Fig. 5: The SOXE-module is driven by the erosion of lineage-specific epigenetic marks.
From: Epigenome erosion and SOX10 drive neural crest phenotypic mimicry in triple-negative breast cancer
a Decision tree for identifying candidate copy-number alteration (CNA) drivers of the SOXE-module. Of 17,694 genes with case-matched GISTIC, RNAseq and WGCNA data, CN, and expression of 130 correlated with the SOXE-module in TNBC, including 25 SOXE-module nodes. b Network influence metrics for SOXE-module nodes coloured according to candidate CN driver status (intramodular connectivity (kWithin), local influence (Eigencentrality) and conductivity (betweenness centrality) defined in Fig. 4a). Boxes show the 10–90th percentiles and median, with whiskers extending to the minimum and maximum values. Mean is indicated with ‘+’. No significant differences by ordinary ANOVA test. c Relationship between SOXE-module levels and mutation signatures in ICGC TNBCs (COSMIC v2 SigProfiler and HRDetect on n = 74 ICGC TNBCs)45. Associations are depicted according to the correlation between SOXE-ME values and signature event count (y-axis); and by the significance of average SOXE-ME differences between ICGC TNBCs with low (quartile-1) vs higher (quartile 2–4) signature burden. d t-Distributed stochastic neighbour embedding (t-SNE) visualisation of genome methylation profile similarities amongst cases in the BRCA-TCGA 450k methylation array dataset. Panels are coloured according to PAM50 intrinsic subtype, SOXE-ME values or global median methylation-b values. Circled cases are epigenetically divergent, basal-like TNBCs that express high levels of the SOXE-module and have eroded methylomes. e Correlation analysis summary showing relationships between SOXE-ME values and region-specific methylation (n = 75 TCGA TNBCs, tumour cellularity ≥0.6; n = 215,323 probes after quality filtering); ****p < 1.0E-07. CGI CpG island, IGR intergenic region, TSS transcription start site, UTR untranslated region. Solo-WCpGW: consensus sequence for late-replicating loci demethylated via replicative senescence. f Unsupervised clustering of the BRCA-TCGA 450k methylation dataset according to ME correlation. Data shown were minimum correlation coefficients of ME values versus gene-averaged methylation-b data from promoter region probes (TSS1500, TSS200 and 5′UTR). Of three clusters inversely correlated with SOXE-module expression, two (a, b) were enriched with developmental ontologies (Supplementary Table 14). g Network influence metrics for SOXE-module genes in the hypomethylated clusters versus other SOXE-module genes, as for (b). Ordinary ANOVA p values: *p < 0.05; **p < 0.01; ***p < 0.001; ns not significant.
