Extended Data Fig. 4: Workflow of causal gene network analysis.

The workflow to infer the causal gene network linking CDKN2A LoF to the downregulation of keratinization was divided into three steps: (A) identification and filtering of the keratinization-related gene modules and associated transcription factors (TFs) using cMonkey2⁸⁸ and ARACNE-AP⁹⁰ (Step 1); (B) prediction of the causal models that link CDKN2A LoF to the dysregulation of keratinization genes through specific TFs using the network edge orienting (NEO) method^87,91 (Step 2); and (C) retention of the causal models with differential expression (FDR < 0.1) of TFs in group 4 compared to 9p21 wild type samples assessed using DESeq2⁷⁷ and significant positive correlation (R > 0.5 and FDR < 0.1) between TF expression and the GSEA NES score of the predicted targets in P-BEs and EACs (Step 3).