Figure 8: cuSCC is molecularly related to carcinogen-driven SCCs of multiple sites.

(a) GSEA analysis of all significant pairwise comparisons in both mouse (CHR versus PAP, CHR versus cuSCC) and human (NS versus AK, AK versus cuSCC, NS versus cuSCC) represented as a CIRCOS plot. For all cancers profiled in the TCGA, normalized enrichment scores for each signature were determined and cancer types ranked by descending order (clockwise) of the sum of squares of all the scores with a penalty. By this measure, cuSCC is most closely related to HNSC, LUSC, basal and HER2+ subtypes of breast cancer (BRCA) and ESCA SCC. (b) Given that HNSC is most closely related to cuSCC by this measure, we show that cuSCC signatures can predict outcome (overall survival) in HNSC with TP53 mutation, used here as a proxy for identifying tumours that do not express high-risk HPV. The cross-species early signatures derived from the linear mixed effects model and the cross-species microRNA functional analysis all predict survival in HNSCC for the top and bottom 25% of outcomes with statistical significance. Multiple hypothesis testing was performed and all of the plots shown are significant with the stated P-values and false discovery rate-adjusted q-values of <0.1 (q=0.021 human early, 0.070 mouse early, 0.049 conserved early and 0.070 conserved miRNA targets). (c) Taken together, our data show that AKs have acquired many of the properties of cuSCC as assessed by SMG, mutational overlap, mutational signatures, chromosomal instability signature, mRNA and transcription factor profiles and functional pair analysis, although overall mutational load and unsupervised microRNA clustering do enable separation of the three sample types.