GENOMIC VARIANTS AND VARIOUS TF BINDING ENRICHMENT RESULT IN ENHANCER HETEROGENEITY IN GASTRIC ADENOCARCINOMA

Abstract

Enhancer variation has been proposed as a major cause of cancer heterogeneity – however, mechanisms driving patient-specific enhancer cartographies remain unclear. Analyzing 128 epigenomic histone modification profiles of primary GC samples, normal gastric tissues, and GC cell lines, we report a comprehensive catalog of 75,730 recurrent predicted enhancers. Applying Capture-based Self-Transcribing Active Regulatory Region sequencing (CapSTARR-seq) to the enhancer catalog, we observed significant correlations between CapSTARR-seq functional activity and H3K27ac/H3K4me1 levels. We show that combining histone modification and CapSTARR-seq 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. This study indicates that combining histone modification and functional assay data may provide a more accurate metric to assess enhancer activity than either platform individually, and provides insights into the relative contribution of genetic and regulatory mechanisms to GC enhancer functional heterogeneity.