Abstract C03: A comprehensive study of genomic alterations reveals deregulation of the cell cycle in most esophageal squamous cell carcinomas

Objective: Esophageal squamous cell carcinoma (ESCC) is a major cause of cancer related mortality. To determine the molecular basis of ESCC development, this investigation sought to comprehensively identify the characteristic genome-wide changes in ESCC, including exonic mutations and structural alterations. The clinical implications of these genetic changes are also analyzed. Methods: Exome sequencing was applied to detect somatic mutations in nine pairs of ESCC and matched blood samples, followed by validation with MassARRAY genotyping and Sanger sequencing. Whole-genome SNP arrays were employed to study copy number changes and the loss of heterozygosity in 55 ESCCs. Results: 108 non-synonymous mutations in 102 genes were identified and validated in nine patients, suggesting a low somatic mutation rate (average 12 per tumor) in our ESCC cases. The chromatin modification process was found to be enriched in gene ontology analysis. Mutated TP53 was seen in five of the nine tumors (55.6%) undergone exome sequencing and in 23/46 tumors in the validation set. Integrating with the SNP array data, we found that tumor genomes with TP53 mutations were much more unstable than those without these mutations. In the landscape of genomic alterations, deletion of 9p21.3 covering CDKN2A (30.9%), amplification of 11q13.3 covering CCND1 (30.9%), and point mutation of TP53 (50.9%) occurred in two-thirds of ESCCs, suggesting deregulation of G1 in cell cycle is the key event in ESCC. Furthermore, six minimal common regions were found to be significantly altered in ESCC and three (9p21.3, 7p11.2, 3p12.1) were associated with lymph node metastasis. Conclusions: Frequent TP53 mutation and genomic instability are highly correlated in ESCC. The amplification of CCND1, deletion of CDKN2A/B, and somatic mutation of TP53 play pivotal roles via G1 deregulation and therefore classify this cancer into major groups. These findings provide clinical significance for future molecular diagnosis and therapeutic targeting. Citation Format: Jian Bai, Qiyan Wang, Kenan Gong, Hong Cai, Yang Ke, Changqing Zeng. A comprehensive study of genomic alterations reveals deregulation of the cell cycle in most esophageal squamous cell carcinomas. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C03.