Epigenomic profiling of primary gastric adenocarcinoma reveals super-enhancer heterogeneity
Authors
Wen Fong Ooi ; Manjie Xing ; Chang Xu ; Xiaosai Yao ; Muhammad Khairul Ramlee ; Mei Chee Lim ; Fan Cao ; Kevin Lim ; Deepak Babu ; Lai-Fong Poon ; Joyce Lin Suling ; Aditi Qamra ; Astrid Irwanto ; James Qu Zhengzhong ; Tannistha Nandi ; Ai Ping Lee-Lim ; Yang Sun Chan ; Su Ting Tay ; Ming Hui Lee ; James O.J. Davies ; Wai Keong Wong ; Khee Chee Soo ; Weng Hoong Chan ; Hock Soo Ong ; Pierce Chow ; Chow Yin Wong ; Sun Young Rha ; Jianjun Liu ; Axel M. Hillmer ; Jim R. Hughes ; Steve Rozen ; Bin Tean Teh ; Melissa Jane Fullwood ; Shang Li ; Patrick Tan ; Regulatory enhancer
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.