Fig. 5
Enhancer-associated CpGs as drivers of ITH in ccRCC. A Heatmap resulting from supervised hierarchical clustering of 236 enhancer-associated CpGs identified using GeneHancer that are predicted to influence expression of their respective gene. Four major clusters are formed. The p-values are the result of χ2 analyses of clusters 1, 2, and 3 against each other. The color bar at the left indicates the genomic feature of each CpG. B Two representative phyloepigenetic trees showing evolutionary methylation changes of regions from the same tumor, with progression from the normal baseline into low grade and then high-grade regions. Major evolutional intervals are highlighted and identify genes with the highest number of CpG methylation changes (red = hypermethylation; blue = hypomethylation). C Boxplots comparing the average Euclidian distance between normal kidney and ccRCC regions with various clinico-pathological parameters (grade, necrosis, SSIGN, and H3K36me3). Each point represents the average distance between a tumor region and the normal kidney samples. D Heatmap showing the correlation coefficients (r) of 34 KIRC survival-associated CpGs significantly associated with expression of their respective genes. The dendrogram separates CpGs with positive r (n = 2; red) from CpGs with negative r (n = 32; blue) correlations. The side bar indicates whether the methylation status is linked to more favorable survival outcome