Mutational Signatures and Clonal Hematopoiesis in Intestinal Metaplasia across Countries with Varying Stomach Cancer Incidence

Intestinal metaplasia (IM) is a premalignant condition associated with increased risk of gastric cancer-a deadly malignancy with varying geographic incidence. High-depth targeted sequencing of more than 1,500 IM samples from six countries identified 47 significantly mutated genes, including driver genes associated with high-risk populations and worse prognosis (ARID1A), KRAS/MAPK signaling (KRAS, BRAF, MAP2K1, MAP3K1, and MAP2K4), and altered mucosal immunity (PIGR). IM whole-genome sequencing and DNA methylation analysis revealed SBS17 as a specific mutational signature separating IMs from normal gastric tissues, associated with late DNA replication, genomic hypomethylation, and tobacco exposure. Beyond epithelial-derived somatic mutations, we observed elevated clonal hematopoiesis (CH) in patients with IM associated with age, smoking, and enhanced risk of progressing to gastric cancer. Patients with CH expansions exhibited co-occurring IM PIGR truncating mutations and greater colonization of the IM microenvironment by orally derived bacteria, suggesting that CH may promote IM progression by modulating host-microbe mucosal immunity. SIGNIFICANCE: This international study identifies recurrent IM driver genes, IM-specific mutational signatures, and alterations in IM-associated immune landscapes and microbiomes. Our results highlight a role for nonepithelial somatic alterations (CH) in IM progression to gastric cancer, offering new translational opportunities for early cancer detection and interception.