Clonal evolution in gastrointestinal cancers: multi-omics insights into tumor heterogeneity, microenvironmental selection, and translational biomarkers
Clonal evolution in hepatocellular carcinoma (HCC), esophageal squamous cell carcinoma (ESCC), and gastric cancer (GC) reflects the interaction of genetic diversification, cell-state plasticity, and tissue-specific selection. Multi-region and single-cell DNA sequencing resolve truncal and subclonal lineages, whereas single-cell and spatial transcriptomics, proteomics, and serial liquid biopsy characterize cellular states, ecological niches, and temporal dynamics. The three cancers differ in dissemination timing, dominant selective pressures, and biomarker maturity: early seeding is best supported in selected HCC cohorts, ESCC is strongly influenced by field cancerization and epithelial-stromal crosstalk, and GC follows subtype- and ecotype-dependent trajectories. We discuss the assumptions and sampling biases that constrain phylogenetic inference, the causal limits of cross-sectional tumor atlases, clonal hematopoiesis, and the incremental value of broad multi-omics over focused assays. Liquid-biopsy detection of minimal residual disease is prognostic, but treatment benefit from marker-guided intervention remains context dependent. Near-term translation requires standardized, decision-linked assays; adaptive therapy and evolutionary steering remain investigational.