Principles of ecDNA random inheritance drive rapid genome change and therapy resistance in human cancers

Lange, Joshua T.; Chen, Celine; Pichugin, Yuriy; Xie, Liangqi; Tang, Jun; Hung, King L.; Yost, Kathryn E.; Shi, Quanming; Erb, Marcella L.; Rajkumar, Utkrisht; Wu, Sihan; Swanton, Charles; Liu, Zhe; Huang, Weini; Chang, Howard Y.; Bafna, Vineet; Henssen, Anton; Werner, Benjamin; Mischel, Paul S.

doi:10.1101/2021.06.11.447968

Cited by 15 publications

(13 citation statements)

References 31 publications

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“…However, the impact of nonchromosomal oncogene inheritance-random identity by descent-is not well understood. Recent research integrating mathematical modeling, unbiased image analysis, CRISPR-based ecDNA tagging, and live-cell imaging has revealed a set of basic "rules" for how random ecDNA inheritance drives oncogene copy number and distribution, resulting in extensive intratumoral ecDNA copy number heterogeneity and rapid adaptation to metabolic stress and targeted cancer treatments (48).…”

Section: Extrachromosomal Dna Mediates Rapid Tumor Evolutionmentioning

confidence: 99%

Extrachromosomal DNA: An Emerging Hallmark in Human Cancer

Bafna

Chang

et al. 2022

Annu. Rev. Pathol. Mech. Dis.

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Human genes are arranged on 23 pairs of chromosomes, but in cancer, tumor-promoting genes and regulatory elements can free themselves from chromosomes and relocate to circular, extrachromosomal pieces of DNA (ecDNA). ecDNA, because of its nonchromosomal inheritance, drives high-copy-number oncogene amplification and enables tumors to evolve their genomes rapidly. Furthermore, the circular ecDNA architecture fundamentally alters gene regulation and transcription, and the higher-order organization of ecDNA contributes to tumor pathogenesis. Consequently, patients whose cancers harbor ecDNA have significantly shorter survival. Although ecDNA was first observed more than 50 years ago, its critical importance has only recently come to light. In this review, we discuss the current state of understanding of how ecDNAs form and function as well as how they contribute to drug resistance and accelerated cancer evolution. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Section: Extrachromosomal Dna Mediates Rapid Tumor Evolutionmentioning

confidence: 99%

Extrachromosomal DNA: An Emerging Hallmark in Human Cancer

Bafna

Chang

et al. 2022

Annu. Rev. Pathol. Mech. Dis.

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“…Another form of accelerated evolution is mediated by ecDNAs. Because ecDNA fragments lack centromeres, the molecules are not attached to the mitotic spindle during cell division, leading to uneven segregation into daughter cells [119][120][121]. The resultant stochastic non-Mendelian inheritance leads to rapid and dynamic changes of oncogene content under selection pressure, in response to tumour microenvironment and targeted therapies, leading to treatment resistance [122][123][124][125].…”

Section: Structural Variation As a Critical Dimension In Tumour Evolu...mentioning

confidence: 99%

Unravelling the tumour genome: The evolutionary and clinical impacts of structural variants in tumourigenesis

Hamdan

Ewing

2022

The Journal of Pathology

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Structural variants (SVs) represent a major source of aberration in tumour genomes. Given the diversity in the size and type of SVs present in tumours, the accurate detection and interpretation of SVs in tumours is challenging. New classes of complex structural events in tumours are discovered frequently, and the definitions of the genomic consequences of complex events are constantly being refined. Detailed analyses of short-read whole-genome sequencing (WGS) data from large tumour cohorts facilitate the interrogation of SVs at orders of magnitude greater scale and depth. However, the inherent technical limitations of short-read WGS prevent us from accurately detecting and investigating the impact of all the SVs present in tumours. The expanded use of long-read WGS will be critical for improving the accuracy of SV detection, and in fully resolving complex SV events, both of which are crucial for determining the impact of SVs on tumour progression and clinical outcome. Despite the present limitations, we demonstrate that SVs play an important role in tumourigenesis. In particular, SVs contribute significantly to late-stage tumour development and to intratumoural heterogeneity. The evolutionary trajectories of SVs represent a window into the clonal dynamics in tumours, a comprehensive understanding of which will be vital for influencing patient outcomes in the future. Recent findings have highlighted many clinical applications of SVs in cancer, from early detection to biomarkers for treatment response and prognosis. As the methods to detect and interpret SVs improve, elucidating the full breadth of the complex SV landscape and determining how these events modulate tumour evolution will improve our understanding of cancer biology and our ability to capitalise on the utility of SVs in the clinical management of cancer patients.

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“…We and others recently identified ecDNA copy number dynamics as a driver of therapy resistance (Lange et al, 2021). Based on these observations, we anticipate that decreases in the number of DDX1 -containing ecDNA under mTORC1 inhibitor treatment could represent one way of treatment evasion in DDX1-MYCN -amplified cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Amplicon structure creates collateral therapeutic vulnerability in cancer

Bei

Brame

Kirchner

et al. 2022

Preprint

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Although DNA amplifications in cancers frequently harbor passenger genes alongside oncogenes, the functional consequence of such co-amplifications and their impact for therapy remains ill-defined. We discovered that passenger co-amplifications can create amplicon structure-specific collateral vulnerabilities. We present the DEAD-box helicase 1 (DDX1) gene as a bona fide passenger co-amplified with MYCN in cancers. Survival of cancer cells with DDX1 co-amplifications strongly depends on the mammalian target of rapamycin complex 1 (mTORC1). Mechanistically, aberrant DDX1 expression inhibits the tricarboxylic acid cycle through a previously unrecognized interaction with dihydrolipoamide S-succinyltransferase, a component of the alpha-ketoglutarate dehydrogenase complex. Cells expressing aberrant DDX1 levels compensate for the metabolic shift by enhancing mTORC1 activity. Consequently, pharmacological mTORC1 inhibition triggered cell death specifically in cells harboring the DDX1 co-amplification. This work highlights a significant contribution of passenger gene alterations to the therapeutic susceptibility of cancers.

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Principles of ecDNA random inheritance drive rapid genome change and therapy resistance in human cancers

Cited by 15 publications

References 31 publications

Extrachromosomal DNA: An Emerging Hallmark in Human Cancer

Extrachromosomal DNA: An Emerging Hallmark in Human Cancer

Unravelling the tumour genome: The evolutionary and clinical impacts of structural variants in tumourigenesis

Amplicon structure creates collateral therapeutic vulnerability in cancer

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