Dual-expression (primitive enterocyte phenotype and neuroendocrine differentiation) gastric adenocarcinoma: the unique high-aggressive subtype.

Gastric adenocarcinoma (GA) is a highly heterogeneous malignant tumor with varying biological behaviors and prognosis. Clinically, we observed some GA exhibiting dual expressions of both primitive enterocyte phenotype (PEP) and euroendocrine differentiation (NED). However, clinicopathological features of this subtype (DEGA) remain unclear. In this research, we enrolled 186 GAPEP patients and divided into DEGA (77, 41.4%) and nDEGA (109, 58.6%) by immunohistochemistry. The DEGA group demonstrated a worse prognosis than the nDEGA group (P = 0.03). Notably, DEGA cases had a higher incidence of nodal metastasis at early stages (T1) compared to nDEGA (50% vs. 7.1%, P = 0.011), and immunohistochemistry evaluation showed persistent NED traits even in metastatic nodes. NED was more prevalent in GAPEP than in nGAPEP, as evidenced by higher Synaptophysin and Chromogranin-A expressions at both the protein and mRNA levels. Human gastric cancer cell line in vitro experiments indicated a correlation between Alpha-Fetoprotein and Synaptophysin, and double knockdown of these two genes resulted in a more pronounced inhibition of proliferation. Single-cell RNA sequencing further highlighted the stemness in DEGA cells. The public datasets also affirmed above DEGA features. Neoadjuvant therapy was less effective for DEGA patients compared to those with nDEGA. Additionally, DEGA significantly differed from neuroendocrine carcinoma (NEC), lacking typical NEC morphological features, consistently expressing PEP markers, and exhibiting distinct genomic and serum marker profiles. In summary, DEGA exhibits distinct aggressive behaviors and molecular characteristics that differentiate it from other gastric adenocarcinomas, implicating it in poor prognosis and therapeutic resistance.