Fig. 4: Frequently mutated regulatory elements (FMREs) at TOP2B binding sites.

a FMREs identified at the binding sites through significant enrichment of small mutations (SNVs, indels) or structural variant breakpoints (SVBPs) in individual cancer types in primary cancers (PCAWG) and metastases (HMF) (one-tailed tests from ActiveDriverWGS, FDR < 0.05). Known cancer genes are labelled. Color strips below the bar chart show site types, primary or metastatic cancers, and the type of mutation involved (small mutation or structural variant). b Circos plot of translocations at FMREs combined from primary cancers and metastases. Known cancer genes at FMREs are labelled. c Functional characteristics of FMREs relative to other binding sites. FMREs in the highest category (bin4) correspond to sites with highest third of gene expression or chromatin interactions from 27 human tissue types, or sites with constitutive CTCF binding in >90% of human tissues. P-values from one-tailed Wilcoxon tests (top) or one-tailed hypergeometric tests (bottom) are shown. d FMREs ranked by the number of promoter-enhancer chromatin interactions. Top genes with FMREs are labelled. e Genes with differential expression associations with alterations in adjacent FMREs (one-tailed F-test, FDR < 0.05). Bars show fold-change values of genes with respect to FMRE mutations. Symbols indicate associations identified from SNVs and indels (circles) or SVBPs (triangles). f Enrichment map of biological processes and molecular pathways enriched in non-coding FMREs (ActivePathways, FDR < 0.05). The network shows enriched pathways as nodes in which similar pathways that share many genes are connected by edges. Pathways were prioritized by mutational enrichments across primary and metastatic cancers. Colors indicate cancer types in which pathways were identified, and white corresponds to pathways only detected across multiple cancer types. Source data are provided as Source Data files.