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Nat Genet. 2016 Feb;48(2):176-82. doi: 10.1038/ng.3470. Epub 2015 Dec 14.

Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
2
Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
3
Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
4
Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
5
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
6
Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
7
Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Abstract

Whole-genome analysis approaches are identifying recurrent cancer-associated somatic alterations in noncoding DNA regions. We combined somatic copy number analysis of 12 tumor types with tissue-specific epigenetic profiling to identify significant regions of focal amplification harboring super-enhancers. Copy number gains of noncoding regions harboring super-enhancers near KLF5, USP12, PARD6B and MYC are associated with overexpression of these cancer-related genes. We show that two distinct focal amplifications of super-enhancers 3' to MYC in lung adenocarcinoma (MYC-LASE) and endometrial carcinoma (MYC-ECSE) are physically associated with the MYC promoter and correlate with MYC overexpression. CRISPR/Cas9-mediated repression or deletion of a constituent enhancer within the MYC-LASE region led to significant reductions in the expression of MYC and its target genes and to the impairment of anchorage-independent and clonogenic growth, consistent with an oncogenic function. Our results suggest that genomic amplification of super-enhancers represents a common mechanism to activate cancer driver genes in multiple cancer types.

PMID:
26656844
PMCID:
PMC4857881
DOI:
10.1038/ng.3470
[Indexed for MEDLINE]
Free PMC Article

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