1. Integrated paired-end enhancer profiling and whole-genome sequencing reveals recurrent CCNE1 and IGF2 enhancer hijacking in primary gastric adenocarcinoma.
- Author
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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, Lam YN, Teo JX, Kaneda A, White KP, Lim WK, Rozen SG, Teh BT, Li S, Skanderup AJ, and Tan P
- Subjects
- Adenocarcinoma genetics, Genomic Structural Variation genetics, Humans, Stomach Neoplasms genetics, Whole Genome Sequencing, Adenocarcinoma metabolism, Cyclin E metabolism, Enhancer Elements, Genetic genetics, Insulin-Like Growth Factor II metabolism, Oncogene Proteins metabolism, Stomach Neoplasms metabolism
- 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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2020
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