UC San Diego

In cancer, oncogenes are frequently amplified on extrachromosomal DNA (ecDNA), circular acentric DNA fragments ranging from hundreds of kilobases to multiple megabases. Oncogene amplification on ecDNA is associated with extremely high copy number and poor prognosis in patients. However, the specific mechanisms through which ecDNA alter cell behavior and tumor evolution are poorly understood. Here, I report that ecDNA are inherited randomly by daughter cells during mitosis. This breakdown of canonical mendelian inheritance patterns results in significant increases in population and tumor heterogeneity. I further demonstrate that cell lines with ecDNA are able to rapidly alter their distribution of ecDNA copy number to adapt and gain resistance to both environmental and therapeutic challenges. Interestingly, investigations into the behavior of multiple species of ecDNA within individual cells demonstrate that while ecDNA is inherited randomly by daughter cells, different ecDNA species are not inherited independently of each other. Further, I show that ecDNA demonstrates an increased frequency of missegregation into micronuclei during mitosis.Finally, I investigate proteins that may be essential for the maintenance and inheritance of ecDNA. Analysis of gene expression data from The Cancer Genome Atlas identifies several proteins involved in chromosomal segregation and DNA repair and metabolism. I specifically analyze the chromokinesins KIF4A and KIF22 and demonstrate that they may play a significant role in ensuring proper segregation of ecDNA into daughter cells. Taken together, the data presented here clearly demonstrate how the random inheritance of ecDNA at each cell division generates a dynamic and heterogeneous distribution of amplified oncogenes. This enables cancer cells to adapt to and resist environmental and therapeutic pressures more readily. I also describe the behavior of ecDNA during mitosis and identify specific proteins that may be able to be targeted to specifically disrupt the proliferation of ecDNA+ cell lines and tumors.