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A comprehensive analysis of clinicopathological features, immunophenotypes, molecular characteristics, and survival in AFPGC contributes to identifying potential therapeutic targets and developing new strategies to manage this disease. A retrospective cohort study was conducted at Shanxi Cancer Hospital from January 2018 to December 2020, involving patients diagnosed with GC and elevated AFP serum levels. Among these, 91 patients underwent immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS) to reveal the immunophenotypic and molecular characteristics of AFPGC. We found that AFPGC is more common in males and primarily occurs in the cardia and antrum of the stomach. A panel of IHC markers including AFP, GPC3, SALL4, CD10, CDX-2, and ATBF1 can be used for the diagnosis and differentiating AFPGC. NGS analysis revealed that <jats:italic>TP53<\/jats:italic> hypermutation was the most frequent molecular event associated with AFPGC. The altered signaling pathways included disease signal transduction, receptor tyrosine kinase signaling and intracellular second messenger signaling pathways. The cumulative incidence of 21 genes, based on the evidence of clinical actionability in the OncoKB, was found to be 59.34%. Among these genes, <jats:italic>CCNE1<\/jats:italic>, <jats:italic>ERBB2<\/jats:italic>, and <jats:italic>EGFR<\/jats:italic> were the most frequently observed. This underscores the potential benefit of targeted therapy for patients with AFPGC. Furthermore, <jats:italic>LRP1B<\/jats:italic> and <jats:italic>ARID1A<\/jats:italic> have been identified as prognostic factors associated with overall survival (OS) and disease-free survival (DFS), respectively. Our results aim to improve AFPGC diagnosis by identifying potential therapeutic targets and prognostic factors, which could help facilitate the development of new treatment strategies.<\/jats:p>","DOI":"10.1007\/s10120-025-01594-x","type":"journal-article","created":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T14:44:11Z","timestamp":1739198651000},"page":"372-383","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Genomic landscape and potential therapeutic targets in alpha-fetoprotein-producing gastric cancer"],"prefix":"10.1007","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9437-9004","authenticated-orcid":false,"given":"Likun","family":"Zan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lulu","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongfeng","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Bu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfeng","family":"Xi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,10]]},"reference":[{"key":"1594_CR1","first-page":"979","volume":"32","author":"D Gitlin","year":"1972","unstructured":"Gitlin D, Perricelli A, Gitlin GM. 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The study was approved by the Research Ethics Committee of the Shanxi Province Cancer Hospital (IIT-2023-020L).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}