Notably, we also found that the mutations in NFE2L2, KEAP1, and CUL3 were almost mutually exclusive (Supplementary Fig. 3C), which was consistent with the finding in SqCC and HNSCC19,20 and indicated that the mutation and dysfunction of the NFE2L2/KEAP1/CUL3 pathway may contribute to the development of ESCC by increasing the resistance to oxidative stress. This evidence concerns the gene CUL3 and esophageal squamous cell carcinoma.