Fig. 4

WGS reveals novel insight into the various (non-coding) aberrations affecting AR regulation. a Mutational overview of top recurrently mutated genes affecting AR regulation and their putative enhancer foci (as detected by GISTIC2). The first track represents the number of genomic mutations per Mbp (TMB) per SNV (blue), InDels (yellow), and MNV (orange) category genome-wide (square-root scale). Samples are sorted based on mutual-exclusivity of the depicted genes and foci. The heatmap displays the type of mutation(s) per sample, (light-)green or (light-)red backgrounds depict copy-number aberrations while the inner square depicts the type of (coding) mutation(s). Relative proportions of mutational categories (coding mutations [SNV, InDels and MNV] (yellow), SV (blue), deep amplifications (green), and deep deletions (red)) per gene and foci are shown in the bar plot next to the heatmap. The presence of chromothripsis (light pink), kataegis (red), CHORD prediction score (HR-deficiency) (pink gradient), MSI status (dark blue), and biopsy location are shown as bottom tracks. b Overview of the copy-number deviations between putative enhancer and gene regions for AR and MYC. Samples were categorized as enhancer- (blue) or gene- (red) enriched if enhancer-to-gene ratio deviated >1 studentized residual (residual in standard deviation units) from a 1:1 ratio. c Copy number and ChIP-seq profiles surrounding the AR and PCAT1/MYC gene loci (with 1.25 additional Mbp up-/downstream). The upper panel displays the selected genomic window and the overlapping genes. The first and second track display the aggregated mean copy number (per 0.1 Mbp window) of the enhancer- and gene-enriched samples, respectively. These profiles identify distinct amplified regions (indicated by red asterisk) in proximity to the respective gene bodies. The 3th to 8th tracks represent AR ChIP-seq profiles (median read-coverage per 0.1 Mbp windows) in two mCRPC patients (# 3 and 4), LNCaP (# 5) and LNCaP with R1881 treatment (# 6), VCaP (# 7) and bicalutamide-resistant VCaP (# 8). The 9th to 11th tracks represent FOXA1 ChIP-seq profiles (median read-coverage per 0.1 Mbp windows) in two mCRPC patients (#9 and 10) and LNCaP with R1881 treatment (# 11). The 12th to 14th tracks represent H3K27ac ChIP-seq profiles (median read-coverage per 0.1 Mbp windows) in two mCRPC patients (# 12 and 13) and LNCaP with R1881 treatment (# 14) reflecting active enhancer regions. ChIP-seq peaks (MACS/MACS2; q < 0.01) are shown as black lines per respective sample