Comprehensive genetic and molecular profiling have previously identified new molecular subtypes and genetic drivers of gastric adenocarcinoma19–21. Studies have also investigated the extent and impact of mutational signatures22,23 and epigenetic dysregulation in gastric cancer (GC) genomes24,25. Yet, it is unknown to what extent mutations in specific non-coding elements may drive GC, a leading cause of global cancer mortality. Here, we performed uniform and accurate identification of somatic single nucleotide variants (SNVs) and insertions/deletions (indels) in 212 GC genomes using an ensemble mutation calling approach. We present a comprehensive statistical approach, incorporating both epigenetic and sequence covariates, to identify non-coding regions with significantly higher mutation burdens over background, indicating positive selection and a role in gastric tumorigenesis. Performing an unbiased genome-wide scan of focal mutation hotspots (~20 bp, as TF binding motifs are typically <20 bp), we detect 34 significant recurring non-coding hotspots—of these, 11 overlapped CBSs. We further characterize these sites by analyzing CBS specific mutation biases, gene expression of neighboring genes, chromosomal instability, and incidence of these mutations in other cancer types. Overall, our analyses nominate these CBS hotspots as candidate drivers of GC. Furthermore, our analysis suggests a general link between CBS mutations and chromosomal instability in gastrointestinal cancers.