RT Journal Article SR Electronic T1 Integrated paired-end enhancer profiling and whole-genome sequencing reveals recurrent CCNE1 and IGF2 enhancer hijacking in primary gastric adenocarcinoma JF Gut JO Gut FD BMJ Publishing Group Ltd and British Society of Gastroenterology SP 1039 OP 1052 DO 10.1136/gutjnl-2018-317612 VO 69 IS 6 A1 Wen Fong Ooi A1 Amrita M Nargund A1 Kevin Junliang Lim A1 Shenli Zhang A1 Manjie Xing A1 Amit Mandoli A1 Jing Quan Lim A1 Shamaine Wei Ting Ho A1 Yu Guo A1 Xiaosai Yao A1 Suling Joyce Lin A1 Tannistha Nandi A1 Chang Xu A1 Xuewen Ong A1 Minghui Lee A1 Angie Lay-Keng Tan A1 Yue Ning Lam A1 Jing Xian Teo A1 Atsushi Kaneda A1 Kevin P White A1 Weng Khong Lim A1 Steven G Rozen A1 Bin Tean Teh A1 Shang Li A1 Anders J Skanderup A1 Patrick Tan YR 2020 UL http://gut.bmj.com/content/69/6/1039.abstract AB Objective Genomic structural variations (SVs) causing rewiring of cis-regulatory elements remain largely unexplored in gastric cancer (GC). To identify SVs affecting enhancer elements in GC (enhancer-based SVs), we integrated epigenomic enhancer profiles revealed by paired-end H3K27ac ChIP-sequencing from primary GCs with tumour whole-genome sequencing (WGS) data (PeNChIP-seq/WGS).Design We applied PeNChIP-seq to 11 primary GCs and matched normal tissues combined with WGS profiles of >200 GCs. Epigenome profiles were analysed alongside matched RNA-seq data to identify tumour-associated enhancer-based SVs with altered cancer transcription. Functional validation of candidate enhancer-based SVs was performed using CRISPR/Cas9 genome editing, chromosome conformation capture assays (4C-seq, Capture-C) and Hi-C analysis of primary GCs.Results PeNChIP-seq/WGS revealed ~150 enhancer-based SVs in GC. The majority (63%) of SVs linked to target gene deregulation were associated with increased tumour expression. Enhancer-based SVs targeting CCNE1, a key driver of therapy resistance, occurred in 8% of patients frequently juxtaposing diverse distal enhancers to CCNE1 proximal regions. CCNE1-rearranged GCs were associated with high CCNE1 expression, disrupted CCNE1 topologically associating domain (TAD) boundaries, and novel TAD interactions in CCNE1-rearranged primary tumours. We also observed IGF2 enhancer-based SVs, previously noted in colorectal cancer, highlighting a common non-coding genetic driver alteration in gastric and colorectal malignancies.Conclusion Integrated paired-end NanoChIP-seq and WGS of gastric tumours reveals tumour-associated regulatory SV in regions associated with both simple and complex genomic rearrangements. Genomic rearrangements may thus exploit enhancer-hijacking as a common mechanism to drive oncogene expression in GC.