Background <p>There is currently no unified consensus on the diagnosis and treatment of hepatoid adenocarcinoma of the stomach (HAS) and non-hepatoid AFP-producing gastric cancer (AFPGC). This study aims to explore the molecular similarities between the two, providing a basis for the diagnosis and precision treatment of these patients.</p> Methods <p>We retrospectively collected tumor tissues, adjacent tissues, and peripheral blood samples from 83 patients for whole-exome sequencing or transcriptome sequencing. Spearman correlation analysis, unsupervised clustering analysis and so on were performed to assess the similarity between different sample groups, explore the molecular features of non-hepatoid AFPGC and HAS, and compare their correlations.</p> Results <p>All the patient groups shared high-frequency mutated genes such as TP53, LRP1B, MUC16, CSMD3, and FAT4. Copy number variation analysis revealed similarities in the copy number variations between the two patient groups. The majority of patients in both groups exhibited amplification of the CCNE1 or ERBB2. PCA analysis based on transcriptomic data showed a clear clustering trend within the HAS and non-hepatoid AFPGC subgroups, which was distinct from conventional gastric adenocarcinoma. Moreover, unsupervised clustering analysis indicated that the samples within the different subgroups of the two groups had similar transcriptional expression patterns. Finally, we identified a potential therapeutic target, FAT4. Mutations in FAT4 further affect transcriptional expression and prognosis in gastric cancer patients, as well as influence immune infiltration and the response to immune checkpoint blockade therapy.</p> Conclusion <p>HAS and non-hepatoid AFPGC exhibit a high degree of similarity at both the genomic and transcriptomic levels.</p> Clinical trial number <p>Not applicable.</p> Graphical Abstract <p></p>