Using a three-step protocol (Extended Data Fig. 4a–c and Methods), we identified 8 and 14 causal models in P-BE and EAC, respectively, linking CDKN2A LoF directly to keratinization gene downregulation through the perturbation of two TFs (SOX15 and TP63; Supplementary Table 11). This evidence concerns the gene SOX15 and Barrett esophagus.