RT Journal Article
SR Electronic
T1 DNA Methylation Alterations Exhibit Intraindividual Stability and Interindividual Heterogeneity in Prostate Cancer Metastases
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP 169ra10
OP 169ra10
DO 10.1126/scitranslmed.3005211
VO 5
IS 169
A1 Aryee, Martin J.
A1 Liu, Wennuan
A1 Engelmann, Julia C.
A1 Nuhn, Philipp
A1 Gurel, Meltem
A1 Haffner, Michael C.
A1 Esopi, David
A1 Irizarry, Rafael A.
A1 Getzenberg, Robert H.
A1 Nelson, William G.
A1 Luo, Jun
A1 Xu, Jianfeng
A1 Isaacs, William B.
A1 Bova, G. Steven
A1 Yegnasubramanian, Srinivasan
YR 2013
UL http://stm.sciencemag.org/content/5/169/169ra10.abstract
AB 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.