Abstract
BACKGROUND: Esophagogastric junction adenocarcinomas (EGJA) pose a serious threat to health and are increasing in incidence. The Siewert classification is the recognized anatomical classification system for guiding the surgical approaches in EGJA. However, the definition of EGJA and its optimal resection strategy remain controversial. This study aims to investigate the distinct molecular relationship between EGJA subtypes and other upper gastrointestinal cancers at the molecular level. METHODS: This study enrolled 198 patients with EGJA, among whom 140 (70.7%) had distal EGJA and 58 (29.3%) had proximal EGJA; 42 patients with gastric adenocarcinoma (GCA); and 36 patients with esophageal squamous cell carcinoma (ESCC). Targeted next-generation sequencing (NGS) of 450 cancer-related genes was performed to identify the genomic alterations. The molecular characteristics of the above patients with proximal/distal EGJA, GCA, and ESCC were analyzed and compared. RESULTS: The genes with high mutation frequency in the EGJA cohort were as follows: TP53 (74%), CCNE1 (14%), ERBB2 (12%), FAT3 (11%), ARID1A (11%), PIK3CA (10%), SPTA1 (10%), CDK6 (9%), FGF3 (9%), and LRP1B (9%). We also found that mutations in FRFR2, ZNF127, and MYC emerged as exploratory, subtype-associated features that may help distinguish distal from proximal EGJA. Furthermore, our data indicated distinct patterns of somatic mutations and copy number alterations between EGJA and GCA and ESCC, as well as between distal and proximal EGJA, suggesting that EGJA may warrant distinct tumor-node-metastasis (TNM) staging with molecular profile. CONCLUSIONS: Our NGS-based analysis revealed 10 high-frequency mutant genes in EGJA and demonstrated significant molecular differences among EGJA, GCA, and ESCC. These findings support the molecular basis for a distinct TNM staging system for EGJA.