(A) CircleMap of PARADIGM-Shift differences associated with SCC tissue origins and TP53 mutation status were created for TP53, TP63, TP73 and target genes identified in this study. Samples were ordered first by tissue origin of SCC (innermost ring), then by TP53 mutation status (second ring), GISTIC score (indicating CNV), mRNA expression level, and finally by PARADIGM activities (outer ring). The Red-blue color intensity reflects magnitude of CNV, expression and PARADIGM activities (red: high, blue: low). TP53 mutation is highlighted (black: truncation, gray: missense). Samples were restricted to the C2-Squamous-like cluster-of-cluster-assignments (COCA), including 156 lung SSC, 293 HNSCC, and 24 bladder SCC samples. Each plot illustrates multiple data types across many samples for a given gene. (B) The PARADIGM activity of ΔNp63 or TP73, and expression of eight target genes are higher across SCC tumors compared with other cancer types as shown in (A). Pearson correlation coefficients between ΔNp63 or TP73 PARADIGM activity and eight target genes presented in (A) were calculated, and the significance of p value was presented in y axis. The PARADIGM activity of ΔNp63 exhibited significant positive correlations with expression of five target genes bound and inducible by TNF-α, and a negative correlation with CEBPA expression. The PARADIGM activity of TP73 exhibited negative associations with with IL-6 and SERPINE1, and a positive association with CDKN1A (p21). (C) PARADIGM SuperPathway subnetwork defining C2-Squamous-like Pan-Cancer 12 integrative subtype. Zoom-in view of network neighborhood surrounding the ΔNp63α tetramer, TAp63γ tetramer, RelA/p50 and Jun/Fos complexes. Color of the nodes reflects activation (red) or repression (blue) within the squamous subtype when compared with the mean of other tumor types. Edge color denotes interaction type: inhibitory (green) and activating (yellow). Node shape reflects feature type: protein (circle), complex (diamond), family or miRNA or RNA (square), abstract concepts (arrowhead). The target genes with cRel, p63 and TAp73 binding identified in this study are highlighted with different colored outer rings as showing in .