Multi-site sequencing supports dual-track evolution and identifies candidate metastasis-associated factors in gastric cancer ovarian metastasis.
Gastric cancer ovarian metastasis (GCOM) is an aggressive clinical entity whose evolutionary dissemination routes and molecular features remain incompletely defined.
We performed whole-exome sequencing and patient-level phylogenetic reconstruction of 81 spatially distinct tumour specimens from 17 patients with GCOM.
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.
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.
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.
We performed whole-exome sequencing and patient-level phylogenetic reconstruction of 81 spatially distinct tumour specimens from 17 patients with GCOM.
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.
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.
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.
Authors
Zhu Zhu, Xing Xing, Ji Ji, Wang Wang, Li Li, Jia Jia, Huangfu Huangfu, Li Li, Fan Fan, Bu Bu, Ji Ji
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