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.