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. <i>TP53</i> was the most frequently mutated gene (66%). Hypoxia, <i>TNF-α</i>/<i>NFκB</i>, mitotic spindle assembly, DNA repair, and <i>p53</i> 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 <i>ERBB2</i>, <i>FGFR1</i>, <i>CDK4</i>, <i>EGFR</i>, <i>MET</i>, and <i>MDM2</i> amplifications and <i>BRCA1/2</i> mutations. <i>MDM2</i> amplification with functional <i>TP53</i> was detected in 5% of HAS patients, which was proved sensitive to <i>MDM2</i> 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.