Clonal evolution in gastrointestinal cancers: multi-omics insights into tumor heterogeneity, microenvironmental selection, and translational biomarkers
TL;DR
This work discusses 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.
Abstract
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.