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Fig. 4 | Clinical Epigenetics

Fig. 4

From: Extensive intratumor regional epigenetic heterogeneity in clear cell renal cell carcinoma targets kidney enhancers and is associated with poor outcome

Fig. 4

Defining epigenetic heterogeneity within cRCC. A Boxplot of the SD of each CpG within sampled regions from each patient. The red dashed line intersects the y axis at y = 0.1. CpGs with a SD greater than 0.1 considered heterogeneous. B Boxplot of the SD of each CpG within all regions of normal kidney and ccRCCs stratified by their SETD2 status. The red dashed line intersects the y axis at y = 0.1. CpGs with a SD greater than 0.1 considered heterogeneous. C Global 5mC of sampled regions from each patient. Each dot represents the mean methylation of a sample using 843,393 autosomal CpGs. D Entropy comparison of normal kidney and SETD2 wt/mt tumor regions. Dots represent the entropy calculated using the amended Shannon entropy for 843,393 CpGs. Dot colors reflect the H3K36me3 status of each tumor/normal region. E Euclidian distance comparison of sampled regions from each patient using 843,393 autosomal CpGs. Dots represent the distance between any two samples originating from the same patient. F Phyloepigenetic tree of the 5000 most variable CpGs among tumor samples. G Supervised hierarchical clustering of the 5,000 most variable CpGs within the ICC 0.4–0.6 group forms three major clusters. P-values result from the χ2 analysis of all clusters against each other and the comparison of cluster 1 against the combination of clusters 2 and 3. CpG features are indicated by the colored bar to the left of the heatmap. H Relative feature distribution of the 5,000 most variable CpGs within the ICC 0.4–0.6 group when normalized to the distribution of all CpGs on the EPIC array over four genomic features. The asterisk indicates a significant distribution difference of the respective feature and the EPIC array. Y-axis – relative difference (log10) of each feature. I Heatmap showing the correlation coefficients (r) of 392 KIRC survival-linked CpGs significantly associated with the expression of their respective genes. The dendrogram separates the CpGs with positive (n = 73; red) from the CpGs with negative (n = 319; blue) correlations. The side bars correspond to the methylation status associated with better survival, and the feature of the CpG. There is a significant over representation (p = 0.011) of CpGs associated with better survival when hypomethylated among the CpGs inversely correlated with the expression of their respective genes. There is no feature distribution difference between the two CpG clusters

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