Coordinated inheritance of extrachromosomal DNAs in cancer cells

The chromosomal theory of inheritance explains that genes on the same chromosome segregate together, while those on different chromosomes assort independently. In cancer, extrachromosomal DNAs (ecDNAs) contribute to oncogene amplification and gene expression dysregulation. Distinct ecDNA sequences can coexist, promoting cooperation among cancer cells. This study reveals that these cooperative ecDNA species are inherited through mitotic co-segregation. Multiple ecDNAs encoding different oncogenes are often found together and correlate in copy number within human cancer cells. During mitosis, these ecDNA species segregate asymmetrically, leading to simultaneous copy-number gains in daughter cells. Active transcription and proximity at mitosis’ onset enhance this co-segregation while inhibiting transcription disrupts it. Computational models elucidate the principles of ecDNA co-segregation, predicting their patterns in cancer cells. This coordinated inheritance supports the co-amplification of ecDNAs, informs therapeutic strategies to target oncogenes, and maintains stability in oncogene interactions and gene regulation across generations.