Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers.
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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. |
Year of Publication | 2016
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Journal | Nat Genet
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Volume | 48
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Issue | 2
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Pages | 176-82
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Date Published | 2016 Feb
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ISSN | 1546-1718
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URL | |
DOI | 10.1038/ng.3470
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PubMed ID | 26656844
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PubMed Central ID | PMC4857881
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Grant list | F32 CA180662 / CA / NCI NIH HHS / United States
R35 CA197568 / CA / NCI NIH HHS / United States
1F32CA180662 / CA / NCI NIH HHS / United States
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