Feng Wei Tan, Li Jian Zhang, Ning Li, Qi Xue, Jian Sun, Yibo Gao, Pan Wang, Ran Yao, Jie He, Shu Geng Gao, Cheng Cheng Zhou, Xue Jiao Shi, Xiao Li Feng, Jing Si Dong, Su Ya Wang, Mei Luo, Lan Jun Zhang, Yu Da Zhao, Zi Tong Li, Zi Yuan Liu, Yue Yu, Xue Da Hu, Zi Ran Zhao, Nan Sun, Zhao Li Chen, Bai Hua Zhang, Bin Qiu, Kang Shao, Zeng Miao Sun, Su Sheng Shi, Fan Zhang, Fang Zhou, and Jia Gen Li
Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers. We performed exome sequencing on 113 tumor-normal pairs, yielding a mean of 82 non-silent mutations per tumor, and 8 cell lines. The mutational profile of ESCC closely resembles those of squamous cell carcinomas of other tissues but differs from that of esophageal adenocarcinoma. Genes involved in cell cycle and apoptosis regulation were mutated in 99% of cases by somatic alterations of TP53 (93%), CCND1 (33%), CDKN2A (20%), NFE2L2 (10%) and RB1 (9%). Histone modifier genes were frequently mutated, including KMT2D (also called MLL2; 19%), KMT2C (MLL3; 6%), KDM6A (7%), EP300 (10%) and CREBBP (6%). EP300 mutations were associated with poor survival. The Hippo and Notch pathways were dysregulated by mutations in FAT1, FAT2, FAT3 or FAT4 (27%) or AJUBA (JUB; 7%) and NOTCH1, NOTCH2 or NOTCH3 (22%) or FBXW7 (5%), respectively. These results define the mutational landscape of ESCC and highlight mutations in epigenetic modulators with prognostic and potentially therapeutic implications.