Integrative proteomic characterization of adenocarcinoma of esophagogastric junction

The molecular subtypes of adenocarcinoma of the esophagogastric junction (AEG) remain to be identified. Here, the authors perform proteogenomic characterisation of AEG tumours with paired normal adjacent tissues and suggest three proteomic subtypes and potential druggable targets. The incidence of adenocarcinoma of the esophagogastric junction (AEG) has been rapidly increasing in recent decades, but its molecular alterations and subtypes are still obscure. Here, we conduct proteomics and phosphoproteomics profiling of 103 AEG tumors with paired normal adjacent tissues (NATs), whole exome sequencing of 94 tumor-NAT pairs, and RNA sequencing in 83 tumor-NAT pairs. Our analysis reveals an extensively altered proteome and 252 potential druggable proteins in AEG tumors. We identify three proteomic subtypes with significant clinical and molecular differences. The S-II subtype signature protein, FBXO44, is demonstrated to promote tumor progression and metastasis in vitro and in vivo. Our comparative analyses reveal distinct genomic features in AEG subtypes. We find a specific decrease of fibroblasts in the S-III subtype. Further phosphoproteomic comparisons reveal different kinase-phosphosubstrate regulatory networks among AEG subtypes. Our proteogenomics dataset provides valuable resources for understanding molecular mechanisms and developing precision treatment strategies of AEG.

Automated summary

By performing proteogenomic characterization of adenocarcinoma of the esophagogastric junction (AEG) tumors, the authors identified three proteomic subtypes and potential druggable targets, providing new insights into the molecular subtypes of this disease.