Faculty, Staff and Student Publications
Publication Date
12-11-2023
Journal
Cancer Cell
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
Graphical Abstract
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Digestive System Diseases Commons, Gastroenterology Commons, Medical Sciences Commons, Oncology Commons
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Associated Data
PMID: 37890493