@article {68368,
	title = {The evolutionary dynamics of extrachromosomal DNA in human cancers.},
	journal = {Nature Genetics},
	year = {2022},
	month = {2022 Sep 19},
	abstract = {<p>Oncogene amplification on extrachromosomal DNA (ecDNA) is a common event, driving aggressive tumor growth, drug resistance and shorter survival. Currently, the impact of nonchromosomal oncogene inheritance-random identity by descent-is poorly understood. Also unclear is the impact of ecDNA on somatic variation and selection. Here integrating theoretical models of random segregation, unbiased image analysis, CRISPR-based ecDNA tagging with live-cell imaging and CRISPR-C, we demonstrate that random ecDNA inheritance results in extensive intratumoral ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted treatment. Observed ecDNAs benefit host cell survival or growth and can change within a single cell cycle. ecDNA inheritance can predict, a priori, some of the aggressive features of ecDNA-containing cancers. These properties are facilitated by the ability of ecDNA to rapidly adapt genomes in a way that is not possible through chromosomal oncogene amplification. These results show how the nonchromosomal random inheritance pattern of ecDNA contributes to poor outcomes for patients with cancer.</p>
},
	issn = {1546-1718},
	doi = {10.1038/s41588-022-01177-x},
	author = {Lange, Joshua T and Rose, John C and Chen, Celine Y and Pichugin, Yuriy and Xie, Liangqi and Tang, Jun and Hung, King L and Yost, Kathryn E and Shi, Quanming and Erb, Marcella L and Rajkumar, Utkrisht and Wu, Sihan and Taschner-Mandl, Sabine and Bernkopf, Marie and Swanton, Charles and Liu, Zhe and Huang, Weini and Chang, Howard Y and Bafna, Vineet and Henssen, Anton G and Werner, Benjamin and Mischel, Paul S}
}
@article {67806,
	title = {ecDNA hubs drive cooperative intermolecular oncogene expression.},
	journal = {Nature},
	volume = {600},
	year = {2021},
	month = {2021 Dec 01},
	pages = {731-6},
	abstract = {<p>Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high expression of oncogenes through gene amplification and altered gene regulation. Gene induction typically involves cis-regulatory elements that contact and activate genes on the same chromosome. Here we show that ecDNA hubs-clusters of around 10-100 ecDNAs within the nucleus-enable intermolecular enhancer-gene interactions to promote oncogene overexpression. ecDNAs that encode multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumours. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the bromodomain and extraterminal domain (BET) protein BRD4 in a MYC-amplified colorectal cancer cell line. The BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-derived-oncogene transcription. The BRD4-bound PVT1 promoter is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent expression of MYC. Furthermore, the PVT1 promoter on an exogenous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic silencing of ecDNA enhancers by CRISPR interference reveals intermolecular enhancer-gene activation among multiple oncogene loci that are amplified on distinct ecDNAs. Thus, protein-tethered ecDNA hubs enable intermolecular transcriptional regulation and may serve as units of oncogene function and cooperative evolution and as potential targets for cancer therapy.</p>
},
	issn = {1476-4687},
	doi = {10.1038/s41586-021-04116-8},
	author = {Hung, King L and Yost, Kathryn E and Xie, Liangqi and Shi, Quanming and Helmsauer, Konstantin and Luebeck, Jens and Sch{\"o}pflin, Robert and Lange, Joshua T and Chamorro Gonz{\'a}lez, Roc{\'\i}o and Weiser, Natasha E and Chen, Celine and Valieva, Maria E and Wong, Ivy Tsz-Lo and Wu, Sihan and Dehkordi, Siavash R and Duffy, Connor V and Kraft, Katerina and Tang, Jun and Belk, Julia A and Rose, John C and Corces, M Ryan and Granja, Jeffrey M and Li, Rui and Rajkumar, Utkrisht and Friedlein, Jordan and Bagchi, Anindya and Satpathy, Ansuman T and Tjian, Robert and Mundlos, Stefan and Bafna, Vineet and Henssen, Anton G and Mischel, Paul S and Liu, Zhe and Chang, Howard Y}
}
