Functional Enhancers Shape Extrachromosomal Oncogene Amplifications

• Published in: Cell Vol. 179; no. 6; pp. 1330 - 1341.e13
• Main Authors: Morton, Andrew R., Dogan-Artun, Nergiz, Faber, Zachary J., MacLeod, Graham, Bartels, Cynthia F., Piazza, Megan S., Allan, Kevin C., Mack, Stephen C., Wang, Xiuxing, Gimple, Ryan C., Wu, Qiulian, Rubin, Brian P., Shetty, Shashirekha, Angers, Stephane, Dirks, Peter B., Sallari, Richard C., Lupien, Mathieu, Rich, Jeremy N., Scacheri, Peter C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.11.2019
• Subjects: Acetylation; Cell Line, Tumor; Cell Survival - genetics; chromatin; Chromatin - metabolism; Chromosomes, Human - genetics; CRISPR-Cas Systems - genetics; DNA, Neoplasm - genetics; double minute; EGFR; enhancer; enhancer elements; Enhancer Elements, Genetic; epigenetic; ErbB Receptors - genetics; ErbB Receptors - metabolism; extrachromosomal DNA; Gene Amplification; gene editing; Genes, Neoplasm; Genetic Loci; glioblastoma; Glioblastoma - genetics; Glioblastoma - pathology; Histones - metabolism; Humans; intergenic DNA; loci; MYC; MYCN; Neuroglia - metabolism; oncogene amplification; Oncogenes; screening; enhancer; double minute; glioblastoma; MYCN; epigenetic; MYC; oncogene amplification; extrachromosomal DNA; EGFR
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2019.10.039

Non-coding regions amplified beyond oncogene borders have largely been ignored. Using a computational approach, we find signatures of significant co-amplification of non-coding DNA beyond the boundaries of amplified oncogenes across five cancer types. In glioblastoma, EGFR is preferentially co-amplified with its two endogenous enhancer elements active in the cell type of origin. These regulatory elements, their contacts, and their contribution to cell fitness are preserved on high-level circular extrachromosomal DNA amplifications. Interrogating the locus with a CRISPR interference screening approach reveals a diversity of additional elements that impact cell fitness. The pattern of fitness dependencies mirrors the rearrangement of regulatory elements and accompanying rewiring of the chromatin topology on the extrachromosomal amplicon. Our studies indicate that oncogene amplifications are shaped by regulatory dependencies in the non-coding genome. [Display omitted] •Enhancers active in the cell of origin are co-amplified with oncogenes•Circular extrachromosomal amplicons are associated with enhancer rewiring•Endogenous and new enhancers on amplicons contribute to cell proliferation•Skewed co-amplification that selects enhancers is found across several tumor types Extrachromosomal oncogene amplification is a common occurrence across a broad range of cancers, yet the chromatin landscape of these high-level amplifications is poorly understood. Using a combination of approaches to explore their chromatin topology and enhancer landscape, Morton et al. observed that these oncogene amplifications are shaped by regulatory dependencies in the non-coding genome.