Faculty, Staff and Student Publications

Publication Date

12-11-2023

Journal

Cancer Cell

DOI

10.1016/j.ccell.2023.10.004

PMID

37890493

PMCID

PMC10729843

PubMedCentral® Posted Date

December 2023

PubMedCentral® Full Text Version

Post-print

Abstract

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

Humans, Stomach Neoplasms, Prospective Studies, Gastric Mucosa, Genomics, Metaplasia, Precancerous Conditions, gastric cancer, intestinal metaplasia, pre-cancer, targeted DNA sequencing, transcriptome sequencing, single-cell sequencing, spatial transcriptomics, cancer screening, cell-of-origin

Published Open-Access

yes

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