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Background  Enhancers are distal  cis -regulatory elements required for cell-specific gene expression and cell fate determination. In cancer, enhancer variation has been proposed as a major cause of inter-patient heterogeneity—however, most predicted enhancer regions remain to be functionally tested.    Methods  We analyzed 132 epigenomic histone modification profiles of 18 primary gastric cancer (GC) samples, 18 normal gastric tissues, and 28 GC cell lines using Nano-ChIP-seq technology. We applied Capture-based Self-Transcribing Active Regulatory Region sequencing (CapSTARR-seq) to assess functional enhancer activity. An Activity-by-contact (ABC) model was employed to explore the effects of histone acetylation and CapSTARR-seq levels on enhancer-promoter interactions.    Results  We report a comprehensive catalog of 75,730 recurrent predicted enhancers, the majority of which are GC-associated  in vivo  (> 50,000) and associated with lower somatic mutation rates inferred by whole-genome sequencing. Applying CapSTARR-seq to the enhancer catalog, we observed significant correlations between CapSTARR-seq functional activity and H3K27ac/H3K4me1 levels. Super-enhancer regions exhibited increased CapSTARR-seq signals compared to regular enhancers, even when decoupled from native chromatin contexture. We show that combining histone modification and CapSTARR-seq functional enhancer data improves the prediction of enhancer-promoter interactions and pinpointing of germline single nucleotide polymorphisms (SNPs), somatic copy number alterations (SCNAs), and  trans -acting TFs involved in GC expression. We identified cancer-relevant genes ( ING1 ,  ARL4C ) whose expression between patients is influenced by enhancer differences in genomic copy number and germline SNPs, and  HNF4α  as a master  trans -acting factor associated with GC enhancer heterogeneity.    Conclusions  Our results indicate that combining histone modification and functional assay data may provide a more accurate metric to assess enhancer activity than either platform individually, providing insights into the relative contribution of genetic ( cis ) and regulatory ( trans ) mechanisms to GC enhancer functional heterogeneity.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13073-021-00970-3.

Integrative epigenomic and high-throughput functional enhancer profiling reveals determinants of enhancer heterogeneity in gastric cancer