FAT1, which encodes a cadherin-like protein commonly expressed in epithelial tissues,44 was mutated in 15% of ESCC tumors. Notably, 13 mutations (77%) were truncating (stop-gain and frameshift) (Table S3). FAT1 is reported to regulate cell-cell adhesion and other cell behavior by controlling actin polymerization.44 Recently, Morris et al. reported that FAT1 suppresses cancer cell growth by binding β-catenin and preventing nuclear localization.44 FAT1 inactivation, via mutations that affect the cytoplasmic domain, leads to aberrant Wnt/β-catenin signaling in multiple cancer types.45 In our cohort, we discovered mutations affecting cadherin repeats and laminin G domains but no mutations affecting the cytoplasmic domain. This observation indicates that mutations affecting FAT1 extracellular domains might disrupt cell-cell associations and increase invasiveness and thus potentially contribute to ESCC tumorigenesis. FBXW7 mutations were observed in eight ESCC tumors in our cohort: these included two nonsense mutations (c.1005T>A [p.Cys335∗] and c.409G>T [p.Glu137∗]), one frameshift deletion (c.736_739del [p.Gly247Profs∗] and inactivating mutations), and five missense mutations predicted to be deleterious by SIFT and PolyPhen-2 analyses (Table S3).46 FBXW7 mutations and copy-number loss and a subsequent decreased FBXW7 level have been observed in various cancer types.46,47 Decreased amounts of FBXW7 are reported to correlate with poor prognosis;47 however, we observed no correlation between FBXW7 mutations and prognosis in our cohort.