title: Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Choi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Francis
authors.affiliation: 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.
authors.forename: Marcin
authors.initials: M
authors.lastname: Imielinski
authors.affiliation: 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.
authors.forename: Hideo
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Cherniack
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.|Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Matthew
authors.identifier: http://orcid.org/0000-0002-9133-8108
authors.initials: M
authors.lastname: Meyerson
mesh_terms: D004742:Enhancer Elements, Genetic; D020022:Genetic Predisposition to Disease; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics*