Multi-omics approaches to unveil the mixed molecular characteristics of hepatoid adenocarcinoma of the stomach with neuroendocrine differentiation.

Abstract

e16109 Background: Hepatoid adenocarcinoma of stomach with neuroendocrine differentiation (HAS-NEC) is an extremely rare subtype of gastric cancer, and there is currently no systematic research focused on this uncommon subtype. This study aims to investigate the clinicopathological and molecular characteristics of this rare subtype, thereby providing a reference for precision therapy for such patients. Methods: We retrospectively collected tumor tissue and adjacent carcinoma tissue samples from 84 patients, along with corresponding clinicopathological information, for whole exome sequencing and transcriptome sequencing. Spearman correlation analysis and unsupervised clustering analysis were employed to explore the molecular characteristics of HAS-NEC and to assess the similarities and differences among the various sample groups. Results: From the perspective of clinical pathological features, HAS-NEC exhibited greater similarity to HAS patients, with no significant differences in all clinicopathological characteristics. HAS-NEC patients possessed distinct genomic features compared to both HAS and NEC patients, with TTN being the most frequently mutated gene, occurring in 90% of cases. Mutations in TET1 were exclusive to HAS-NEC patients and were not detected in the other two groups. At the transcriptional level, HAS-NEC patients showed greater similarity to HAS patients, demonstrating more comparable transcriptional expression patterns. Lastly, we identified a potential therapeutic target, ZFHX4, whose mutations influence the transcriptional expression and prognosis of gastric cancer patients, further impacting immune infiltration and response to immunotherapy. Conclusions: Patients with HAS-NEC exhibited unique molecular biological characteristics that could not be simply viewed as a combination of HAS and NEC.