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GSTP1 promoter methylation is associated with recurrence in early stage prostate cancer.

ABSTRACT: Recurrent prostate cancer remains a major problem. Staging, grading and prostate specific antigen level at surgery are helpful but still imperfect predictors of recurrence. For this reason there is an imperative need for additional biomarkers that add to the prediction of currently used prognostic factors.We evaluated the extent of promoter methylation of genes previously reported as aberrantly methylated in prostate cancer (AIM1, APC, CCND2, GPX3, GSTP1, MCAM, RAR?2, SSBP2 and TIMP3) by quantitative fluorogenic methylation-specific polymerase chain reaction. We used cancer tissue from a nested case-control study of 452 patients surgically treated for prostate cancer. Recurrence cases and controls were compared and the association between methylation extent and recurrence risk was estimated by logistic regression adjusting for patient age at prostatectomy, prostatectomy year, stage, grade, surgical margins and preprostatectomy prostate specific antigen. All statistical tests were 2-sided with p ?0.05 considered statistically significant.The extent of GSTP1 methylation was higher in patients with recurrence than in controls (p = 0.01), especially patients with early disease, ie organ confined or limited extraprostatic extension (p = 0.001). After multivariate adjustment GSTP1 promoter methylation at or above the median was associated with an increased risk of recurrence, including in men with early disease (each p = 0.05).Greater GSTP1 promoter methylation in cancer tissue was independently associated with the risk of recurrence in patients with early prostate cancer. This suggests that GSTP1 promoter methylation may be a potential tissue based recurrence marker.

SUBMITTER: Maldonado L

PROVIDER: S-EPMC4390043 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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GSTP1 promoter methylation is associated with recurrence in early stage prostate cancer.

Maldonado Leonel L Brait Mariana M Loyo Myriam M Sullenberger Lauren L Wang Kevin K Peskoe Sarah B SB Rosenbaum Eli E Howard Roslyn R Toubaji Antoun A Albadine Roula R Netto George J GJ Hoque Mohammad O MO Platz Elizabeth A EA Sidransky David D

The Journal of urology 20140421 5

<h4>Purpose</h4>Recurrent prostate cancer remains a major problem. Staging, grading and prostate specific antigen level at surgery are helpful but still imperfect predictors of recurrence. For this reason there is an imperative need for additional biomarkers that add to the prediction of currently used prognostic factors.<h4>Materials and methods</h4>We evaluated the extent of promoter methylation of genes previously reported as aberrantly methylated in prostate cancer (AIM1, APC, CCND2, GPX3, G ...[more]

PMID: 24769028

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Project description:Glutathione S-transferase pi 1 (GSTP1) is lowly expressed in normal prostate luminal cells and becomes induced in most proliferative inflammatory atrophy (PIA) lesions. GSTP1 becomes silenced in prostatic intraepithelial neoplasia (PIN) and prostate adenocarcinoma (CaP) via cytosine-phospho-guanine (CpG) island promoter hypermethylation. However, GSTP1 methylation patterns in PIA and PIN, and their relationship to patterns in CaP are poorly understood. We used bisulfite genomic sequencing to examine patterns of GSTP1 promoter CpG island methylation in laser capture microdissected benign, PIA, PIN, and CaP regions from 32 subjects that underwent radical prostatectomy. We analyzed 908 sequence clones across 24 normal epithelium, 37 PIA, 18 PIN, and 23 CaP regions, allowing assessment of 34,863 CpG sites with allelic phasing. Normal and PIA lesions were mostly unmethylated with 0.52 and 1.3% of total CpG sites methylated, respectively. PIN and CaP lesions had greater methylation with 24% and 51% of total CpG sites methylated, respectively. The degree of GSTP1 methylation showed progression from PIA << PIN < CaP. PIN lesions showed more partial methylation compared with CaP lesions. Partially methylated lesions were enriched for methylation changes at AP1 and SP1 transcription factor binding sites. These results demonstrate that methylation density in the GSTP1 CpG island in PIN was intermediate relative to that in normal prostate epithelium/PIA and CaP lesions. These results are consistent with gradual spreading of DNA methylation centered at the SP1/AP1 transcription factor binding sites in precursor lesions, with subsequent spreading of methylation across the entire CpG island in transition to CaP.Prevention relevanceDNA hypermethylation at the GSTP1 promoter progressively spreads from being unmethylated in normal prostate to intermediate levels in precursor lesions to extensive methylation in cancer. This molecular progression of GSTP1 promoter methylation patterns in early prostate carcinogenesis could be useful for identification and interception of prostate cancer precursors.

Project description:BACKGROUND:Loss of BIN1 tumor suppressor expression is abundant in human cancer and its frequency exceeds that of genetic alterations, suggesting the role of epigenetic regulators (DNA methylation). BIN1 re-expression in the DU145 prostate cancer cell line after 5-aza-2'-deoxycytidine treatment was recently reported but no methylation of the BIN1 promoter CpG island was found in DU145. METHODS:Methylation-sensitive arbitrarily-primed PCR was used to detect genomic loci abnormally methylated in breast cancer. BIN1 CpG island fragment was identified among the differentially methylated loci as a result of direct sequencing of the methylation-sensitive arbitrarily-primed PCR product and subsequent BLAST alliance. BIN1 CpG island cancer related methylation in breast and prostate cancers was confirmed by bisulphite sequencing and its methylation frequency was evaluated by methylation sensitive PCR. Loss of heterozygosity analysis of the BIN1 region was performed with two introgenic and one closely adjacent extragenic microsatellite markers.BIN1 expression was evaluated by real-time RT-PCR. RESULTS:We have identified a 3'-part of BIN1 promoter CpG island among the genomic loci abnormally methylated in breast cancer. The fragment proved to be methylated in 18/99 (18%) and 4/46 (9%) breast and prostate tumors, correspondingly, as well as in MCF7 and T47D breast cancer cell lines, but was never methylated in normal tissues and lymphocytes as well as in DU145 and LNCaP prostate cancer cell lines. The 5'-part of the CpG island revealed no methylation in all samples tested. BIN1 expression losses were detected in MCF7 and T47D cells and were characteristic of primary breast tumors (10/13; 77%), while loss of heterozygosity was a rare event in tissue samples (2/22 informative cases; 9%) and was ruled out for MCF7. CONCLUSION:BIN1 promoter CpG island is composed of two parts differing drastically in the methylation patterns in cancer. This appears to be a common feature of cancer related genes and demands further functional significance exploration. Although we have found no evidence of the functional role of such a non-core methylation in BIN1 expression regulation, our data do not altogether rule this possibility out.

Project description:BackgroundCurrent clinical tools have limited accuracy in differentiating patients with localized prostate cancer who are at risk of recurrence from patients with indolent disease. We aimed to identify a gene expression signature that jointly with clinical variables could improve upon the prediction of clinical recurrence after RP for patients with stage T2 PCa.MethodsThe study population includes consented patients who underwent a radical retropubic prostatectomy (RP) and bilateral pelvic lymph node dissection at the University of Southern California in the PSA-era (1988-2008). We used a nested case-control study of 187 organ-confined patients (pT2N0M0): 154 with no recurrence ("controls") and 33 with clinical recurrence ("cases"). RNA was obtained from laser capture microdissected malignant glands representative of the overall Gleason score of each patient. Whole genome gene expression profiles (29,000 transcripts) were obtained using the Whole Genome DASL HT platform (Illumina, Inc). A gene expression signature of PCa clinical recurrence was identified using stability selection with elastic net regularized logistic regression. Three existing datasets generated with the Affymetrix Human Exon 1.0ST array were used for validation: Mayo Clinic (MC, n = 545), Memorial Sloan Kettering Cancer Center (SKCC, n = 150), and Erasmus Medical Center (EMC, n = 48). The areas under the ROC curve (AUCs) were obtained using repeated fivefold cross-validation.ResultsA 28-gene expression signature was identified that jointly with key clinical variables (age, Gleason score, pre-operative PSA level, and operation year) was predictive of clinical recurrence (AUC of clinical variables only was 0.67, AUC of clinical variables, and 28-gene signature was 0.99). The AUC of this gene signature fitted in each of the external datasets jointly with clinical variables was 0.75 (0.72-0.77) (MC), 0.90 (0.86-0.94) (MSKCC), and 0.82 (0.74-0.91) (EMC), whereas the AUC for clinical variables only in each dataset was 0.72 (0.70-0.74), 0.86 (0.82-0.91), and 0.76 (0.67-0.85), respectively.ConclusionsWe report a novel gene-expression based classifier identified using agnostic approaches from whole genome expression profiles that can improve upon the accuracy of clinical indicators to stratify early stage localized patients at risk of clinical recurrence after RP. Prostate 76:1239-1256, 2016. © 2016 Wiley Periodicals, Inc.

Project description:BackgroundInhibitor of DNA binding/Inhibitor of differentiation 4 (ID4) is a critical factor for cell proliferation and differentiation in normal vertebrate development. ID4 has regulative functions for differentiation and growth of the developing brain. The role of ID1, ID2 and ID3 are expected to be oncogenic due to their overexpression in pancreatic cancer and colorectal adenocarcinomas, respectively. Aside from these findings, loss of ID3 expression was demonstrated in ovarian cancer. The aim of the present study was to reveal the factual role of ID4 in carcinogenesis in more detail, since its role for the pathogenesis of human breast cancer has been discussed controversially, assigning both oncogenic and tumour suppressive functions.MethodsID4 promoter methylation, ID4 mRNA expression and ID4 protein expression were analysed in primary human breast cancer specimens using methylation-specific PCR (MSP) (n=170), semiquantitative realtime RT-PCR (n=46) and immunhistochemistry (n=3), respectively. In order to demonstrate a functional association of ID4 promoter methylation with its gene silencing, we performed DNA demethylation analysis with four human breast cell lines using MSP and semiquantitative realtime RT-PCR. In addition, we performed correlations of ID4 promoter methylation with ID4 mRNA and ID4 protein expression in matched samples of breast tumour and corresponding normal tissue. We carried out statistical analyses in order to find correlations between ID4 promoter methylation and clinicopathological parameters.ResultsFrequent ID4 promoter methylation was observed in primary breast cancer samples (69%, 117/170). We found a tight correlation (P<0.0001) between ID4 promoter methylation and loss of ID4 expression in primary breast cancer 3 specimens. Demethylating treatment with breast cancer cell lines was associated with clear ID4 mRNA re-expression. Tumours with ID4 promoter methylation showed distinct loss of ID4 expression on both transcription and protein level. Interestingly, ID4 promoter methylation was a factor for unfavourable recurrence-free survival (P=0.036) and increased risk for lymph node metastasis (P=0.030).ConclusionID4 is indeed a novel tumour suppressor gene in normal human breast tissue and is epigenetically silenced during cancer development, indicating increased risk for tumour relapse. Thus, ID4 methylation status could serve as a prognostic biomarker in human breast cancer.

Project description:Background and Objectives: One of the most frequent genetic alterations reported to date in prostate cancer (PC) is aberrant methylation of glutathione transferase P1 (GSTP1). Taking into consideration the involvement of oxidative stress in PC pathogenesis and recent advances in scientific understanding of the role of GSTP1*Ala114Val rs1138272 polymorphism in carcinogenesis, we hypothesized that this single-nucleotide polymorphism (SNP) influences the risk of PC independently of, or in combination with, other GST polymorphisms, including GSTP1*IIe105Val rs1695 or GSTM1 and GSTT1 deletion polymorphisms. Materials and Methods: Genotyping was performed in 237 PC cases and in 236 age-matched controls by multiplex polymerase chain reaction (PCR) for deletion of GST polymorphisms and by quantitative PCR for SNPs. Results: We found that carriers of either GSTP1*Val (rs1138272) or GSTP1*Val (rs1695) variant alleles had a PC risk compared to individuals with both referent alleles (OR = 4.93, 95%CI: 2.89-8.40, p < 0.001 and OR = 1.8, 95%CI: 1.19-2.73, p = 0.006, respectively). Additionally, in a haplotype analysis we found that individuals with GSTP1*C haplotype, represented by both variant alleles (GSTP1*Val rs1695 + GSTP1*Val rs1138272), had a 5.46 times higher risk of PC development compared to individuals with the most frequent haplotype (95%CI = 2.56-11.65, p < 0.001), suggesting a potential role of those variants in PC susceptibility. A regression analysis on the number of risk-associated alleles per individual (GSTM1*active, GSTT1*null, GSTP1*Val rs1695 and GSTP1*Val rs1138272) showed a significant increase in the risk of developing PC, from 3.65-fold in carriers of two risk alleles (95%CI = 1.55-8.61, p = 0.003) to an approximately 12-fold increase in carriers of all four risk alleles (95%CI = 3.05-44.93, p < 0.001). Conclusion: Prostate cancer may be influenced by multiple glutathione transferase (GST) polymorphic genes, especially GSTP1, highlighting the role of gene-gene interactions in human susceptibility to this cancer.

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GSTP1 promoter methylation is associated with recurrence in early stage prostate cancer.

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GSTP1 promoter methylation is associated with recurrence in early stage prostate cancer.

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