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Genome-wide methylation analysis of prostate tissues reveals global methylation patterns of prostate cancer.

ABSTRACT: Altered genome methylation is a hallmark of human malignancies. In this study, high-throughput analyses of concordant gene methylation and expression events were performed for 91 human prostate specimens, including prostate tumor (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. Among the methylated CpG islands, 11,481 islands were found located in the promoter and exon 1 regions of 9295 genes. Genes (7641) were methylated frequently across OD, AT, and T samples, whereas 239 genes were differentially methylated in only T and 785 genes in both AT and T but not OD. Genes with promoter methylation and concordantly suppressed expression were identified. Pathway analysis suggested that many of the methylated genes in T and AT are involved in cell growth and mitogenesis. Classification analysis of the differentially methylated genes in T or OD produced a specificity of 89.4% and a sensitivity of 85.7%. The T and AT groups, however, were only slightly separated by the prediction analysis, indicating a strong field effect. A gene methylation prediction model was shown to predict prostate cancer relapse with sensitivity of 80.0% and specificity of 85.0%. These results suggest methylation patterns useful in predicting clinical outcomes of prostate cancer.

SUBMITTER: Luo JH

PROVIDER: S-EPMC3668028 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Genome-wide methylation analysis of prostate tissues reveals global methylation patterns of prostate cancer.

Luo Jian-Hua JH Ding Ying Y Chen Rui R Michalopoulos George G Nelson Joel J Tseng George G Yu Yan P YP

The American journal of pathology 20130410 6

Altered genome methylation is a hallmark of human malignancies. In this study, high-throughput analyses of concordant gene methylation and expression events were performed for 91 human prostate specimens, including prostate tumor (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. Among the methylated CpG islands, 11,481 islands were ...[more]

PMID: 23583283

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Project description:Pancreatic cancer (PC) is the fourth leading cause of cancer deaths in the United States with a five-year patient survival rate of only 6%. Early detection and treatment of this disease is hampered due to lack of reliable diagnostic and prognostic markers. Recent studies have shown that dynamic changes in the global DNA methylation and gene expression patterns play key roles in the PC development; hence, provide valuable insights for better understanding the initiation and progression of PC. In the current study, we used DNA methylation, gene expression, copy number, mutational and clinical data from pancreatic patients. We independently investigated the DNA methylation and differential gene expression profiles between normal and tumor samples and correlated methylation levels with gene expression patterns. We observed a total of ~23-thousand differentially methylated CpG sites (???0.1) between normal and tumor samples, where majority of the CpG sites are hypermethylated in PC, and this phenomenon is more prominent in the 5'UTRs and promoter regions compared to the gene bodies. Differential methylation is observed in genes associated with the homeobox domain, cell division and differentiation, cytoskeleton, epigenetic regulation and development, pancreatic development and pancreatic signaling and pancreatic cancer core signaling pathways. Correlation analysis suggests that methylation in the promoter region and 5'UTR has mostly negative correlations with gene expression while gene body and 3'UTR associated methylation has positive correlations. Regulatory element analysis suggests that HOX cluster and histone core proteins are upstream regulators of hypomethylation, while SMAD4, STAT4, STAT5B and zinc finger proteins (ZNF) are upstream regulators of hypermethylation. Non-negative matrix factorization (NMF) clustering of differentially methylated sites generated three clusters in PCs suggesting the existence of distinct molecular subtypes. Cluster 1 and cluster 2 showed samples enriched with clinical phenotypes like neoplasm histological grade and pathologic T-stage T3, respectively, while cluster 3 showed the enrichment of samples with neoplasm histological grade G1. To the best of our knowledge, this is the first genome-scale methylome analysis of PC data from TCGA. Our clustering analysis provides a strong basis for future work on the molecular subtyping of epigenetic regulation in pancreatic cancer.

Dataset Information

Genome-wide methylation analysis of prostate tissues reveals global methylation patterns of prostate cancer.

Publications

Genome-wide methylation analysis of prostate tissues reveals global methylation patterns of prostate cancer.

Similar Datasets

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