Circles of DNA unassociated with chromosomes, extrachromosomal DNAs (ecDNA) encode multiple copies of cancer genes and drive tumor evolution, growth and drug resistance. Identifying where ecDNA comes from has been an important challenge of cancer research. In December, a team led by Ludwig San Diego’s Don Cleveland and Peter Campbell of the Sanger Center reported in Nature that ecDNAs are formed by chromothripsis—or the shattering and shuffled reassembly of chromosomes. While earlier work led by Don and Peter had established that chromothripsis of missegregated chromosomes can produce the complex genome rearrangements found in many tumors, the researchers now report that chromothripsis drives the evolution of gene amplification in cancer through production of ecDNA, including the induction of drug resistance through the generation of ecDNAs carrying a gene that inactivates an anticancer drug. They showed that once formed, ecDNA undergoes successive rounds of chromothripsis to spawn additional rearranged ecDNAs that drive increased drug resistance by further amplification of genes responsible for the resistance. The study lays the groundwork for combination therapy in which a chemotherapeutic drug is paired with another drug that prevents the DNA fragments created by chromosomal shattering from closing to form ecDNA circles.
This article appeared in the April 2021 issue of Ludwig Link. Click here to download a PDF (1.4 MB).