Genomic landscape of paired primary and peritoneal metastatic lesions in gastric cancer highlights evolutionary dynamics and mutational drivers

INTRODUCTION: Peritoneal metastasis is a prevalent form of gastric cancer spread, often resulting in poor outcomes. Due to the lack of clinical recommendation for surgery, current omics studies are limited to analyzing suspending malignant cells in ascites using external controls, rather than examining peritoneal metastatic nodules alongside their paired primary tumors. OBJECTIVES: This study aims to elucidate the genomic landscape of gastric cancer peritoneal metastasis and identify key genetic drivers by comparing peritoneal dissemination lesions and their corresponding primary samples. METHODS: Whole-exome sequencing of 30 samples from 15 gastric cancer patients with peritoneal metastasis was conducted. We compared mutational and copy number variations, explored actionable targets and biomarkers, and contextualized our findings with the TCGA cohort. RESULTS: We identified distinct mutation patterns in gastric cancer with peritoneal metastasis, including increased mutation frequency in the cadherin superfamily and Fanconi anemia pathway. Peritoneal metastasis and primary lesions frequently harbored both parental clones and specific subclones. Well-known driver mutations (e.g., TP53, FAT1, CDH1, ARID1A) occurred early in gastric cancer tumorigenesis, while peritoneal metastasis-specific mutations (e.g., FADS6, NDUFS7, DUSP4) and mutational signatures were linked to adverse outcomes. DEK amplification was significantly higher in peritoneal metastasis lesions (46.7 %) versus primary tumors (13.3 %), with DEK expression levels closely associated with gastric cancer stemness signatures, validated through in vitro and in vivo studies. CONCLUSION: Our study elucidates clonal evolution in gastric cancer peritoneal metastasis, identifies mutational drivers, and highlights potential therapeutic targets. These findings provide valuable insights for developing precise treatment strategies for gastric cancer patients with peritoneal metastasis.