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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.

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


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.

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