Integrated paired-end enhancer profiling and whole-genome sequencing reveals recurrent CCNE1 and IGF2 enhancer hijacking in primary gastric adenocarcinoma.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • June 2020

Published In

Volume / Issue

  • 69 / 6

Start / End Page

  • 1039 - 1052

PubMed ID

  • 31542774

Electronic International Standard Serial Number (EISSN)

  • 1468-3288

International Standard Serial Number (ISSN)

  • 0017-5749

Digital Object Identifier (DOI)

  • 10.1136/gutjnl-2018-317612

Language

  • eng