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)

Aberrant DNA methylation patterns may be the earliest somatic genome changes in prostate cancer. Using real-time methylation-specific PCR, we assessed the extent of hypermethylation at 16 CpG islands in DNA from seven prostate cancer cell lines (LNCaP, PC-3, DU-145, LAPC-4, CWR22Rv1, VCaP, and C42B), normal prostate epithelial cells, normal prostate stromal cells, 73 primary prostate cancers, 91 metastatic prostate cancers, and 25 noncancerous prostate tissues. We found that CpG islands at GSTP1, APC, RASSF1a, PTGS2, and MDR1 were hypermethylated in >85% of prostate cancers and cancer cell lines but not in normal prostate cells and tissues; CpG islands at EDNRB, ESR1, CDKN2a, and hMLH1 exhibited low to moderate rates of hypermethylation in prostate cancer tissues and cancer cell lines but were entirely unmethylated in normal tissues; and CpG islands at DAPK1, TIMP3, MGMT, CDKN2b, p14/ARF, and CDH1 were not abnormally hypermethylated in prostate cancers. Receiver operator characteristic curve analyses suggested that CpG island hypermethylation changes at GSTP1, APC, RASSF1a, PTGS2, and MDR1 in various combinations can distinguish primary prostate cancer from benign prostate tissues with sensitivities of 97.3-100% and specificities of 92-100%. Hypermethylation of the CpG island at EDNRB was correlated with the grade and stage of the primary prostate cancers. PTGS2 CpG island hypermethylation portended an increased risk of recurrence. Furthermore, CpG island hypermethylation patterns in prostate cancer metastases were very similar to the primary prostate cancers and tended to show greater differences between cases than between anatomical sites of metastasis.
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PMID:Hypermethylation of CpG islands in primary and metastatic human prostate cancer. 1502 33

Gene methylation is an important molecular event in prostate carcinogenesis that may have diagnostic and prognostic significance. We evaluated the methylation status of eight genes implicated in prostate carcinogenesis. DNA was extracted from archived paraffin-embedded tumor blocks from 90 prostate cancer patients. Gene methylation status of eight genes (GSTP1, RASSF1A, RARbeta2, CD44, EDNRB, E-cadherin, Annexin-2, and Caveolin-1) was determined using real-time methylation-sensitive PCR techniques. Differences in gene methylation among race, tumor grade and disease stage were evaluated by chi-square test. Of the eight genes, GSTP1, RASSF1A, and RARbeta2 methylation was highly prevalent across tumors (>60% for all three genes) whereas CD44, E-cadherin and EDNRB methylation was less prevalent (33, 24 and 29%, respectively). Annexin-2 and Caveolin-1 were not methylated in any of the tumors examined. Methylation of RARbeta2, CD44 and E-cadherin was correlated with tumor grade but not stage. Interestingly, methylation of EDNRB, a gene involved in angiogenesis, was correlated with stage of disease but not tumor grade. With the possible exception of CD44, we did not observe differences in gene methylation between racial categories for the genes under study. In summary, our data suggest that evaluation of the methylation of a panel of genes may have diagnostic and prognostic utility in prostate cancer.
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PMID:A survey of gene-specific methylation in human prostate cancer among black and white men. 1503 50

During the last ten years our knowledge of genetic alterations in prostate cancer has significantly increased. For example, several chromosomal loci possibly harboring predisposing or somatically mutated genes have been suggested. Still, we lack the comprehensive molecular model for the development and progression of prostate cancer. Only a few genes have been found to be aberrant in a significant proportion of prostate cancer. These include GSTP1, PTEN, TP53, and AR. Thus, they are natural targets for new treatment strategies.
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PMID:Molecular mechanisms of prostate cancer. 1514 39

It is well established that DNA hypermethylation of tumor suppressor and tumor-related genes can occur in cancer cells and that each cancer subtype has specific gene sets that are commonly susceptible to methylation and silencing. Glutathione S-transferase (GSTP1) is one example of a gene that is hypermethylated and inactivated in the majority of prostate cancers. We previously reported that hypermethylation of the GSTP1 CpG island promoter in prostate cancer cells is initiated by a combination of transcriptional gene silencing (by removal of the Sp1 sites) and seeds of methylation that, instead of being constantly removed because of demethylation associated with transcription, acts as a catalyst for the spread of methylation across the CpG island. In this study, we now demonstrate that the seeds of DNA methylation also play an important role in initiating chromatin modification. Our results address a number of central questions about the temporal relationship between gene expression, DNA hypermethylation, and chromatin modification in cancer cells. We find that for the GSTP1 gene, (a). histone acetylation is independent of gene expression, (b). histone deacetylation is triggered by seeds of DNA methylation, (c). the spread of DNA hypermethylation across the island is linked to MBD2 and not MeCP2 binding, and (d). histone methylation occurs after histone deacetylation and is associated with extensive DNA methylation of the CpG island. These findings have important implications for understanding the biochemical events underlying the mechanisms responsible for abnormal hypermethylation of CpG island-associated genes in cancer cells.
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PMID:Transcriptional gene silencing promotes DNA hypermethylation through a sequential change in chromatin modifications in cancer cells. 1517 96

Genetic studies have provided remarkable clues to the causes of prostate cancer (PCa). For example, in addition to the expected role of androgens in facilitating the development of PCa, the possibility that infections might lead to prostate cancer has been raised with the identification of RNASEL and MSR1 as familial prostate cancer genes; that insight will profoundly affect future studies and may ultimately lead to new approaches to the prevention of prostate cancer. The identification of key molecular alterations in prostate cancer cells implicates carcinogen defenses, including GSTP1, growth factor signaling pathways (such as NKX3.1, PTEN and p27) and androgens as critical determinants of the phenotype of PCa cells and defines specific targets for detection, diagnosis and treatment of PCa.
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PMID:Molecular mechanisms in prostate cancer. A review. 1521 88

Several reports suggest that the glutathione-S-transferase (GST) family of enzymes is involved in a variety of cancers, due to their carcinogen-detoxification properties. A polymorphism in codon 105 of the pi variant (GSTP1 I105V), which affects the enzymatic activity of the enzyme, has been linked to the incidence of cancers from different organs. However, the published data in prostate cancer (PCa) is controversial. Some studies report an association with the GSTP1 I105V polymorphism and sporadic PCa, whereas other studies report no association. Recently, one study showed a positive correlation between the GSTP1 I105V polymorphism and familial PCa in a Japanese population. In the present study, we assessed the correlation of the GSTP1 I105V polymorphism with familial and sporadic PCa in an American population. We analyzed DNA samples from 438 patients with familial PCa, 499 patients with sporadic PCa, and 510 controls. We found no significant association between the GSTP1 I105V polymorphism and familial or sporadic PCa when compared to the control group [odds ratio (OR) =1.0 (0.74-1.37); P=0.58]. Moreover, no association was found after stratification for age of diagnosis, Gleason grade, or lymph node involvement [OR =0.84 (0.65-1.09), P=0.37]. These data indicate that there is no associated risk for sporadic or familial PCa in American families containing the GSTP1 I105V polymorphism.
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PMID:Gluthatione-S-transferase P1 polymorphism I105V in familial and sporadic prostate cancer. 1552 8

The glutathione S-transferase (GST) gene superfamily encodes for enzymes involved in conjugation of electrophilic compounds to glutathione. Several polymorphisms in the GST genes have been implicated as risk factors for prostate cancer. We did a meta-analysis of 11 studies with GSTM1 genotyping (2,063 prostate cancer cases and 2,625 controls), 10 studies with GSTT1 genotyping (1,965 cases and 2,554 controls), and 12 studies with GSTP1 genotyping (2,528 cases and 3,076 controls). The random effects odds ratio was 1.08 [95% confidence interval (95% CI), 0.93-1.25, no significant between-study heterogeneity] for the GSTM1 null versus nondeleted genotype and 0.90 (95% CI, 0.73-1.12; P = 0.03 for heterogeneity) for the GSTT1 null versus nondeleted genotype. Overall, the random effects odds ratio was 1.05 (95% CI, 0.90-1.21; P < 0.01 for heterogeneity) for the GSTP1-Val versus GSTP1-Ile allele. For all three polymorphisms, there was a trend for the presence of an association in the earliest published studies, but this did not seem to be validated in subsequent research. For GSTT1, larger studies gave different results than smaller ones. The meta-analysis shows that these three polymorphisms are unlikely to be major determinants of susceptibility to prostate cancer on a wide population basis.
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PMID:Association of GSTM1, GSTT1, and GSTP1 gene polymorphisms with the risk of prostate cancer: a meta-analysis. 1566 93

The incidence and mortality of prostate cancer (PC) is approximately 2-fold higher among African-Americans as compared to Caucasians and very low in Asian. We hypothesize that inactivation of GSTP1 genes through CpG methylation plays a role in the pathogenesis of PC, and its ability to serve as a diagnostic marker that differs among ethnic groups. GSTP1 promoter hypermethylation and its correlation with clinico-pathological findings were evaluated in 291 PC (Asian = 170; African-American = 44; Caucasian = 77) and 172 benign prostate hypertrophy samples (BPH) (Asian = 96; African-American = 38; Caucasian = 38) using methylation-specific PCR. In PC cells, 5-aza-dC treatment increased expression of GSTP1 mRNA transcripts. The methylation of all CpG sites was found in 191 of 291 PC (65.6%), but only in 34 of 139 BPH (24.5%). The GSTP1 hypermethylation was significantly higher in PC as compared to BPH in each ethnic group (p < 0.0001). Logistic regression analysis (PC vs. BPH) showed that African-Americans had a higher hazard ratio (HR) (13.361) compared to Caucasians (3.829) and Asian (8.603). Chi-square analysis showed correlation of GSTP1 hypermethylation with pathological findings (pT categories and higher Gleason sum) in Asian PC (p < 0.0001) but not in African-Americans and Caucasian PC. Our results suggest that GSTP1 hypermethylation is a sensitive biomarker in African-Americans as compared to that in Caucasians or Asian, and that it strongly influences tumor progression in Asian PC. Ours is the first study investigating GSTP1 methylation differences in PC among African-American, Caucasian and Asian.
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PMID:Ethnic group-related differences in CpG hypermethylation of the GSTP1 gene promoter among African-American, Caucasian and Asian patients with prostate cancer. 1580 Sep 5

Dietary factors appear to be involved in the high incidence of prostate cancer in "Westernized" countries, implicating dietary carcinogens such as heterocyclic amines (HAs) in the initiation of prostate carcinogenesis. We examined 24 human prostate samples with respect to their potential for activation and detoxification of HAs and the presence of DNA adducts formed in vivo. Cytochromes P450 1B1, 3A4 and 3A5 were expressed at low levels (<0.1-6.2 pmol/mg microsomal protein). N-Acetyltransferase (NAT) activities, using p-aminobenzoic acid (NAT1) and sulfamethazine (NAT2) as substrates, were <5-5,500 and <5-43 pmol/min/mg cytosolic protein, respectively. Glutathione S-transferases (GSTs) P1, M2 and M3 were expressed at 0.038-1.284, 0.005-0.126 and 0.010-0.270 microg/mg cytosolic protein, respectively; GSTM1 was expressed in all GSTM1-positive samples (0.012-0.291 microg/mg cytosolic protein); and GSTA1 was expressed at low levels (<0.01-0.11 microg/mg cytosolic protein). Binding of N-hydroxy-PhIP to DNA in vitro occurred primarily by an AcCoA-dependent process (<1-54 pmol/mg/DNA), PAPS- and ATP-dependent binding being <1-7 pmol/mg DNA. In vivo, putative PhIP- or 4-aminobiphenyl-DNA adducts were found in 4 samples (0.4-0.8 adducts/10(8) bases); putative hydrophobic adducts were found in 6 samples (8-64 adducts/10(8) bases). Thus, the prostate appears to have low potential for N-hydroxylation of HAs but greater potential for activation of N-hydroxy HAs to genotoxic N-acetoxy esters. The prostate has potential for GSTP1-dependent detoxification of ATP-activated N-hydroxy-PhIP but little potential for detoxification of N-acetoxy-PhIP by GSTA1. However, there were no significant correlations between expression/activities and DNA adducts formed in vitro or in vivo, DNA adducts in vivo possibly reflecting carcinogen exposure.
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PMID:Expression of cytochromes P450 and glutathione S-transferases in human prostate, and the potential for activation of heterocyclic amine carcinogens via acetyl-coA-, PAPS- and ATP-dependent pathways. 1588 May 31

Inter-individual differences in cancer susceptibility may be mediated in part through polymorphic variability in the bioactivation and detoxification of carcinogens. The glutathione S-transferases (GSTs), which are active in detoxification of wide variety of carcinogens, have been consistently implicated as cancer susceptibility genes in this context. We here assessed the association of GSTM1 and GSTP1 polymorphisms with susceptibility to prostate cancer in a case-control study of 75 patients and 100 age-matched controls in a South Indian population. The GSTM1 null polymorphism was detected by PCR and the GSTP1 Ile105Val polymorphism by PCR-RFLP using peripheral blood DNA. There was no significant link between the null genotype of GSTM1 and risk of prostate cancer (OR-1.79; 95% CI-0.78-4.11; P-0.18). However, the GSTP1 Ile/Val genotype was significantly associated with a decreased risk for prostate cancer (OR-0.36; 95% CI-0.18-0.73; P<0.001). Analysis of the variant GSTM1 and GSTP1 genotypes in combination did not reveal any significant difference between cases and controls, even with a stratified analysis tumor grades. Thus our study indicates that the GSTP1 Ile/Val genotype may decrease risk of prostate cancer in the South Indian population.
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PMID:Polymorphisms at GSTM1 and GSTP1 gene loci and risk of prostate cancer in a South Indian population. 1623 91


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