Spatiotemporal genomic profiling of intestinal metaplasia reveals clonal dynamics of gastric cancer progression

Cancer Cell. 2023 Dec 11;41(12):2019-2037.e8. doi: 10.1016/j.ccell.2023.10.004. Epub 2023 Oct 26.


Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. Analyzing 1,256 gastric samples (1,152 IMs) across 692 subjects from a prospective 10-year study, we identify 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9). Single-cell and spatial profiles highlight changes in tissue ecology and IM lineage heterogeneity, including an intestinal stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling reveals expression-based molecular subtypes of IM associated with incomplete histology, antral/intestinal cell types, ARID1A mutations, inflammation, and microbial communities normally associated with the healthy oral tract. We demonstrate that combined clinical-genomic models outperform clinical-only models in predicting IMs likely to transform to GC. By highlighting strategies for accurately identifying IM patients at high GC risk and a role for microbial dysbiosis in IM progression, our results raise opportunities for GC precision prevention and interception.

Keywords: cancer screening; cell-of-origin; gastric cancer; intestinal metaplasia; pre-cancer; single-cell sequencing; spatial transcriptomics; targeted DNA sequencing; transcriptome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gastric Mucosa / pathology
  • Genomics
  • Humans
  • Metaplasia / genetics
  • Precancerous Conditions* / genetics
  • Prospective Studies
  • Stomach Neoplasms* / genetics
  • Stomach Neoplasms* / metabolism