Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1527-1533 |
| Number of pages | 7 |
| Journal | Nature genetics |
| Volume | 54 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 2022 |
ASJC Scopus subject areas
- Genetics
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The evolutionary dynamics of extrachromosomal DNA in human cancers. / Lange, Joshua T.; Rose, John C.; Chen, Celine Y. et al.
In: Nature genetics, Vol. 54, No. 10, 10.2022, p. 1527-1533.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - The evolutionary dynamics of extrachromosomal DNA in human cancers
AU - Lange, Joshua T.
AU - Rose, John C.
AU - Chen, Celine Y.
AU - Pichugin, Yuriy
AU - Xie, Liangqi
AU - Tang, Jun
AU - Hung, King L.
AU - Yost, Kathryn E.
AU - Shi, Quanming
AU - Erb, Marcella L.
AU - Rajkumar, Utkrisht
AU - Wu, Sihan
AU - Taschner-Mandl, Sabine
AU - Bernkopf, Marie
AU - Swanton, Charles
AU - Liu, Zhe
AU - Huang, Weini
AU - Chang, Howard Y.
AU - Bafna, Vineet
AU - Henssen, Anton G.
AU - Werner, Benjamin
AU - Mischel, Paul S.
N1 - Funding Information: The eDyNAmiC research was facilitated by Cancer Grand Challenges (grant no. CGCSDF-2021\100007) with support from Cancer Research UK and the National Cancer Institute. This study was supported by a grant from the National Brain Tumour Society and National Institutes of Health (NIH) grant no. R01-CA238349 to P.S.M. H.Y.C. is an investigator of the Howard Hughes Medical Institute and was also supported by NIH grant no. R35-CA209919. A Barts Charity Lectureship MGU045 and UKRI Future Leaders Fellowship supported B.W. The UCSD microscopy core is supported by National Institute of Neurological Disorders and Stroke (no. NS047101). NIH grant nos. U24CA264379 and 1R01GM114362 supported V.B. The A.P. Giannini Foundation supported J.C.R. The German Research Foundation (grant no. 398299703) supported A.G.H. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant no. 949172). The Cancer Prevention and Research Institute of Texas (no. RR210034) supported S.W. We thank C. Zhang from the Howard Chang Laboratory for providing technical assistance with the CRISPR-C experiments. C.S. is a Royal Society Napier Research Professor (no. RSRP\R\210001). This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (no. FC001169), the UK Medical Research Council (no. FC001169) and the Wellcome Trust (no. FC001169). This research was funded in whole, or in part, by the Wellcome Trust (no. FC001169). For the purpose of open access, the authors applied a CC BY public copyright licence to any author-accepted manuscript version arising from this submission. C.S. is funded by Cancer Research UK (TRACERx (no. C11496/A17786), PEACE (C416/A21999) and CRUK Cancer Immunotherapy Catalyst Network), Cancer Research UK Lung Cancer Centre of Excellence (no. C11496/A30025), the Rosetrees Trust, Butterfield and Stoneygate Trusts, NovoNordisk Foundation (ID16584), Royal Society Professorship Enhancement Award (no. RP/EA/180007), the National Institute for Health Research Biomedical Research Centre at University College London Hospitals, the Cancer Research UK-University College London Centre, Experimental Cancer Medicine Centre and the Breast Cancer Research Foundation (no. BCRF 20-157). This work was supported by a Stand Up To Cancer (SU2C)‐LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (grant no. SU2C-AACR-DT23-17 to S. M. Dubinett and A. E. Spira). SU2C is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C.S. is in receipt of an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant no. 835297). Funding from the Vienna Science and Technology Fund (no. LS18-111), Austrian Science Fund (nos. I4162 and P35841-B) and St. Anna Kinderkrebsforschung supported S.T.-M. We thank D. Nathanson for provision of clinical data. We thank A. Desai for usage of equipment and experimental advice. Funding Information: P.S.M. is cofounder of Boundless Bio. He has equity and chairs the scientific advisory board, for which he is compensated. V.B. is a cofounder, consultant, scientific advisory board member and has an equity interest in Boundless Bio. and Abterra Biosciences. The terms of this arrangement have been reviewed and approved in accordance with its conflict-of-interest policies. H.Y.C. is a cofounder of Accent Therapeutics, Boundless Bio, Cartography Biosciences, Orbital Therapeutics, and advisor of 10X Genomics, Arsenal Biosciences and Spring Discovery. J.T.L. was employed by Boundless Bio after completing this work. C.S. acknowledges grant support from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Pfizer, Roche-Ventana, Invitae (previously ArcherDX, collaboration in minimal residual disease sequencing technologies) and Ono Pharmaceutical. He is an AstraZeneca advisory board member and chief investigator for the AZ MeRmaiD 1 and 2 clinical trials and is also chief investigator of the NHS-Galleri trial. He has consulted for Amgen, AstraZeneca, Pfizer, Novartis, GSK, MSD, Bristol Myers Squibb, Illumina, Genentech, Roche-Ventana, GRAIL, Medicxi, Metabomed, Bicycle Therapeutics, Roche Innovation Centre Shanghai and the Sarah Cannon Research Institute. C.S. had stock options in ApoGen Biotechnologies and GRAIL until June 2021, has currently stock options in Epic Bioscience and Bicycle Therapeutics, and has stock options and is a cofounder of Achilles Therapeutics. C.S. holds patents relating to assay technology to detect tumor recurrence (PCT/GB2017/053289), targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), determining human leukocyte antigen loss of heterozygosity (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221), identifying patients who respond to cancer treatment (PCT/GB2018/051912), a US patent relating to detecting tumor mutations (PCT/US2017/28013), methods for lung cancer detection (US20190106751A1) and both European and US patents related to identifying insertion/deletion mutation targets (PCT/GB2018/051892). The other authors declare no competing interests. Funding Information: The eDyNAmiC research was facilitated by Cancer Grand Challenges (grant no. CGCSDF-2021\100007) with support from Cancer Research UK and the National Cancer Institute. This study was supported by a grant from the National Brain Tumour Society and National Institutes of Health (NIH) grant no. R01-CA238349 to P.S.M. H.Y.C. is an investigator of the Howard Hughes Medical Institute and was also supported by NIH grant no. R35-CA209919. A Barts Charity Lectureship MGU045 and UKRI Future Leaders Fellowship supported B.W. The UCSD microscopy core is supported by National Institute of Neurological Disorders and Stroke (no. NS047101). NIH grant nos. U24CA264379 and 1R01GM114362 supported V.B. The A.P. Giannini Foundation supported J.C.R. The German Research Foundation (grant no. 398299703) supported A.G.H. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant no. 949172). The Cancer Prevention and Research Institute of Texas (no. RR210034) supported S.W. We thank C. Zhang from the Howard Chang Laboratory for providing technical assistance with the CRISPR-C experiments. C.S. is a Royal Society Napier Research Professor (no. RSRP\R\210001). This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (no. FC001169), the UK Medical Research Council (no. FC001169) and the Wellcome Trust (no. FC001169). This research was funded in whole, or in part, by the Wellcome Trust (no. FC001169). For the purpose of open access, the authors applied a CC BY public copyright licence to any author-accepted manuscript version arising from this submission. C.S. is funded by Cancer Research UK (TRACERx (no. C11496/A17786), PEACE (C416/A21999) and CRUK Cancer Immunotherapy Catalyst Network), Cancer Research UK Lung Cancer Centre of Excellence (no. C11496/A30025), the Rosetrees Trust, Butterfield and Stoneygate Trusts, NovoNordisk Foundation (ID16584), Royal Society Professorship Enhancement Award (no. RP/EA/180007), the National Institute for Health Research Biomedical Research Centre at University College London Hospitals, the Cancer Research UK-University College London Centre, Experimental Cancer Medicine Centre and the Breast Cancer Research Foundation (no. BCRF 20-157). This work was supported by a Stand Up To Cancer (SU2C)‐LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (grant no. SU2C-AACR-DT23-17 to S. M. Dubinett and A. E. Spira). SU2C is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C.S. is in receipt of an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant no. 835297). Funding from the Vienna Science and Technology Fund (no. LS18-111), Austrian Science Fund (nos. I4162 and P35841-B) and St. Anna Kinderkrebsforschung supported S.T.-M. We thank D. Nathanson for provision of clinical data. We thank A. Desai for usage of equipment and experimental advice. Publisher Copyright: © 2022, The Author(s).
PY - 2022/10
Y1 - 2022/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85138131215&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85138131215&partnerID=8YFLogxK
U2 - 10.1038/s41588-022-01177-x
DO - 10.1038/s41588-022-01177-x
M3 - Article
C2 - 36123406
AN - SCOPUS:85138131215
SN - 1061-4036
VL - 54
SP - 1527
EP - 1533
JO - Nature Genetics
JF - Nature Genetics
IS - 10
ER -