Functional Enhancers Shape Extrachromosomal Oncogene Amplifications

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-ampli...

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Bibliographic Details
Published in:Cell Vol. 179; no. 6; p. 1330
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 27.11.2019
Subjects:
Acetylation
Cell Line, Tumor
Cell Survival - genetics
Chromatin - metabolism
Chromosomes, Human - genetics
CRISPR-Cas Systems - genetics
DNA, Neoplasm - genetics
Enhancer Elements, Genetic
ErbB Receptors - genetics
ErbB Receptors - metabolism
Gene Amplification
Genes, Neoplasm
Genetic Loci
Glioblastoma - genetics
Glioblastoma - pathology
Histones - metabolism
Humans
Neuroglia - metabolism
Oncogenes
enhancer
MYCN
double minute
glioblastoma
epigenetic
MYC
oncogene amplification
extrachromosomal DNA
EGFR
ISSN:1097-4172, 1097-4172
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Summary: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.
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2019.10.039