DNA methylation alterations exhibit intraindividual stability and interindividual heterogeneity in prostate cancer metastases.

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Aryee, Martin J ; Liu, Wennuan ; Engelmann, Julia C. ; Nuhn, Philipp ; Gurel, Meltem ; Haffner, Michael C ; Esopi, David ; Irizarry, Rafael A ; Getzenberg, Robert H ; Nelson, William G ; Luo, Jun ; Xu, Jianfeng ; Isaacs, William B ; Bova, G Steven ; Yegnasubramanian, Srinivasan

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Date of publication of this fulltext: 05 Aug 2014 09:18

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Item type:	Article
Journal or Publication Title:	Science translational medicine
Publisher:	American Association for the Advancement of Science
Volume:	5
Number of Issue or Book Chapter:	169
Page Range:	169ra10
Date:	23 January 2013
Institutions:	Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Statistische Bioinformatik (Prof. Spang)
Identification Number:	Value Type 18337604 PubMed ID 10.1126/scitranslmed.3005211 DOI
Classification:	Notation Type Alleles MESH Clone Cells MESH DNA Methylation/genetics MESH DNA-Binding Proteins/genetics MESH Epigenesis, Genetic MESH Gene Expression Regulation, Neoplastic MESH Genetic Heterogeneity MESH Genomics MESH Humans MESH Male MESH Neoplasm Metastasis MESH Polymorphism, Single Nucleotide/genetics MESH Prostatic Neoplasms/pathology MESH Protein Structure, Tertiary MESH
Dewey Decimal Classification:	500 Science > 500 Natural sciences & mathematics 500 Science > 570 Life sciences 600 Technology > 610 Medical sciences Medicine
Status:	Published
Refereed:	Yes, this version has been refereed
Created at the University of Regensburg:	Partially
Item ID:	30526

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Abstract

Human cancers almost ubiquitously harbor epigenetic alterations. Although such alterations in epigenetic marks, including DNA methylation, are potentially heritable, they can also be dynamically altered. Given this potential for plasticity, the degree to which epigenetic changes can be subject to selection and act as drivers of neoplasia has been questioned. We carried out genome-scale analyses ...

Abstract

Human cancers almost ubiquitously harbor epigenetic alterations. Although such alterations in epigenetic marks, including DNA methylation, are potentially heritable, they can also be dynamically altered. Given this potential for plasticity, the degree to which epigenetic changes can be subject to selection and act as drivers of neoplasia has been questioned. We carried out genome-scale analyses of DNA methylation alterations in lethal metastatic prostate cancer and created DNA methylation "cityscape" plots to visualize these complex data. We show that somatic DNA methylation alterations, despite showing marked interindividual heterogeneity among men with lethal metastatic prostate cancer, were maintained across all metastases within the same individual. The overall extent of maintenance in DNA methylation changes was comparable to that of genetic copy number alterations. Regions that were frequently hypermethylated across individuals were markedly enriched for cancer- and development/differentiation-related genes. Additionally, regions exhibiting high consistency of hypermethylation across metastases within individuals, even if variably hypermethylated across individuals, showed enrichment for cancer-related genes. Whereas some regions showed intraindividual metastatic tumor heterogeneity in promoter methylation, such methylation alterations were generally not correlated with gene expression. This was despite a general tendency for promoter methylation patterns to be strongly correlated with gene expression, particularly at regions that were variably methylated across individuals. These findings suggest that DNA methylation alterations have the potential for producing selectable driver events in carcinogenesis and disease progression and highlight the possibility of targeting such epigenome alterations for development of longitudinal markers and therapeutic strategies.

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Metadata last modified: 02 Jun 2018 08:02

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