Comparative Genomic Analysis of Esophageal Adenocarcinoma and Squamous Cell Carcinoma

TLDR

Esophageal cancer is the sixth leading cause of cancer death. The study aimed to investigate the genetic origins of esophageal cancer. Exomic sequencing was performed on 11 esophageal adenocarcinomas and 12 esophageal squamous cell carcinomas from the United States. The analysis revealed that inactivating NOTCH1 mutations occurred in 21 % of ESCCs but not in EACs, with distinct mutation spectra between the subtypes, higher NOTCH1 mutation frequency in North American ESCCs compared to Chinese, and most EAC mutations already present in Barrett esophagus, underscoring genetic differences and supporting NOTCH1 as a tumor suppressor and a genetic basis for EAC evolution from Barrett esophagus.

Abstract

Esophageal cancer ranks sixth in cancer death. To explore its genetic origins, we conducted exomic sequencing on 11 esophageal adenocarcinomas (EAC) and 12 esophageal squamous cell carcinomas (ESCC) from the United States. Interestingly, inactivating mutations of NOTCH1 were identified in 21% of ESCCs but not in EACs. There was a substantial disparity in the spectrum of mutations, with more indels in ESCCs, A:T>C:G transversions in EACs, and C:G>G:C transversions in ESCCs (P < 0.0001). Notably, NOTCH1 mutations were more frequent in North American ESCCs (11 of 53 cases) than in ESCCs from China (1 of 48 cases). A parallel analysis found that most mutations in EACs were already present in matched Barrett esophagus. These discoveries highlight key genetic differences between EACs and ESCCs and between American and Chinese ESCCs, and suggest that NOTCH1 is a tumor suppressor gene in the esophagus. Finally, we provide a genetic basis for the evolution of EACs from Barrett esophagus.