Integrated paired-end enhancer profiling and whole-genome sequencing reveals recurrent CCNE1
enhancer hijacking in primary gastric adenocarcinoma.
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).
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.
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.
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.
Ooi, WF; Nargund, AM; Lim, KJ; Zhang, S; Xing, M; Mandoli, A; Lim, JQ; Ho, SWT; Guo, Y; Yao, X; Lin, SJ; Nandi, T; Xu, C; Ong, X; Lee, M; Tan, AL-K; Lam, YN; Teo, JX; Kaneda, A; White, KP; Lim, WK; Rozen, SG; Teh, BT; Li, S; Skanderup, AJ; Tan, P
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