The better understood SMGs in ESCC can be categorized according to their functions in: (i) genes involved in cell cycle regulation (TP53, CDKN2A, RB1, CREBBP), (ii) genes involved in the PI3K/AKT/mTOR pathway (PIK3CA, PTEN), (iii) genes involved in the NOTCH signaling pathway (NOTCH1, NOTCH3, FBXW7), iv) genes involved in cell adhesion (AJUBA, FAT1), v) genes involved in chromatin remodeling (MLL2, KDM6A, EP300, BAP1), (vi) genes involved in the NRF2 pathway (NFE2L2, CUL3) and vii) genes involved in epidermal differentiation (ZNF750) [25,26,27,28,29,30,31]. The gene discussed is CUL3; the disease is esophageal squamous cell carcinoma.