Molecular Characteristic of Proximal and Distal Esophagogastric Junction Adenocarcinomas

Abstract Introduction : Esophagogastric junction adenocarcinomas (00000000) are devastating diseases with increasing incidence. The Siewert classification is the well accepted anatomical classification system for EGJA to guide surgical approaches. However, the definition of EGJA and its optimal resection strategy are still debatable. Methods 198 EGJA patients, of which 140 (70.7%) were distal EGJA, 58 (29.3%) were proximal EGJA, 42 gastric adenocarcinoma (GCA) patients and 36 esophageal squammous cell carcinomas (ESCC) patients were enrolled. Targeted next-generation sequencing (NGS) of 450 cancer-related genes was performed to identify the genomic alterations. The molecular characteristics of the above EGJA, GCA and ESCC were analyzed and compared. Results Gene alterations with a high mutation frequency in EGJA in this cohort were identified: TP53 (74%), CCNE1 (14%), ERBB2 (12%), FAT3 (11%), ARID1A (11%), PIK3CA (10%), SPTA1 (10%), CDK6 (9%), FGF3 (9%), LRP1B (9%). Compared with GCA and ESCC, EGJA may better benefit from PIK3CA inhibitors due to high-frequency mutations in PIAK-AKT-related genes. We also found that FRFR2, ZNF127 and MYC mutations maybe biomarkers to distinguish distal EGJA from proximal EGJA. Conclusion Our data identify differences of EGJA from GCA and ESCC, as well as distal/proximal EGJA at the genomic level, suggesting that a unique TNM staging for EGJA may be required.