Zhang, XiaoyangChoi, PeterFrancis, Joshua M.Imielinski, MarcinWatanabe, HideoCherniack, Andrew D.Meyerson, Matthew2016-07-142016Zhang, Xiaoyang, Peter S. Choi, Joshua M. Francis, Marcin Imielinski, Hideo Watanabe, Andrew D. Cherniack, and Matthew Meyerson. 2016. “Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers.” Nature genetics 48 (2): 176-182. doi:10.1038/ng.3470. http://dx.doi.org/10.1038/ng.3470.1061-4036http://nrs.harvard.edu/urn-3:HUL.InstRepos:27662049Whole genome analysis approaches are revealing recurrent cancer-associated somatic alterations in non-coding 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 non-coding regions harboring super-enhancers near KLF5, USP12, PARD6B and MYC are associated with over-expression 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 over-expression. 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 demonstrate that genomic amplification of super-enhancers represents a common mechanism to activate cancer driver genes in multiple cancer types.en-USJournal Article2016-07-1410.1038/ng.3470