Figure 2

Pan-cancer methylome representation for ten cancer cohorts from The Cancer Genome Atlas. The Cancer Genome Atlas PANCAN12 DNA methylation data, representing 24,980 CpG sites acquired from the 27 k Illumina platform and corresponding to 2,224 tumor samples, were downloaded from the University of California Santa Cruz Cancer Genomics Browser [119]. CpG sites located on chromosome X and Y were removed, as well as the ones associated with single-nucleotide polymorphisms (n = 2,750). DNA methylation data for ten tumor entities - OV (n = 600), UCEC (n = 117), BRCA (n = 315), LUAD (n = 126), LUSC (n = 133), READ (n = 67), COAD (n = 166), GBM (n = 287), KIRC (n = 219) and AML (n = 194) - are included in the PANCAN12 dataset. For each of the tumor entities, color-coded on the top of the graph, the 500 most variable CpGs of the remaining 21,844 data points were selected. From the overlap, Qlucore Omics Explorer 3.0 software was used to select the 1,430 most variable CpGs, which were then hierarchically clustered as a heat map. Beta values are offset by −0.5 to shift the whole dataset to values between −0.5 (in dark blue) and 0.5 (in yellow) for improved graphical display [119]. DNA methylation patterns show relatively high homogeneity within tumor entities. We do not observe a common CpG island methylator phenotype-like group across several tumor types, suggesting that the ‘tissue of origin’ methylation signature is a strong decisive factor for the pattern. Colorectal cancer shows the highest overall methylation, whereas kidney cancer is characterized by low variance of methylation. The methylation patterns of ovarian, endometrial and breast cancer display a similar distribution of high and low methylation. CpG sites fall into high and intermediate DNA methylation clusters, covering all tumors entities, and a low methylation cluster with genes methylated in glioblastoma multiforme (GBM) or colorectal tumors and unmethylated in ovarian cancer. Unexpectedly, the high methylation cluster shows enrichment for membrane-associated genes including claudins (CLDN) and cadherins (CDH), while polycomb repressor complex PRC2 target genes are highly enriched in the intermediate and low methylation clusters. Some of these genes, as well as a selection of differentially methylated genes mentioned in the text such as MLH1, APC, BRCA1/2 and VHL, are indicated on the right side of the graph. For abbreviations of the tumor entities see Table 1.