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

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. HenssenBenjamin Werner, Paul S. Mischel

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

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	https://doi.org/10.1038/s41588-022-01177-x
State	Published - Oct 2022

ASJC Scopus subject areas

Genetics

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Lange, J. T., Rose, J. C., Chen, C. Y., Pichugin, Y., Xie, L., Tang, J., Hung, K. L., Yost, K. E., Shi, Q., Erb, M. L., Rajkumar, U., Wu, S., Taschner-Mandl, S., Bernkopf, M., Swanton, C., Liu, Z., Huang, W., Chang, H. Y., Bafna, V., ... Mischel, P. S. (2022). The evolutionary dynamics of extrachromosomal DNA in human cancers. Nature genetics, 54(10), 1527-1533. https://doi.org/10.1038/s41588-022-01177-x

Lange, JT, Rose, JC, Chen, CY, Pichugin, Y, Xie, L, Tang, J, Hung, KL, Yost, KE, Shi, Q, Erb, ML, Rajkumar, U, Wu, S, Taschner-Mandl, S, Bernkopf, M, Swanton, C, Liu, Z, Huang, W, Chang, HY, Bafna, V, Henssen, AG, Werner, B & Mischel, PS 2022, 'The evolutionary dynamics of extrachromosomal DNA in human cancers', Nature genetics, vol. 54, no. 10, pp. 1527-1533. https://doi.org/10.1038/s41588-022-01177-x

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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.",

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The evolutionary dynamics of extrachromosomal DNA in human cancers

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