Similar Datasets
Project description:DNA methylation alterations are a universal feature of cancer. In prostate cancer, site specific DNA methylation changes have been suggested as driver in disease initial and progression. Here we provide a comprehensive assessment of DNA methylation changes in prostate cancer patient derived xenograft (PDX) models. We delineate patterns of both site specific and global methylation changes and nominate novel candidates for biomarker development.
2023-12-31 | GSE227086 | GEO
Project description:Beginning with precursor lesions, aberrant DNA methylation marks the entire spectrum of prostate cancer progression. We mapped the global DNA methylation patterns in prostate tissues (n=17) and cells (n=2) from fifty nanograms of genomic DNA using Methylplex-Next Generation Sequencing (M-NGS). A Hidden Markov Model (HMM)-based algorithm previously used for Chip-Seq data analysis(http://www.sph.umich.edu/csg/qin/HPeak) was used to locate peaks from mapped reads obtained in each sequencing run. The total methylation events in intergenic/intronic regions between benign adjacent and cancer tissues were comparable. While approximately 20% of all CpG islands (CGIs) (68,508) were methylated in tissues, promoter CGI methylation gradually increased from ~12.6% in benign samples to 19.3% and 21.8% in localized and metastatic cancer tissues. We found distinct patterns in promoter methylation around transcription start sites, where methylation occurred directly on the CGIs, flanking regions and on CGI sparse promoters. Among the 6,691 methylated promoters in prostate tissues, 2481 differentially methylated regions (DMRs) are cancer specific and several previously studied targets were among them. A novel cancer specific DMR in WFDC2 promoter showed 77% methylation in cancer (17/22), 100% methylation in transformed prostate cell lines (6/6), none in the benign tissues (0/10) and normal PrEC cells. Integration of LNCaP DNA methylation and H3K4me3 data suggested a role for DNA methylation in alternate transcription start site utilization. While methylated promoters containing CGIs had mutually exclusive H3K4me3 modification, the histone mark was absent in CGI sparse promoters. Finally, we observed difference in methylation of LINE-1 elements between transcription factor ERG positive and negative cancers. The comprehensive methylome map presented here will further our understanding of epigenetic regulation of the prostate cancer genome.
2011-05-09 | GSE27618 | GEO
Project description:Background: Global DNA methylation alterations are hallmarks of cancer. The tumor-suppressive TET enzymes, which are involved in DNA demethylation, are decreased in prostate cancer (PCa); in particular, TET2 is specifically targeted by androgen-dependent mechanisms of repression in PCa and may play a central role in carcinogenesis. Thus, identification of key genes targeted by TET2 dysregulation may provide further insight into cancer biology. Results: Using a CRISPR/Cas9-derived TET2-knockout prostate cell line, and through whole-transcriptome and whole-methylome sequencing, we identified seven candidate genes – ASB2, ETNK2, MEIS2, NRG1, NTN1, NUDT10, and SRPX – exhibiting reduced expression and increased promoter methylation, a pattern characteristic of tumor suppressors. Decreased expression of these genes significantly discriminates between recurrent and non-recurrent prostate tumors from the Cancer Genome Atlas (TCGA) cohort (n=423), and ASB2, NUDT10, and SRPX were significantly correlated with lower recurrence-free survival in patients by Kaplan-Meier analysis. ASB2, MEIS2, and SRPX also showed significantly lower expression in high-risk Gleason score 8 tumors as compared to low or intermediate risk tumors, suggesting that these genes may be particularly useful as indicators of PCa progression. Furthermore, methylation array probes in the TCGA dataset, which were proximal to the highly conserved, differentially methylated sites identified in our TET2-knockout cells, were able to significantly distinguish between matched prostate tumor and normal prostate tissues (n=50 pairs). Except ASB2, all genes exhibited significantly increased methylation at these probes, and methylation status of at least one probe for each of these genes showed association with measures of PCa progression such as recurrence, stage, or Gleason score. Since ASB2 did not have any probes within the TET2-knockout differentially methylated region, we validated ASB2 methylation in an independent series of matched tumor-normal samples (n=19) by methylation-specific qPCR, which revealed concordant and significant increases in promoter methylation within the TET2-knockout site. Conclusions: Our study identifies seven genes governed by TET2 loss in PCa which exhibit association between their methylation and expression status and measures of PCa progression. As differential methylation profiles and TET2 expression are associated with advanced PCa, further investigation of these specialized TET2 targets may provide important insights into patterns of carcinogenic gene dysregulation.
2019-04-05 | GSE128399 | GEO
Project description:Prostate cancer is the second most common cancer among men worldwide. Alterations in the DNA methylation pattern can be one of the leading causes for prostate cancer formation. This study is the first high throughput sequencing study investigating genome-wide DNA methylation patterns in a large cohort of 51 tumor and 53 benign prostate samples using MeDIP-Seq. Comparative analyses identified more than 147,000 cancer-associated epigenetic alterations. Additionally, global methylation patterns demonstrate significant differences based on the TMPRSS2:ERG rearrangement status. We propose the hypermethylation of miRNA-26a as an alternative pathway of ERG rearrangement independent EZH2 activation. The observed increase in differential methylation events in fusion negative tumors can explain the tumorigenic process in the absence of genomic rearrangements.
2012-12-06 | GSE35342 | GEO
Project description:DNA methylation analysis of paired prostate tumor and noncancerous tissues was perform in order to identify potential DNA methylation biomarkers for prostate cancer diagnostics and prognosis. Based on comparison of tumors versus noncancerous tissues and cases with and without biochemical disease recurrence (BCR), several gene targets were selected for more detailed analysis. Differences in methylation were further confirmed by means of methylation-specific PCR and significantly correlated with gene expression. Survival analysis indicated various combinations of DNA methylation biomarkers as significant prognosticaters of time to BCR, therefore, showing their potential clinical significance.
2017-04-30 | GSE89243 | GEO
Project description:Methylation-sequencing in prostate cancer cells
| PRJNA742719 | ENA
Project description:A major challenge in the clinical management of prostate cancer is the inability to definitively diagnose indolent versus aggressive cases. Contributing to this challenge is a lack of basic science understanding of the molecular basis behind aggressiveness subtypes in prostate cancer. DNA methylation is the epigenetic addition of a methyl group to the DNA base cytosine and has been found to regulate cell proliferation and environmental adaptation. We hypothesized that DNA methylation changes are a mechanism by which an aggressive cancer attains phenotypes that distinguish it from indolent cases via disruption of regulatory networks. This hypothesis was tested by comparing DNA methylation between benign prostate and both low grade (Gleason score 6) and high grade (Gleason score 8 to 10) groups. Methylome-wide next generation sequencing was performed on formalin-fixed paraffin embedded (FFPE) samples from radical prostatectomy cases using MBD-isolated genome sequencing (MiGS). This technique uses a DNA methylation binding protein (MBD) to purify fragments from a genomic library with a high level of CpG DNA methylation. These fragments were then sequenced via next generation sequencing, the reads were aligned to a reference genome, and then the reads were counted within non-overlapping 50bp windows genome wide. Statistical analysis was then performed on these windowed counts to produce differentially methylated regions (DMRs).
2015-11-01 | GSE66505 | GEO
Project description:In spite of its prevalence as one of the world’s leading malignancies, prostate cancer (PCa) continues to evade molecular taxonomic sub-classification. However, gross clinical differences are observed within the umbrella term ‘prostate adenocarcinoma’; the majority of tumors appear indolent in nature, whilst a subset manifest aggressively. Contributing factors towards this resistance to molecular classification are an atypically low mutation frequency and a poorly delineated pathobiology. Conversely, epigenetic changes are evidenced to be amongst the earliest and most-widespread aberrations in PCa . We thus hypothesized that delineating epigenomic alterations during the stepwise progression of PCa would improve our understanding of the disease pathobiology and the molecular underpinning of indolent and aggressive tumors. Herein, we report the first epigenomic roadmap of prostate tumorigenesis, in which we dissected DNA methylation and microRNA expression in enriched epithelial cells across the entire trajectory of PCa, through tumor initiation, primary disease and metastatic dissemination. Infinium Human Methylation450K Beachip (Illumina) technology was employed to assess the methylation status of >485,000 CpG sites throughout the genome across six histological stages of prostate cancer (PCa) tumorigenesis: benign (n=10), proliferative inflammatory atrophy (PIA; n=7), high grade prostatic intra-epithelial neoplasia (HGPIN; n=6), indolent PCa (PCI, n=7), agressive PCa (PCA; n=8) and lethal metastatic PCa (PCM; n=6). Three peripheral blood lymphocytes (PBL) samples were also included for control purposes.
2021-09-01 | GSE157272 | GEO
Project description:Genome wide DNA methylation profiling of androgen-sensitive and –refractory prostate cancer cells. The Illumina Infinium HumanMethylation450 Beadchip was used to obtain DNA methylation profiles across approximately 480.000 CpGs in Prostate cancer cell lines showing different sensitivity to hormonal treatments. Samples included the androgen receptor negative cell lines PC3 and DU145, the androgen sensitive cell line LNCaP and the LNCaP abl cell line expressing androgen receptor but refractory prostate cancer cell line to hormonal treatments.
2023-12-31 | GSE217962 | GEO
Project description:Castration-resistant prostate cancer (CRPC) is a heterogeneous disease associated with phenotypic subtypes that drive differences in therapy response and outcomes. Histologic transformation to castration-resistant neuroendocrine prostate cancer (CRPC-NE) is associated with distinct epigenetic alterations, including acquired changes in DNA methylation. The current diagnosis of CRPC-NE is challenging and relies on metastatic biopsy. Here, we developed a targeted DNA methylation assay based on the analysis of large tissue datasets to detect CRPC-NE using plasma cell-free DNA (cfDNA) non-invasively. The assay quantifies tumor content and a phenotype evidence score that captures the spectrum of CRPC phenotypes, leveraging a few hundred informative genomic regions to also inform the expression and/or transcriptional state of genes of interest. We qualified the assay in independent clinical cohorts, including 158 plasma samples, achieving a phenotypic evidence score AUC > 0.93 for detecting pathology-confirmed CRPC-NE, and revealing associations between methylation-defined tumor content and clinical outcomes in two prospective phase 2 clinical trials (NCT01799278 and NCT00514540) designed toward aggressive variant CRPC and CRPC-NE, supporting the application of targeted DNA methylation for CRPC-NE detection and patient stratification.
2023-12-11 | GSE245745 | GEO