Regulatory enhancer elements in solid tumours remain poorly characterized. Here we apply micro-scale chromatin profiling to survey the distal enhancer landscape of primary gastric adenocarcinoma (GC), a leading cause of global cancer mortality. Integrating 110 epigenomic profiles from primary GCs, normal gastric tissues and cell lines, we highlight 36,973 predicted enhancers and 3,759 predicted super-enhancers respectively. Cell-line-defined super-enhancers can be subclassified by their somatic alteration status into somatic gain, loss and unaltered categories, each displaying distinct epigenetic, transcriptional and pathway enrichments. Somatic gain super-enhancers are associated with complex chromatin interaction profiles, expression patterns correlated with patient outcome and dense co-occupancy of the transcription factors CDX2 and HNF4α. Somatic super-enhancers are also enriched in genetic risk SNPs associated with cancer predisposition. Our results reveal a genome-wide reprogramming of the GC enhancer and super-enhancer landscape during tumorigenesis, contributing to dysregulated local and regional cancer gene expression.
Bibliographical noteFunding Information:
We thank the Sequencing and Scientific Computing teams at the Genome Institute of Singapore for sequencing services and data management capabilities, and the Duke-NUS Genome Biology Facility for sequencing services. We also thank Ioana Cutcutache, Huang Kie Kyon, Longyu Hu, Niantao Deng, Simeen Malik and Nisha Padmanabhan for helpful discussions. This work was supported by core funding from the Genome Institute of Singapore under the Agency for Science, Technology and Research, Biomedical Research Council Young Investigator Grant 1510851024, National Medical Research Council grants TCR/009-NUHS/2013 and NMRC/STaR/0026/2015, Ministry of Education Academic Research Fund (AcRF) Tier 2 (MOE2014-T2-1-138), and by the National Research Foundation Singapore through an NRF Fellowship awarded to M.J.F (NRF-NRFF2012-054). J.R.H. was supported by a Wellcome Trust Strategic Award (reference 106130/Z/14/Z) and Medical Research Council (MRC) Core funding. J.O.J.D. was funded byWellcome Trust Clinical Research Training Fellowship ref 098931/Z/12/Z. Other sources of support include the RNA Biology Center at the Cancer Science Institute of Singapore, NUS, as part of funding under the Singapore Ministry of Education Academic Research Fund Tier 3, and by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative.
© 2016 The Author(s).
All Science Journal Classification (ASJC) codes
- Physics and Astronomy(all)
- Biochemistry, Genetics and Molecular Biology(all)