The study provides a comprehensive molecular analysis of 164 oesophageal carcinomas, distinguishing between oesophageal squamous cell carcinomas (ESCC) and oesophageal adenocarcinomas (EAC). ESCCs showed genomic amplifications of CCND1 and TP63, while ERBB2, VEGFA, and GATA4/GATA6 were more commonly amplified in EACs. EACs closely resembled chromosomally unstable gastric adenocarcinomas, suggesting they may be considered a single disease entity. However, DNA hypermethylation was more prevalent in EACs. These findings provide a framework for more rational categorization of these tumors and potential new therapeutic targets. The study also highlights the need for separate clinical trials for ESCC and EAC, as they exhibit distinct molecular characteristics.The study provides a comprehensive molecular analysis of 164 oesophageal carcinomas, distinguishing between oesophageal squamous cell carcinomas (ESCC) and oesophageal adenocarcinomas (EAC). ESCCs showed genomic amplifications of CCND1 and TP63, while ERBB2, VEGFA, and GATA4/GATA6 were more commonly amplified in EACs. EACs closely resembled chromosomally unstable gastric adenocarcinomas, suggesting they may be considered a single disease entity. However, DNA hypermethylation was more prevalent in EACs. These findings provide a framework for more rational categorization of these tumors and potential new therapeutic targets. The study also highlights the need for separate clinical trials for ESCC and EAC, as they exhibit distinct molecular characteristics.