Comparative Genomic Analysis of Esophageal Adenocarcinoma and Squamous Cell Carcinoma

Abstract

Esophageal cancer (EC) ranks sixth in cancer death. To explore its genetic origins, we performed exomic sequencing on 11 adenocarcinomas (EAC) and 12 squamous cell carcinomas (ESCCs) 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’s esophagus (BE). These discoveries highlight key genetic differences between EAC and ESCC, American and Chinese ESCC, and suggest that NOTCH1 is a tumor suppressor gene in the esophagus. Finally, we provide a genetic basis for the evolution of EACs from BE.

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

“…HNSCC and ESCC have some common risk factors and may be closely related 54, 55. Similar mutation pattern of NOTCH1 was also revealed by genomic characterization ESCCs 8. Exomic sequencing of 12 ESCCs in parallel with 12 esophageal adenocarcinomas (EAC) revealed frequent NOTCH1 mutations in 21% of ESCCs but not in EACs 8.…”

“…Similar mutation pattern of NOTCH1 was also revealed by genomic characterization ESCCs 8. Exomic sequencing of 12 ESCCs in parallel with 12 esophageal adenocarcinomas (EAC) revealed frequent NOTCH1 mutations in 21% of ESCCs but not in EACs 8. Notably, different NOTCH1 alternation patterns were observed in patients from different ethnical populations: NOTCH1 appears to mutate more frequently in North American ESCCs (21%) than Chinese ESCCs (2%).…”

“…As we have described, the tumor suppressor role of Notch was relatively well established in CSCC, unlike for HNSCC 43. Until recently, the NOTCH1 has drawn much attention as it was identified as one of the most frequently mutated genes in SCCs of cutaneous 5, head and neck 6, 7, 53, esophageal 8, 56, and lungs 88. We summarized the NOTCH1 mutation patterns in five different SCCs, and explored the biological consequences of these mutations based on the Up‐to‐date structural information of Notch signaling.…”

“…However, Notch signaling activation can be tumor suppressive or oncogenic, depending on cellular context 4. Recently, considerable NOTCH gene mutations were identified in different types of squamous cell carcinoma 5, 6, 7, 8, 9, questioning the general role of Notch pathway in SCCs.…”

Comprehensive Genomic Profiling of Advanced Esophageal Squamous Cell Carcinomas and Esophageal Adenocarcinomas Reveals Similarities and Differences

“…In recent years, promising information has emerged from comprehensive genomic profiling of relapsed and refractory cancers including separate evaluation of major esophageal cancers such as EAC and ESCC [21][22][23][24]. These research studies have identified potential genomic targets for patients with esophageal cancers, but comprehensive molecular testing has not been widely adopted in routine clinical practice for esophageal cancer.…”