Journal: Cancer discovery
This study characterizes the genomic and microenvironmental landscape of gastric intestinal metaplasia (IM), a premalignant precursor to gastric cancer, using high-depth targeted sequencing of >1,500 IM samples from six countries, along with whole-genome sequencing and DNA methylation profiling.
Key findings:
1. Recurrently mutated genes in IM
- Identified 47 significantly mutated genes.
- Notable drivers include:
- ARID1A – associated with higher-risk populations and worse prognosis.
- KRAS/MAPK pathway genes – KRAS, BRAF, MAP2K1, MAP3K1, MAP2K4.
- PIGR – implicating altered mucosal immunity in IM biology.
2. Mutational signature specific to IM
- An IM-specific mutational signature, SBS17, separates IM from normal gastric tissue.
- SBS17 is associated with:
- Late DNA replication timing,
- Genomic hypomethylation,
- Tobacco exposure.
3. Clonal hematopoiesis (CH) in patients with IM
- Patients with IM show elevated CH, linked to:
- Older age,
- Smoking,
- Increased risk of progression to gastric cancer.
- CH expansions co-occur with:
- Truncating PIGR mutations in IM epithelium.
- Greater colonization of IM lesions by orally derived bacteria.
4. Proposed biology and translational implications
- The data suggest that nonepithelial somatic alterations (CH) can influence IM progression, likely by modulating host–microbe mucosal immunity.
- This opens avenues for:
- Early detection strategies incorporating CH and IM genomic markers.
- Interception approaches targeting mucosal immunity and microbiome interactions in high-risk IM.