DNA Methylation Alterations Exhibit Intraindividual Stability and Interindividual Heterogeneity in Prostate Cancer Metastases

被引：213

作者：

Aryee, Martin J. ^{[1
,2
]}

Liu, Wennuan ^{[3
]}

Engelmann, Julia C. ^{[1
]}

Nuhn, Philipp ^{[1
]}

Gurel, Meltem ^{[1
]}

Haffner, Michael C. ^{[1
]}

Esopi, David ^{[1
]}

Irizarry, Rafael A. ^{[4
]}

Getzenberg, Robert H. ^{[1
,5
]}

Nelson, William G. ^{[1
,5
]}

Luo, Jun ^{[1
,5
]}

Xu, Jianfeng ^{[3
]}

Isaacs, William B. ^{[1
,5
]}

Bova, G. Steven ^{[6
]}

Yegnasubramanian, Srinivasan ^{[1
,7
]}

机构：

[1] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA

[2] Johns Hopkins Univ, Dept Oncol, Div Biostat, Baltimore, MD 21231 USA

[3] Wake Forest Univ, Bowman Gray Sch Med, Ctr Canc Genom, Ctr Genom & Personalized Med Res, Winston Salem, NC 27157 USA

[4] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA

[5] Johns Hopkins Univ, Brady Urol Inst, Baltimore, MD 21287 USA

[6] Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21287 USA

[7] Johns Hopkins Univ, Johns Hopkins Phys Sci Oncol Ctr, Baltimore, MD 21231 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2013年 / 5卷 / 169期

关键词：

CPG-ISLAND HYPERMETHYLATION; INTESTINAL NEOPLASIA; HYPOMETHYLATION; BENIGN; TRANSFERASE; HYPERPLASIA; SUPPRESSION; INSTABILITY; PROGRESSION; EXPRESSION;

D O I：

10.1126/scitranslmed.3005211

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：13

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