Molecular characteristics and metastatic mechanism of patients diagnosed with Krukenberg tumor from gastric cancer

Purpose Krukenberg tumors (KTs) represent a distinct form of ovarian metastasis originating from gastric cancer (GC) and are associated with dismal clinical outcomes. Despite their clinical significance, the molecular landscape and underlying mechanisms driving KTs development remain largely undefined. Methods We conducted whole-exome sequencing on paired primary gastric and metastatic ovarian tumors from 11 patients with KTs in a retrospective cohort. Results TP53 (54.5%) and EIF1AX (45.5%) were the most frequently mutated genes in KTs. Mutational signatures analysis revealed associations with age and mismatch repair deficiency. Mutations in TP53 , EIF1AX , and FBXW7 , along with MYC -amplification,were highly consistent between matched primary tumors and KTs. Importantly, compared to primary GC, KTs harbored distinct mutational landscapes, including mutually exclusive receptor tyrosine kinase (RTK) gene amplifications and a significantly higher burden of copy number variations (CNVs). Furthermore, patients exhibiting high-level CNVs or TP53 mutations had worse survival outcomes. Genomic comparisons between matched tumors demonstrated low concordance (median shared mutations: 6.3%), supporting the hypothesis of early clonal divergence and a parallel progression model of metastasis. Conclusion Frequent TP53 and EIF1AX mutations may play a critical role in the ovarian metastasis of GC. KTs demonstrate distinct mutational profiles compared with their primary counterparts, consistent with a parallel progression model, highlighting the need for tailored therapeutic approaches targeting metastasis-specific alterations.