Epigenomic profiling of primary gastric adenocarcinoma reveals super-enhancer heterogeneity.
Ooi WF., Xing M., Xu C., Yao X., Ramlee MK., Lim MC., Cao F., Lim K., Babu D., Poon LF., Lin Suling J., Qamra A., Irwanto A., Qu Zhengzhong J., Nandi T., Lee-Lim AP., Chan YS., Tay ST., Lee MH., Davies JO., Wong WK., Soo KC., Chan WH., Ong HS., Chow P., Wong CY., Rha SY., Liu J., Hillmer AM., Hughes JR., Rozen S., Teh BT., Fullwood MJ., Li S., Tan P.
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.