter (GSTP1) hypermethylation was evaluated by methylation-sensitive restriction endonuclease digestion and PCR amplification. Telomerase activity was detected in LNCaP cells recovered from normal seminal ejaculates but was not found in all nine samples from patients with prostate cancer. The sensitivity of GSTP1 analysis was similar to telomerase analysis for the detection of LNCaP cells from normal ejaculate samples but was positive in ejaculates from four out of nine patients with prostate cancer. GSTP1 DNA methylation status is more sensitive than telomerase analysis for the detection of malignant cells in seminal ejaculates from patients with prostate cancer.
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PMID:Comparison of telomerase activity and GSTP1 promoter methylation in ejaculate as potential screening tests for prostate cancer. 1097 Jul 25


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