The evolutionary dynamics of extrachromosomal DNA in human cancers

Joshua T Lange; John C Rose; Celine Y Chen; Yuriy Pichugin; Liangqi Xie; Jun Tang; King L Hung; Kathryn E Yost; Quanming Shi; Marcella L Erb; Utkrisht Rajkumar; Sihan Wu; Sabine Taschner-Mandl; Marie Bernkopf; Charles Swanton; Zhe Liu; Weini Huang; Howard Y Chang; Vineet Bafna; Anton G Henssen; Benjamin Werner; Paul S Mischel

doi:10.1038/s41588-022-01177-x

The evolutionary dynamics of extrachromosomal DNA in human cancers

Nat Genet. 2022 Oct;54(10):1527-1533. doi: 10.1038/s41588-022-01177-x. Epub 2022 Sep 19.

Authors

Joshua T Lange^#^{1

2}, John C Rose^#³, Celine Y Chen^#⁴, Yuriy Pichugin^#^{5

6}, Liangqi Xie^{7

8}, Jun Tang^{1

2}, King L Hung³, Kathryn E Yost³, Quanming Shi³, Marcella L Erb⁹, Utkrisht Rajkumar¹⁰, Sihan Wu¹¹, Sabine Taschner-Mandl¹², Marie Bernkopf¹², Charles Swanton^{13

14

15}, Zhe Liu⁷, Weini Huang^{16

17}, Howard Y Chang^{18

19}, Vineet Bafna²⁰, Anton G Henssen^{4

21

22

23}, Benjamin Werner²⁴, Paul S Mischel^{25

26}

Affiliations

¹ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
² ChEM-H, Stanford University, Stanford, CA, USA.
³ Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁵ Department of Evolutionary Theory, Max Planck Institute for Evolutionary Biology, Plön, Germany.
⁶ Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ, USA.
⁷ Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA.
⁸ Department of Molecular and Cell Biology, Li Ka Shing Center for Biomedical and Health Sciences, California Institute for Regenerative Medicine Center of Excellence, University of California, Berkeley, CA, USA.
⁹ University of California San Diego Light Microscopy Core Facility, Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
¹⁰ Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA.
¹¹ Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹² St. Anna Children's Cancer Research Institute, Vienna, Austria.
¹³ Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK.
¹⁴ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
¹⁵ Department of Medical Oncology, University College London Hospitals, London, UK.
¹⁶ Group of Theoretical Biology, The State Key Laboratory of Biocontrol, School of Life Science, Sun Yat-sen University, Guangzhou, China. [email protected].
¹⁷ Department of Mathematics, Queen Mary University of London, London, UK. [email protected].
¹⁸ Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
¹⁹ Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA. [email protected].
²⁰ Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA. [email protected].
²¹ Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany.
²² German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany.
²³ Berlin Institute of Health, Berlin, Germany.
²⁴ Evolutionary Dynamics Group, Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.
²⁵ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
²⁶ ChEM-H, Stanford University, Stanford, CA, USA. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Biological Evolution
DNA
Extrachromosomal Inheritance
Humans
Neoplasms* / genetics
Neoplasms* / pathology
Oncogenes*

Substances

DNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding