Integrated paired-end enhancer profiling and whole-genome sequencing reveals recurrent CCNE1 and IGF2 enhancer hijacking in primary gastric adenocarcinoma. Issue 6 (21st September 2019)

• Record Type: Journal Article
• Authors: Ooi, Wen Fong; Nargund, Amrita M; Lim, Kevin Junliang; Zhang, Shenli; Xing, Manjie; Mandoli, Amit; Lim, Jing Quan; Ho, Shamaine Wei Ting; Guo, Yu; Yao, Xiaosai; Lin, Suling Joyce; Nandi, Tannistha; Xu, Chang; Ong, Xuewen; Lee, Minghui; Tan, Angie Lay-Keng; Lam, Yue Ning; Teo, Jing Xian; Kaneda, Atsushi; White, Kevin P; Lim, Weng Khong; Rozen, Steven G; Teh, Bin Tean; Li, Shang; Skanderup, Anders J; Tan, Patrick
• Is Part Of: Gut. Volume 69:Issue 6(2020)
• Page Start: 1039
• Page End: 1052
• Publication Date: 2019-09-21
• Subjects: gastric cancer; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2018-317612
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : 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.