We next applied the MutSigCV method36 to identify SMGs in the combined 192 ESCC tumors (Figure S1E) and discovered nine such genes driven by point mutations (false discovery rate, q < 0.1) and six further genes with p < 0.01 (Figure 3A). Eleven of these 15 genes—including AJUBA, ZNF750, FAT1, FBXW7 (MIM 606278), and PTCH1 (MIM 601309) and the chromatin-remodeling genes CREBBP (MIM 600140) and BAP1 (MIM 603089)—harbored frequent inactivating mutations. Although AJUBA, ZNF750, FAT1, and FBXW7 were recently implicated as tumor suppressors in ESCC,7,37 their roles in mice models and the mechanisms by which they function as tumor suppressors are limited. As in other cancers,38,39 particularly EAC,19 this analysis also identified well-known cancer-associated genes, such as TP53 (MIM 191170), PIK3CA, and CDKN2A (MIM 600160), as SMGs in ESCC, thus providing evidence of common dysfunctions in cell-cycle control and apoptotic signaling.