Figure 1.

DNA methylation cityscapes of lethal metastatic prostate cancer. DNA hypermethylation (top) and DNA hypomethylation (bottom) alterations in multiple anatomically distinct metastatic deposits obtained by rapid autopsy from each of 13 men that died of metastatic prostate cancer are shown. In these cityscape plots, each chromosome is folded into a two-dimensional neighborhood demarcated by light gray lines, following a Hilbert curve. In the cityscapes, each structure represents a region harboring a DNA methylation alteration in at least one tumor compared with a series of benign prostate tissues. The height of the structures represents the number of tumors having the alteration at that region. Tall structures, skyscrapers in the cityscape, are nearly universally altered in methylation in all metastases studied, and short structures (huts) are infrequently altered. The color represents the degree of maintenance of each alteration across all metastases within each subject normalized to the overall variability (R²). Hypermethylated promoter regions of cancer-related genes from the NCI Cancer Gene Index that were in the upper 10th percentile for frequency (height) or maintenance (color) are labeled on the cityscape. A region on chromosome 5, harboring the APC promoter, is magnified in the “blowout” showing the Hilbert curve indicated in the white path and shows multiple clustered hypermethylated regions with varying frequency and maintenance in this region. Although DNA hypomethylation was pervasive in large blocks across the genome, DNA hypermethylation was much more focal and often highly maintained across all metastases within subjects even when the overall frequency of these alterations was low across subjects. Highly frequent (skyscrapers) and/or highly maintained (orange to red) alterations in the hypermethylation cityscape were enriched for (1) overlap with gene promoters, particularly those associated with development/differentiation and cancer-related genes, and (2) inverse correlation with cis gene expression. Thus, in the backdrop of a general tendency for losing methylation across the genome, hypermethylation alterations were highly maintained, and appeared to be selected for across metastatic dissemination. (From Aryee et al. 2013; reprinted, with permission, from the American Association for the Advancement of Science ©2013.)