Exploring the molecular characteristics of the malignant potential of gastric adenocarcinoma with enteroblastic differentiation

Aims Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare subset of alpha‐fetoprotein (AFP)‐producing carcinomas with poor prognosis. However, the molecular features associated with the malignant potential of GEAD remain partially elucidated. Methods and results In this study, the relationship between clinicopathological parameters and aggressive biological behaviour was analysed in 37 patients with GAED. The results showed that GAED tended to infiltrate the deep layer of the gastric wall and possessed more frequent vascular invasion than conventional gastric adenocarcinoma (CGA) ( P < 0.001). All distant metastases were observed in the GAED group, not the CGA group ( P < 0.001). High HER2 expression was found in nearly 24.32% of the informative cases, and none showed EBV‐encoded RNA positivity or deficient mismatch repair. The most frequently mutated gene in GAED was p53 . Programmed cell death‐ligand 1 (PD‐L1) immunostaining revealed 13 patients with a combined positive score (CPS) ≥ 5 (65%, 13 of 20). Thus, based on these molecular markers (immunostaining, in situ hybridisation and mutation analysis), GAED may be classified as a unique subgroup of the chromosomal instability subtype with HER2 + /EBV − /MSS/TP53 + /PD‐L1 + . Next‐generation sequencing analyses showed that mutations in the TOPI , ELOA and NOTCH3 genes were found only in GAED, and abnormally expressed genes in GAED were significantly enriched in hepatocellular carcinoma‐, gland development‐, and gastric cancer‐related pathways. Conclusion The HER2 + /EBV − /MSS/TP53 + /PD‐L1 + profile and hepatocellular carcinoma‐related pathways may be significant in the malignant potential of GAED. In addition to anti‐HER2 therapy, immune check‐point inhibitors may be an effective treatment option for patients with GAED.