Comprehensive Analysis of Genomic Alterations in Hepatoid Adenocarcinoma of the Stomach and Identification of Clinically Actionable Alterations

Abstract

Hepatoid adenocarcinoma of the stomach (HAS) is a rare malignancy with aggressive biological behavior. This study aimed to compare the genetic landscape of HAS with liver hepatocellular carcinoma (LIHC), gastric cancer (GC), and AFP-producing GC (AFPGC) and identify clinically actionable alterations. Thirty-eight cases of HAS were collected for whole-exome sequencing. Significantly mutated genes were identified. TP53 was the most frequently mutated gene (66%). Hypoxia, TNF-α/NFκB, mitotic spindle assembly, DNA repair, and p53 signaling pathways mutated frequently. Mutagenesis mechanisms in HAS were associated with spontaneous or enzymatic deamination of 5-methylcytosine to thymine and defective homologous recombination-related DNA damage repair. However, LIHC was characteristic of exposure to aflatoxin and aristolochic acid. The copy number variants (CNVs) in HAS was significantly different compared to LIHC, GC, and AFPGC. Aggressive behavior-related CNVs were identified, including local vascular invasion, advanced stages, and adverse prognosis. In 55.26% of HAS patients there existed at least one clinically actionable alteration, including ERBB2, FGFR1, CDK4, EGFR, MET, and MDM2 amplifications and BRCA1/2 mutations. MDM2 amplification with functional TP53 was detected in 5% of HAS patients, which was proved sensitive to MDM2 inhibitors. A total of 10.53% of HAS patients harbored TMB > 10 muts/Mb. These findings improve our understanding of the genomic features of HAS and provide potential therapeutic targets.

Liver metastasis from hepatoid adenocarcinoma of the stomach: a case report and literature review

“…Despite these efforts, the precise causes of HAS and the potential involvement of the AFP gene in its development remain uncertain. Some researchers propose that HAS might arise from pluripotent stem cells, and mutations in genes like TP53 and ATBF1 could contribute to AFP production in gastric cancer cells ( 12 , 13 ). Patients with HAS often exhibit nonspecific symptoms including abdominal pain, bloating, and discomfort.…”

Immunohistochemical characteristics and potential therapeutic regimens of hepatoid adenocarcinoma of the stomach: a study of 139 cases

“…They found that immunoscore was an independent risk factor for OS and they thought immunotherapy was a promising treatment method for HAS patients. In 2022, Zhao et al found that 10.53% of HAS patients harbored tumor mutation burden (TMB) >10 muts/Mb [ 32 ]. Likewise, Jiang et al found HAS patients harbored more TMB than non‐HAS patients (mean TMB: 18.5/Mb versus 12.6/Mb, p = 0.021) [ 13 ].…”

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

“…GAED and HAC constitute the two primary pathological types of AFPGC, are prone to liver metastasis and have poor survival prognoses. However, unlike HAC which was first recognized in 1970 22 and studied relative thoroughly and comprehensively [23][24][25] , there are no more explorations at the molecular level to understand its pathogenesis, prognosis-related genes or treatment targets in GAED. In this study, we investigated the molecular mechanisms underlying the aggressive biological behaviour of GAED.…”