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October 16, 2019  |  Jola Glotzer

Enhancer-hijacking in gastric cancer

CBC Senior Investigator Kevin White, UChicago and Tempus, contributes to a recently published study about the role and the type of genomic rearrangements in the pathogenesis of gastric cancer

CBC Senior Investigator, Kevin White, UChicago and Tempus, is a co-author on the Gut publication

Gastric cancer (GC) is a leading cause of global cancer mortality with high incidence in East Asia, Eastern Europe and Central/South America, thereby understanding its underlying genomic components is crucial from both diagnostic and therapeutic perspectives. A recent study published in the journal Gut entitled “Integrated paired-end enhancer profiling and whole-genome sequencing reveals recurrent CCNE1 and IGF2 enhancer hijacking in primary gastric adenocarcinoma,” suggesting that disruptions and malfunctions of gene cis-regulatory elements at these loci occur in GC and play a role in its pathogenesis.

Using two complementary methods, paired-end H3K27ac ChIP-sequencing (PeNChIP-seq) and whole-genome sequencing (WGS), the authors identified ~150 GC enhancer-based SVs and observed recurrent enhancer-hijacking events at two genes previously implicated in CG pathogenesis, CCNE1 (8%) and IGF2 (4%). Such genomic rearrangements due to enhancer-hijacking are discussed as a potential common mechanism to drive oncogene expression in GC.

Kevin White, currently Chief Scientific Officer of biotech start-up Tempus Labs, is one of the co-authors on the paper. White was recruited to UChicago in 2006 with the help of a generous CBC Resources Fund Award and was also designated the first CBC Senior Investigator. In addition, he received a CBC Lever Award (2008) for the project: “Chicago Center for Systems Biology (CCSB).” White participated in the CBC Science Day (2011) and the 4th Annual CBC Symposium (2006) on “Infrastructures for Systems Biology.” He also served on the CBC Proteomics Informatics Scientific Board (2007-2009) and the CBC Spark Council (2008-2011). The CBC is grateful for Kevin’s time and dedication serving on CBC boards and for his support of the CBC programs and mission.

Publication linked to *CBC funding:

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. Integrated paired-end enhancer profiling and whole-genome sequencing reveals recurrent CCNE1 and IGF2 enhancer hijacking in primary gastric adenocarcinoma. Gut. 2019 Sep 21. [Epub ahead of print] (PubMed)

ABSTRACT:

Landscape of GC enhancer-based SVs using PeNChIP-seq and WGS. (A) Distribution of tumour-associated enhancer-based SVs by rearrangement classes (complex variants, tandem duplications, deletions and inversions). (B) Fraction of tumour-associated enhancer-based SVs with deregulated target gene expression by rearrangement classes. Yellow dotted boxes correspond to classes where the proportion of enhancer-based SVs associated with deregulated target gene expression is significant (empirical p value <0.05). Target genes were deemed deregulated if they exhibited at least fourfold difference in matched RNA-seq profiles and >1.0 FPKM difference. (Source: Gut)

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.

Featured CBC Community member(s):

Kevin White, UChicago

ARTICLES PUBLISHED IN THE PAST ABOUT THE FEATURED CBC COMMUNITY MEMBER(S):

August 5, 2019
▸ Pathogenesis of sun-protected melanomas
CBC Senior Investigator, Kevin White, UChicago (currently Tempus), investigates genetic heterogeneity of sun-protected melanomas

June 13, 2019
▸ Germline genetic risk variants and carcinogenesis
Kevin White, CBC Senior Investigator, UChicago and President of Tempus Labs, contributed to a recent study in the International Journal of Cancer, which examined associations between germline variants and somatic mutation signatures in breast cancer across diverse populations and geographic locations

June 7, 2019
▸ Noncoding RNA and cancer
CBC Senior Investigator, Kevin White, UChicago and Tempus, demonstrates that post-transcriptional editing of noncoding RNA, seen in many types of cancers, may actually play a role in carcinogenesis itself

May 22, 2018
▸ “Oligometastasis,” or a cancer that has metastasized but just to a few sites, not globally, is still treatable. CBC Senior Investigator, Kevin White, UChicago, contributes to the discovery.

March 28, 2018
▸ In 2006, CBC invested $1 million to help recruit Kevin White to UChicago. Twelve years later, White is president of Tempus, a Chicago-based health technology company, that has now reached ‘unicorn’ status!

November 11, 2017
▸ Chicago-based Tempus shows why Midwest healthcare companies drew preferential investment in 2017

November 5, 2017
▸ CBC cancer researchers and Globus will develop a HIPAA-protected cloud database to share collaborative cancer research

February 1, 2017
▸ January 2017 CBC-funded publications
Twenty peer-reviewed research papers acknowledging CBC funding were published in January 2017. Congratulations to all!

March 24, 2014
▸ Study Reveals a Major Mechanism Driving Kidney Cancer Progression
Misplaced protein provides promising drug target

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