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

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
Lam YN
Teo JX
Kaneda A
White KP
Lim WK
Rozen SG
Teh BT
Li S
Skanderup AJ
Tan P
Source :
Gut [Gut] 2020 Jun; Vol. 69 (6), pp. 1039-1052. Date of Electronic Publication: 2019 Sep 21.
Publication Year :
2020

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).<br />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.<br />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.<br />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.<br />Competing Interests: Competing interests: None declared.<br /> (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Details

Language :
English
ISSN :
1468-3288
Volume :
69
Issue :
6
Database :
MEDLINE
Journal :
Gut
Publication Type :
Academic Journal
Accession number :
31542774
Full Text :
https://doi.org/10.1136/gutjnl-2018-317612