Abstract 2225: Comprehensive molecular characterization of esophageal squamous cell carcinoma

Abstract

Abstract Background Esophageal squamous cell carcinoma (ESCC) is a world-wide prevalent cancer, which is particularly common in certain regions of Asia. However, the genetic alterations of this disease have not been fully described. Methods We determined the mutational landscape of ESCC through whole-exome or targeted deep sequencing of 139 tumor/germline pairs. The somatic copy number variations (SCNV) of over 180 ESCC tumors were analyzed by SNP-array or array-CGH. Candidate driver mutations were mathematically calculated by the most updated algorithm MutSigCV, and the protein expression of which were thoroughly evaluated by immunohistochemistry. Finally, biological effects of candidate drivers were examined through functional studies in vitro and in vivo. Results Deep sequencing and computational analysis identified frequent and novel driver mutations affecting genes such as FAT1 (11.5%), ZNF750 (7.2%), EP300 (7.9%) and MLL2 (18.0%). FAT1 and ZNF750 genes were homozygouly deleted in 3.5% and 3.4% ESCCs, respectively, and their RNA transcripts and proteins were expressed at much lower levels in primary tumors compared to adjacent normal esophageal epithelial. Importantly, silencing of wild-type FAT1 or ZNF750 expression with siRNA/shRNAs significantly promoted cell proliferation and decreased cell differentiation, whereas ectopic expression of these genes resulted in opposite biological consequences. These genetic alterations and biological evidence strongly suggest that FAT1 and ZNF750 likely encode tumor suppressors which are frequently disrupted in ESCC. Furthermore, by integrating the landscape of somatic mutation, SCNV and protein dysregulation, we proposed that RTK-PI3K-MAPK pathways, cell cycle and epigenetic regulation are frequently altered by multiple molecular mechanisms in esophageal tumors. Finally, our systematic approaches uncovered many novel druggable candidates in this disease, such as FGFR1, ALK and XPO1. Conclusions By demonstrating the genomic landscape of over 180 ESCC cases, our integrated study unmasks a number of novel genetic lesions in ESCC and provides an important molecular foundation for understanding esophageal tumors and developing therapeutic targets. Citation Format: Dechen Lin, Xuan Meng, Liang Xu, Lingwen Ding, Manoj Garg, Henry Yang, Lizhen Liu, Jiajie Hao, Mingrong Wang, Yasunobu Nagata, Yusuke Sato, Yusuke Okuno, Seishi Ogawa, Phillip Koeffler. Comprehensive molecular characterization of esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2225. doi:10.1158/1538-7445.AM2014-2225