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)

Prostate cancer has become 1 of the most commonly diagnosed cancers in the United States and 1 of the leading causes of cancer death in North America and Western Europe. Survey studies of prostate tissues obtained at autopsy indicate that the development of life-threatening prostate cancer in the US likely occurs over decades. Insights from epidemiologic studies implicate environmental factors, principally dietary components, as major risk factors for prostate cancer development. An accumulating body of basic research data suggests that normal and neoplastic prostate cells may be subjected to a relentless barrage of genome-damaging stresses, and that dietary components and male sex steroids might modulate the level of genome threatening insults. Finally, over the past 5 years, analyses of somatic genome alterations in prostatic carcinoma cells have revealed that somatic inactivation of GSTP1, encoding the carcinogen-detoxification enzyme glutathione S-transferase pi, may serve as an initiating genome lesion for prostatic carcinogenesis. These diverse observations can be integrated into a transcendent mechanistic hypothesis for the pathogenesis of prostate cancer: normal prostate cells acquiring somatic GSTP1 defects may suffer chronic genome damage, influenced by dietary practices, that promote neoplastic transformation, while prostatic carcinoma cells, which characteristically contain defective GSTP1 alleles, remain susceptible to further genome-damaging stresses that promote malignant cancer progression. 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.
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PMID:The molecular pathogenesis of prostate cancer: Implications for prostate cancer prevention. 1129 93

Prostate cancer continues to be the most frequently diagnosed cancer in men in the United States. Despite aggressive intervention, a significant number of men with prostate cancer will not be cured of their disease and will face the possibility of metastatic disease. Thus, development of potent prevention strategies to diminish or eliminate this threat is in order. Cellular exposure to chronic oxidative stress may be 1 possible etiologic factor in the development of many cancers, including prostate cancer. Oxygen radicals can attack DNA directly and result in the accumulation of potentially promutagenic oxidized DNA bases such as 8-hydroxydeoxyguanosine. In addition, chronic oxidant stress may also result in lipid peroxidation and the subsequent generation of a range of reactive products that can damage DNA. Disruption of certain genes may result in cellular tolerance to oxidative genomic injury. GSTP1 is an enzyme that helps catalyze the conjugation reaction between potentially damaging electrophiles and glutathione. Inactivation of GSTP1 has been documented to occur in nearly 100% of human prostate cancers; it is also frequently inactivated in prostatic intraepithelial neoplasia lesions. This inactivation may leave the cell vulnerable to oxidative DNA damage and/or tolerant to accumulation of oxidized DNA base adducts. These base adducts can be measured by several quantitative methods, such as gas chromatography-mass spectrometry with selected ion monitoring. These sophisticated methods can be readily integrated into prostate cancer chemoprevention studies of new and developing prevention agents by providing quantitative assessment of oxidative DNA damage before and after administration of these candidate chemopreventive drugs. The combination of genetic information, state-of-the-art assessment tools, and novel agents will allow rational, directed prostate cancer chemoprevention studies to be performed and, together, will help determine the role of chronic oxidative stress in the carcinogenic process of prostate cancer.
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PMID:Oxidative stress in chemoprevention trials. 1129 12

Several polymorphic glutathione-S-transferase (GST) enzymes are involved in the metabolism of a number of potential prostate carcinogens and are thought to engage in the transport of steroid hormones. A case-control study was conducted to determine the association of the GSTP1, GSTM1 and GSTT1 polymorphisms and prostate-cancer risk. The study population consisted of 166 patients with previously untreated, histologically proven prostate cancer and 166 age-matched control patients with benign prostatic hyperplasia (BPH), all of them Caucasians. In the GSTP1 gene, 2 polymorphic alleles, GSTP1*B and GSTP1*C, have been described in addition to the wild-type allele, GSTP1*A. Both polymorphic GSTP1 alleles have an A-to-G transition in exon 5, causing an isoleucine-to-valine change. The GSTP1*C allele has an additional transition from C to T. For GSTM1 as well as GSTT1, the polymorphic allele is a deletion of the gene. The proportion of individuals homozygous for the GSTP1 variant alleles (GSTP1*B/*B, GSTP1*B/*C and GSTP1*C/*C) was significantly lower in prostate-cancer patients (4.8%) than in BPH controls (14.5%), and the odds ratio (OR) was 0.24 [95% confidence interval (CI) = 0.09-0.61). The heterozygous genotypes (GSTP1*A/*B and GSTP1*A/*C) were also lower in the cancer group, though this was not significant. On the contrary, no significant effect on prostate-cancer risk was detectable for either GSTM1 (OR = 0.86, 95% CI = 0.55-1.36) or GSTT1 (OR = 0.78, 95% CI = 0.43-1.42). Of the polymorphic GSTs, GSTP1 is the most interesting candidate as a biomarker for prostate-cancer risk as we found a 76% reduced risk in men homozygous for the polymorphic GSTP1 alleles compared to those with wild-type GSTP1.
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PMID:Polymorphisms of glutathione-S-transferase genes (GSTP1, GSTM1 and GSTT1) and prostate-cancer risk. 1130 47

There is evidence suggesting that polymorphic variations in the glutathione S-transferases (GSTs) are associated with cancer susceptibility. Inter-individual differences in cancer susceptibility may be mediated in part through polymorphic variability in the bioactivation and detoxification of carcinogens. The GSTs have been consistently implicated as cancer susceptibility genes in this context. The GST supergene family includes several loci with well characterized polymorphisms. Approximately 50% of the Caucasian population are homozygous for deletions in GSTM1 and approximately 20% are homozygous for deletions in GSTT1, resulting in conjugation deficiency of mutagenic electrophiles to glutathione. The GSTP1 gene has a polymorphism at codon 105 resulting in an Ile to Val substitution which consequently alters the enzymatic activity of the protein and this has been suggested as a putative high-risk genotype in various cancers. We investigated the relationship between GST polymorphisms and young onset prostate cancer in a case-control study. GSTM1, GSTT1 and GSTP1 genotypes were determined for 275 prostate cancer patients and for 280 geographically matched control subjects. We found no significant difference in the frequency of GSTM1 or GSTT1 null genotypes between cases and controls. GSTP1 genotype was, however, significantly associated with prostate cancer risk: the Ile/Ile homozygotes had the lowest risk and there was a trend in increasing the risk with the number of 105 Val alleles: Ile/Val odds ratio (OR)= 1.30 (95% FCI 0.99-1.69), Val/Val OR = 1.80 (95% FCI 1.11-2.91); Ptrend = 0.026. These results suggest that the GSTP1 polymorphism may be a risk factor for developing young onset prostate cancer. We also found that carrying more than one putative high-risk allele in the carcinogen metabolizing GST family was associated with an elevated risk for early onset prostate cancer (OR 2.48, 95% FCI 1.22-5.04, Ptrend = 0.017).
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PMID:Relationship between glutathione S-transferase M1, P1 and T1 polymorphisms and early onset prostate cancer. 1143 10

Novel approaches for the early detection and management of prostate cancer are urgently needed. Clonal genetic alterations have been used as targets for the detection of neoplastic cells in bodily fluids from many cancer types. A similar strategy for molecular diagnosis of prostate cancer requires a common and/or early genetic alteration as a specific target for neoplastic prostate cells. Hypermethylation of regulatory sequences at the glutathione S-transferase pi (GSTP1) gene locus is found in the majority (>90%) of primary prostate carcinomas, but not in normal prostatic tissue or other normal tissues. We hypothesized that urine from prostate cancer patients might contain shed neoplastic cells or debris amenable to DNA analysis. Matched specimens of primary tumor, peripheral blood lymphocytes (normal control), and simple voided urine were collected from 28 patients with prostate cancer of a clinical stage amenable to cure. Genomic DNA was isolated from the samples, and the methylation status of GSTP1 was examined in a blinded manner using methylation-specific PCR. Decoding of the results revealed that 22 of 28 (79%) prostate tumors were positive for GSTP1 methylation. In 6 of 22 (27%) cases, the corresponding urine-sediment DNA was positive for GSTP1 methylation, indicating the presence of neoplastic DNA in the urine. Furthermore, there was no case where urine-sediment DNA harbored methylation when the corresponding tumor was negative. Although we only detected GSTP1 methylation in under one-third of voided urine samples, we have demonstrated that molecular diagnosis of prostate neoplasia in urine is feasible. 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.
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PMID:Molecular detection of prostate cancer in urine by GSTP1 hypermethylation. 1155 85

GSTP1 CpG island hypermethylation is the most common somatic genome alteration described for human prostate cancer (PCA); lack of GSTP1 expression is characteristic of human PCA cells in vivo. We report here that loss of GSTP1 function may have been selected during the pathogenesis of human PCA. Using a variety of techniques to detect GSTP1 CpG island DNA hypermethylation in PCA DNA, we found only hypermethylated GSTP1 alleles in each PCA cell in all but two PCA cases studied. In these two cases, CpG island hypermethylation was present at only one of two GSTP1 alleles in PCA DNA. In one of the cases, DNA hypermethylation at one GSTP1 allele and deletion of the other GSTP1 allele were evident. In the other case, an unmethylated GSTP1 allele was detected, accompanied by abundant GSTP1 expression. GSTP1 CpG island DNA hypermethylation was responsible for lack of GSTP1 expression by LNCaP PCA cells: treatment of the cells with 5-azacytidine (5-aza-C), an inhibitor of DNA methyltransferases, reversed the GSTP1 promoter DNA hypermethylation, activated GSTP1 transcription, and restored GSTP1 expression. GSTP1 promoter activity, assessed via transfection of GSTP1 promoter-CAT reporter constructs in LNCaP cells, was inhibited by SssI-catalyzed CpG dinucleotide methylation. Remarkably, although selection for loss of GSTP1 function may be inferred for human PCA, GSTP1 did not act like a tumor suppressor gene, as LNCaP cells expressing GSTP1, either after 5-aza-C treatment or as a consequence of transfection with GSTP1 cDNA, grew well in vitro and in vivo. Perhaps, GSTP1 inactivation may render prostatic cells susceptible to additional genome alterations, caused by electrophilic or oxidant carcinogens, that provide a selective growth advantage.
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PMID:GSTP1 CpG island hypermethylation is responsible for the absence of GSTP1 expression in human prostate cancer cells. 1169 42

Hypermethylation of CpG island is a common mechanism for the inactivation of tumor-related genes. In the present study, we analyzed 13 genitourinary cancer cell lines for aberrant DNA methylation of 5 tumor-related genes using methylation- specific polymerase chain reaction (MSP). GSTP1 was methylated in 5 (38.5%), E-cadherin in 1 (8%), VHL in 1 (8%), and MGMT and hMLH1 in none (0%). Six out of thirteen genitourinary cancer cell lines had methylation of at least one of five genes; 5 had one gene methylated, and, 1 had two genes methylated. Methylation of these 5 genes was not detected in any of the bladder cancer cell lines. GSTP1 was methylated in all of the 3 prostate cancer cell lines. We conclude that aberrant hypermethylation may be an important mechanism for the inactivation of cancer-related genes in kidney and prostate cancer cell lines.
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PMID:Hypermethylation of tumor-related genes in genitourinary cancer cell lines. 1174 58

Environmental factors, especially the diet, play a prominent role in the epidemic of prostate cancer (PCA), in the United States. Many candidate dietary components have been proposed to influence human prostatic carcinogenesis, including fat, calories, fruits and vegetables, anti-oxidants, and various micronutrients, but the specific roles dietary agents play in promoting or preventing PCA remain controversial. We have collected evidence to suggest that GSTP1, the gene encoding the pi-class glutathione S-transferase (GST), may serve a "caretaker" function for prostatic cells. Although GSTP1 can be detected in normal prostatic epithelium, in almost all PCA cases, PCA cells fail to express GSTP1 polypeptides, and lack of GSTP1 expression most often appears to be the result of somatic "CpG island" DNA methylation changes. Loss of GSTP1 function also appears to be characteristic of prostatic epithelial neoplasia (PIN) lesions, thought to represent PCA precursors. We have recently learned that a new candidate early PCA precursor lesion, proliferative inflammatory atrophy (PIA), characterized by proliferating prostatic cells juxtaposed to inflammatory cells, contains epithelial cells that express high levels of GSTP1. These findings have formed the basis for a new model of prostatic carcinogenesis, in which prostatic cells in PIA lesions, subjected to a barrage of inflammatory oxidants, induce GSTP1 expression as a defense against oxidative genome damage. When cells with defective GSTP1 genes appear amongst the PIA cells, such cells become vulnerable to oxidants and electrophiles that inflict genome damage that tends to promote neoplastic transformation to PIN and PCA cells. Subsequently, PIN and PCA cells with defective GSTPI genes remain vulnerable to similar stresses tending to promote malignant progression. This new model for prostatic carcinogenesis has implications for the design of new prostate cancer prevention strategies. Rational prevention approaches might include: (i) restoration of GSTPI expression via treatment with inhibitors of CpG methylation, (ii) compensation for inadequate GSTPI activity via treatment with inducers of general GST activity, and (iii) abrogation of genome-damaging stresses via avoidance of exogenous carcinogens and/or reduction of endogenous carcinogenic (particularly oxidant) stresses.
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PMID:Preneoplastic prostate lesions: an opportunity for prostate cancer prevention. 1179 33

Understanding what triggers hypermethylation of tumour suppressor genes in cancer cells is critical if we are to discern the role of methylation in the oncogenic process. CpG sites in CpG island promoters, that span most tumour suppressor genes, remain unmethylated in the normal cell, despite the fact that CpG sites are the prime target for de novo methylation by the DNA methyltransferases. The CpG island-associated with the GSTP1 gene is an intriguing example of a CpG rich region which is susceptible to hypermethylation in the majority of prostate tumours and yet is unmethylated in the normal prostate cell. In this study we evaluate a number of factors purported to be involved in hypermethylation to test their role in triggering hypermethylation of GSTP1 in prostate cancer DU145 and LNCaP cells. We find that hypermethylation is not associated with (1) elevated expression of the DNA methyltranferases, or (2) removal of Sp1 transcription factor binding sites in the CpG island or (3) removal of CpG island boundary elements or (4) prior gene silencing. Instead our results support a model that requires a combination of prior gene silencing and random "seeds" of methylation to trigger hypermethylation of the GSTP1 gene in the prostate cancer cell. 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.
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PMID:Hypermethylation trigger of the glutathione-S-transferase gene (GSTP1) in prostate cancer cells. 1185 Aug 22

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). This family-based study utilized the transmission disequilibrium test to examine whether there was evidence that these polymorphisms could account for familial aggregation of prostate cancer. Seventy-nine North American pedigrees were studied. Most of these families had 3 or more affected first-degree relatives. Genotype information was obtained on 578 individuals. The reconstruction combined transmission disequilibrium test (RC-TDT) was used to test for linkage. There was no evidence of linkage to the CAG and GGC repeat sequences in the AR gene or the pentanucleotide (ATAAA) repeat in the GSTP1 gene when each allele was analyzed separately or when alleles were grouped by repeat length. Our findings do not support the hypothesis that familial clustering of prostate cancer in high-risk families is attributable to these genetic variants.
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PMID:Transmission/disequilibrium tests of androgen receptor and glutathione S-transferase pi variants in prostate cancer families. 1194 76


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