Epigenomic profiling of primary gastric adenocarcinoma reveals super-enhancer heterogeneity

Abstract

Regulatory enhancer elements in solid tumours remain poorly characterized. Here we apply micro-scale chromatin profiling to survey the distal enhancer landscape of primary gastric adenocarcinoma (GC), a leading cause of global cancer mortality. Integrating 110 epigenomic profiles from primary GCs, normal gastric tissues and cell lines, we highlight 36,973 predicted enhancers and 3,759 predicted super-enhancers respectively. Cell-line-defined super-enhancers can be subclassified by their somatic alteration status into somatic gain, loss and unaltered categories, each displaying distinct epigenetic, transcriptional and pathway enrichments. Somatic gain super-enhancers are associated with complex chromatin interaction profiles, expression patterns correlated with patient outcome and dense co-occupancy of the transcription factors CDX2 and HNF4α. Somatic super-enhancers are also enriched in genetic risk SNPs associated with cancer predisposition. Our results reveal a genome-wide reprogramming of the GC enhancer and super-enhancer landscape during tumorigenesis, contributing to dysregulated local and regional cancer gene expression.

Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene

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Hotspots of aberrant enhancer activity in fibrolamellar carcinoma reveal molecular mechanisms of oncogenesis and intrinsic drug resistance

“…enhancers) stratify FLC from NML samples better than transcription at proximal TREs or gene bodies, similar to previous reports (Corces et al, 2016(Corces et al, , 2018. These findings are consistent with other studies (Franco et al, 2018;Van Groningen et al, 2017;Ooi et al, 2016) that have shown enhancer activity is more sensitive than gene expression for sample classification (e.g., tumor-normal, tumor subtypes, cell types). Unlike other methods to identify enhancers, such as assay for transposaseaccessible chromatin using sequencing (ATAC-seq) or chromatin immunoprecipitation and sequencing (ChIP-seq) for enhancer-associated histone modifications or proteins, ChRO-seq identifies active regulatory elements as well as actively transcribed genes.…”

Winding back Wnt signalling: potential therapeutic targets for treating gastric cancers

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