Fig. 6: Impact of CDKN2A LoF on epithelium differentiation in P-BE and EAC.
a, Gene regulatory network linking CDKN2A LoF to the downregulation of keratinization genes through TF deregulations. b–d, Distributions of gene expression values of SOX15 in n = 17 patients with P-BE (P = 0.002) (b) and SOX15 (P = 0.04) (c) and TP63 (d) in n = 26 patients with EAC of group 4 and 9p21 wild type (31 P-BE and 184 patients with EAC, respectively). Distributions were compared using two-sided Wilcoxon’s rank sum test. FC and FDR from the differential gene expression analysis with DESeq2 (ref. 77) are also shown. Boxplot shows first and third quartiles, whiskers extend to the lowest and highest value within the 1.5× interquartile range and the line indicates the median. e, Overlap between keratinization genes targeted by SOX15 and TP63 in P-BE and EAC. f,g, Preranked GSEA plots using as signature keratinization genes targeted by SOX15 in P-BE (f) and by SOX15 and TP63 in EAC (g). Genes were ranked from the most upregulated to the most downregulated in group 4 compared to 9p21 wild-type samples. For EAC, only the top 2,000 downregulated genes are shown. h–j, Correlation plots between keratinization GSEA NES and the gene expression values of SOX15 in P-BE (h) and SOX15 (i) and TP63 (j) in EAC. Coefficients and associated P values from two-sided Spearman’s correlation test are reported. k–n, Preranked GSEA plots using gene signatures for quiescent basal cells (k), proliferating basal cells (l), early suprabasal cells (m) and late suprabasal cells (n) in P-BE and EAC group 4. P values in (e–g and k–n) were estimated by permutation. ES, enrichment score; TF, transcription factor; GSEA, gene set enrichment analysis.
