FGFR2-anchored spatial transcriptomic programs reveal a stromal-enriched state associated with the genomically stable subtype in gastric cancer

Fibroblast growth factor receptor 2 ( FGFR2 ) is an oncogenic driver and therapeutic target in gastric cancer, but bulk profiling cannot resolve its intratumoral spatial organization. We investigated FGFR2 -anchored spatial states and their molecular, prognostic and pharmacogenomic correlates. We analyzed 10 × Genomics Visium data from 10 gastric-cancer sections (GSE251950; 26,557 post-quality-control spots), defined FGFR2 -high spots by within-section z score > 1, and tested sensitivity to threshold, sequencing depth and three hotspot-detection methods. Four 50-gene spatial signatures were projected into The Cancer Genome Atlas stomach adenocarcinoma (TCGA-STAD; n = 435) and Asian Cancer Research Group (ACRG; n = 295) cohorts and related to molecular subtype, survival, FGFR2 copy number and Cancer Dependency Map (DepMap) Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) drug-response data. FGFR2 expression showed positive spatial autocorrelation in 8 of 10 sections. FGFR2 -high spots were epithelial-dominant and adaptive-immune-poor with within-spot cancer-associated fibroblast (CAF) depletion, whereas the patient-level FGFR2 -Stromal subtype showed CAF, endothelial and extracellular-matrix enrichment. FGFR2 -Stromal was strongly associated with the genomically stable (GS) class (odds ratio = 4.64; P = 6.4 × 10 −7 ). Overall survival differed among TCGA-STAD spatial subtypes (log-rank P = 0.025), but the ACRG Stromal-versus-Proliferative association was significant in univariate analysis and attenuated after molecular-subtype adjustment (hazard ratio = 1.42; P = 0.065). Spatial subtype added modest discrimination beyond clinical variables (Δ Harrell's concordance index [C-index] ≈ + 0.016) and little beyond established tumor-microenvironment signatures (Δ ≈ + 0.001). A within-microsatellite-instability (MSI) signal was not reproduced in ACRG, and no PRISM compound reached significance in 37 gastric-origin cell lines. FGFR2 -anchored spatial programs reveal an epithelial-dominant, adaptive-immune-poor local state and a bulk-projected stromal state associated with the GS subtype. These computational findings are hypothesis-generating and require validation in balanced, higher-resolution and functionally annotated cohorts.