Speaker
Description
Circular, megabase-size, episomal DNA termed extrachromosomal DNA (ecDNA) drive the evolution of about 20% of all tumours, promoting oncogene heterogeneity and therapy resistance \cite{A,B,C}. While recent studies have elucidated its role in driving cell-to-cell phenotypic variation, little remains known about if, or how, the genomic structure of ecDNA itself evolves during tumour evolution. And yet, clinical observations suggest that it does \cite{D,E}. But how does this impact tumour evolution? Here, we utilised computational modelling to show that ecDNA-driven tumours evolve upon a fitness landscape spanned by ecDNA abundance and size, and that tumours optimise their ecDNA genomic structure to drive fitter phenotypes. We employ this model to explain the inverse relationship between ecDNA abundance and size observed across a range of human tumours. EcDNA fitness landscapes are tissue- and oncogene-specific, with common oncogene-amplifying ecDNAs, such as EGFR-ecDNA in glioblastoma or MYCN-ecDNA in neuroblastoma, displaying strong patterns of ecDNA structural optimisation, unlike weaker oncogenic ecDNAs. We show that HeLa cells traverse this fitness landscape in vitro by losing superfluous passenger genes on DHFR-amplifying ecDNAs in order to develop resistance to methotrexate. Overall, this work demonstrates that structural evolution of ecDNA itself drives tumour evolution and provides a framework for understanding oncogenesis and predicting treatment responses.
Bibliography
@article{A,
title = {Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity},
volume = {543},
copyright = {2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.},
issn = {1476-4687},
url = {https://www.nature.com/articles/nature21356},
doi = {10.1038/nature21356},
abstract = {Circular extrachromosomal DNA is found in nearly half of human cancers of a wide variety of histologic types, increasing the copy number of driver oncogenes and intratumoral heterogeneity more effectively than chromosomal amplification and contributing to tumor evolution.},
language = {en},
number = {7643},
urldate = {2022-10-10},
journal = {Nature},
publisher = {Nature Publishing Group},
author = {Turner, Kristen M. and Deshpande, Viraj and Beyter, Doruk and Koga, Tomoyuki and Rusert, Jessica and Lee, Catherine and Li, Bin and Arden, Karen and Ren, Bing and Nathanson, David A. and Kornblum, Harley I. and Taylor, Michael D. and Kaushal, Sharmeela and Cavenee, Webster K. and Wechsler-Reya, Robert and Furnari, Frank B. and Vandenberg, Scott R. and Rao, P. Nagesh and Wahl, Geoffrey M. and Bafna, Vineet and Mischel, Paul S.},
month = mar,
year = {2017},
note = {Number: 7643},
keywords = {Cancer genetics, Cancer},
pages = {122--125},
}
@article{B,
title = {Extrachromosomal {DNA} is associated with oncogene amplification and poor outcome across multiple cancers},
volume = {52},
copyright = {2020 The Author(s), under exclusive licence to Springer Nature America, Inc.},
issn = {1546-1718},
url = {https://www.nature.com/articles/s41588-020-0678-2},
doi = {10.1038/s41588-020-0678-2},
abstract = {Extrachromosomal DNA (ecDNA) amplification promotes intratumoral genetic heterogeneity and accelerated tumor evolution1–3; however, its frequency and clinical impact are unclear. Using computational analysis of whole-genome sequencing data from 3,212 cancer patients, we show that ecDNA amplification frequently occurs in most cancer types but not in blood or normal tissue. Oncogenes were highly enriched on amplified ecDNA, and the most common recurrent oncogene amplifications arose on ecDNA. EcDNA amplifications resulted in higher levels of oncogene transcription compared to copy number-matched linear DNA, coupled with enhanced chromatin accessibility, and more frequently resulted in transcript fusions. Patients whose cancers carried ecDNA had significantly shorter survival, even when controlled for tissue type, than patients whose cancers were not driven by ecDNA-based oncogene amplification. The results presented here demonstrate that ecDNA-based oncogene amplification is common in cancer, is different from chromosomal amplification and drives poor outcome for patients across many cancer types.},
language = {en},
number = {9},
urldate = {2022-10-10},
journal = {Nat Genet},
publisher = {Nature Publishing Group},
author = {Kim, Hoon and Nguyen, Nam-Phuong and Turner, Kristen and Wu, Sihan and Gujar, Amit D. and Luebeck, Jens and Liu, Jihe and Deshpande, Viraj and Rajkumar, Utkrisht and Namburi, Sandeep and Amin, Samirkumar B. and Yi, Eunhee and Menghi, Francesca and Schulte, Johannes H. and Henssen, Anton G. and Chang, Howard Y. and Beck, Christine R. and Mischel, Paul S. and Bafna, Vineet and Verhaak, Roel G. W.},
month = sep,
year = {2020},
note = {Number: 9},
keywords = {Cancer, Genetics research},
pages = {891--897},
}
@article{C,
title = {Targeted {Therapy} {Resistance} {Mediated} by {Dynamic} {Regulation} of {Extrachromosomal} {Mutant} {EGFR} {DNA}},
volume = {343},
url = {https://www.science.org/doi/10.1126/science.1241328},
doi = {10.1126/science.1241328},
number = {6166},
urldate = {2022-10-11},
journal = {Science},
publisher = {American Association for the Advancement of Science},
author = {Nathanson, David A. and Gini, Beatrice and Mottahedeh, Jack and Visnyei, Koppany and Koga, Tomoyuki and Gomez, German and Eskin, Ascia and Hwang, Kiwook and Wang, Jun and Masui, Kenta and Paucar, Andres and Yang, Huijun and Ohashi, Minori and Zhu, Shaojun and Wykosky, Jill and Reed, Rachel and Nelson, Stanley F. and Cloughesy, Timothy F. and James, C. David and Rao, P. Nagesh and Kornblum, Harley I. and Heath, James R. and Cavenee, Webster K. and Furnari, Frank B. and Mischel, Paul S.},
month = jan,
year = {2014},
pages = {72--76},
}
@article{D,
title = {Extrachromosomal {DNA} in the cancerous transformation of {Barrett}’s oesophagus},
volume = {616},
copyright = {2023 The Author(s)},
issn = {1476-4687},
url = {https://www.nature.com/articles/s41586-023-05937-5},
doi = {10.1038/s41586-023-05937-5},
abstract = {Oncogene amplification on extrachromosomal DNA (ecDNA) drives the evolution of tumours and their resistance to treatment, and is associated with poor outcomes for patients with cancer1–6. At present, it is unclear whether ecDNA is a later manifestation of genomic instability, or whether it can be an early event in the transition from dysplasia to cancer. Here, to better understand the development of ecDNA, we analysed whole-genome sequencing (WGS) data from patients with oesophageal adenocarcinoma (EAC) or Barrett’s oesophagus. These data included 206 biopsies in Barrett’s oesophagus surveillance and EAC cohorts from Cambridge University. We also analysed WGS and histology data from biopsies that were collected across multiple regions at 2 time points from 80 patients in a case–control study at the Fred Hutchinson Cancer Center. In the Cambridge cohorts, the frequency of ecDNA increased between Barrett’s-oesophagus-associated early-stage (24\%) and late-stage (43\%) EAC, suggesting that ecDNA is formed during cancer progression. In the cohort from the Fred Hutchinson Cancer Center, 33\% of patients who developed EAC had at least one oesophageal biopsy with ecDNA before or at the diagnosis of EAC. In biopsies that were collected before cancer diagnosis, higher levels of ecDNA were present in samples from patients who later developed EAC than in samples from those who did not. We found that ecDNAs contained diverse collections of oncogenes and immunomodulatory genes. Furthermore, ecDNAs showed increases in copy number and structural complexity at more advanced stages of disease. Our findings show that ecDNA can develop early in the transition from high-grade dysplasia to cancer, and that ecDNAs progressively form and evolve under positive selection.},
language = {en},
number = {7958},
urldate = {2024-04-26},
journal = {Nature},
publisher = {Nature Publishing Group},
author = {Luebeck, Jens and Ng, Alvin Wei Tian and Galipeau, Patricia C. and Li, Xiaohong and Sanchez, Carissa A. and Katz-Summercorn, Annalise C. and Kim, Hoon and Jammula, Sriganesh and He, Yudou and Lippman, Scott M. and Verhaak, Roel G. W. and Maley, Carlo C. and Alexandrov, Ludmil B. and Reid, Brian J. and Fitzgerald, Rebecca C. and Paulson, Thomas G. and Chang, Howard Y. and Wu, Sihan and Bafna, Vineet and Mischel, Paul S.},
month = apr,
year = {2023},
keywords = {Cancer genomics, Oncogenes, Oesophageal cancer},
pages = {798--805},
}
@article{E,
title = {Extrachromosomal {DNA}–{Driven} {Oncogene} {Spatial} {Heterogeneity} and {Evolution} in {Glioblastoma}},
volume = {15},
issn = {2159-8274},
url = {https://doi.org/10.1158/2159-8290.CD-24-1555},
doi = {10.1158/2159-8290.CD-24-1555},
abstract = {We study spatial patterns of ecDNA-amplified oncogenes and their evolutionary properties in human GBM, revealing an ecDNA landscape and ecDNA oncogene–specific evolutionary histories. ecDNA accumulation can precede clonal expansion, facilitating the emergence of EGFR oncogenic variants, reframing our interpretation of genomic data in a large subset of GBMs.See related commentary by Korsah et al., p. 1979},
number = {10},
urldate = {2025-11-25},
journal = {Cancer Discov},
author = {Noorani, Imran and Haughey, Magnus and Luebeck, Jens and Rowan, Andrew and Grönroos, Eva and Terenzi, Francesco and Wong, Ivy Tsz-Lo and Pradella, Davide and Lisi, Marta and Kittel, Jeanette and Sharma, Natasha and Bailey, Chris and Weeden, Clare E. and Bell, Donald M. and Joo, Eric and Barbè, Vittorio and Jones, Matthew G. and Hung, King L. and Nye, Emma L. and Green, Mary and Meader, Lucy and Norton, Emma J. and Fabian, Mark and Kanu, Nnennaya and Jamal-Hanjani, Mariam and Santarius, Thomas and Ventura, Andrea and Nicoll, James A.R. and Boche, Delphine and Chang, Howard Y. and Bafna, Vineet and Huang, Weini and Mischel, Paul S. and Swanton, Charles and Werner, Benjamin},
month = oct,
year = {2025},
pages = {2078--2095},
}
