Methylation profiling defines a widespread field defect in histologically normal prostate tissue associated with prostate cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Bing Yang
PROVIDER: E-GEOD-38982 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:We evaluated the presence of genome-wide epigenetic differences at 385,000 loci using Encode HG18 DNA methylation arrays in 5 non-tumor-associated (NTA) and 4 histologically undistinguished tumor-associated (TA) prostate tissues. We identified 615 probes to be differentially methylated (p<0.05) in TA prostate, with 537 (87%) hypomethylated and 78 (13%) hypermethylated.
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Project description:High-throughput analyses of concordant gene methylation and expression events were carried out for 91 human prostate specimens, including prostate cancer (T), matched normal adjacent to tumor (AT), and organ donor (OD). Methylated DNA in genomic DNA was immunoprecipitated with anti-methylcytidine antibodies and detected by Affymetrix human whole genome SNP 6.0 chips. Methylated genomic DNA was purified by 5-hmc antibodies and Affymetrix SNP arrays were performed according to the manufacturer's manual. Copy number analysis of Affymetrix human SNP arrays was performed for both 5mc- and genomic DNA of prostate cancer samples. Methylations of genes were called when the allel amplification was reported in 5_mc DNA, and the background of the detection was suppressed by matched DNA sample. we used copy number of each probe set as baseline to detect the enrichment of methylated DNA from the same sample. Therefore, each specimen has two arrays; one is straight copy number (*SNP.CEL), another methylation enriched DNA (*5MC_SNP.CEL). Each CNV probe is based on the design from Affymetrix but no SNP ID was assigned.
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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. We mapped the global DNA methylation patterns in prostate tissues (n=17; data not available in GEO - being deposited in dbGaP for controlled access) and cells (n=2) from fifty nanograms of genomic DNA using Methylplex-Next Generation Sequencing (M-NGS). For replicate analysis in cell lines, a total of 4 runs were completed for PrEC prostate normal cell line, and 5 runs were completed for LNCaP prostate cancer cell line. For tissue samples, 2 benign prostate samples were ran twice on illumina next generation sequencing platform to access overall repeatability of M-NGS.
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