The evolutionary dynamics of extrachromosomal DNA in human cancersMore about Open Access at the Crick
Authors listJoshua 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
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.
Journal Nature Genetics
Issue number 10