Multi-site sequencing supports dual-track evolution and identifies candidate metastasis-associated factors in gastric cancer ovarian metastasis.

BACKGROUND

Gastric cancer ovarian metastasis (GCOM) is an aggressive clinical entity whose evolutionary dissemination routes and molecular features remain incompletely defined.

METHODS

We performed whole-exome sequencing and patient-level phylogenetic reconstruction of 81 spatially distinct tumour specimens from 17 patients with GCOM.

RESULTS

Ovarian metastases showed a higher tumour mutational burden than matched primary tumours and substantial inter-lesional genomic heterogeneity. Phylogenetic reconstruction supported two major evolutionary routes of ovarian dissemination: lymph node-dependent evolution, in which ovarian metastases were phylogenetically associated with lymph node-related lineages, and lymph node-independent evolution, in which ovarian and lymph node metastases diverged along separate branches. Putative driver-gene alterations were relatively enriched in the shared/truncal mutational fraction, and SCAF4 emerged as an understudied candidate metastasis-associated factor. In GC cells, SCAF4 depletion was accompanied by widespread alterations in RNA splicing and interferon-related transcriptional programs and enhanced proliferative, migratory, invasive, and clonogenic phenotypes.

CONCLUSIONS

These findings support a dual-route evolutionary framework for GCOM and nominate SCAF4 as a candidate metastasis-associated factor, providing a genomic basis for understanding the biological heterogeneity of ovarian dissemination in GC.

HIGHLIGHTS: A multi-site genomic sequencing and phylogenetic reconstruction in matched gastric primaries and ovarian metastases was performed. Uncovered two distinct evolutionary routes for gastric cancer ovarian metastasis: lymph node-dependent and lymph node-independent evolutionary patterns. Genomic and functional analyses nominate SCAF4 as a candidate metastasis-associated factor.