Researchers have found that cancer cells contain shattered chromosomes that can allow a tumor to become more aggressive and help it resist chemotherapy drugs.
Cancers evolve over several steps, and one of the earliest occurs when mutations create a tumor — a group of abnormal cells. A mutation can involve anything from changing a single letter in DNA to rearranging an entire chromosome.
The most extreme rearrangement is to shatter chromosomes, a phenomenon known as ‘chromothripsis’ — Greek for ‘shattered color’ (chromosome means ‘colored body’). Breaking DNA into (sometimes hundreds of) pieces separates genes, allowing a tumor to gain novel combinations that increase the activity of key genes whose actions may decrease the effectiveness of anti-cancer drugs.
Shattering chromosomes leaves behind rings of genetic material called ‘circular extrachromosomal DNA’, or ecDNA. According to a 2019 study by researchers at the University of California at San Diego, La Jolla, up to half of all cells in many types of cancer have rings that help tumors grow, and their latest research now shows that ecDNA also enables them to develop resistance to therapeutic drugs.
The new study involved reading DNA sequences in tumor cells during a cancer’s evolution. That genome sequencing showed that chromosomes were repeatedly shattered while the cells divided, which allowed them to acquire various genetic combinations from their circular extrachromosomal DNA — including genes for resistance to methotrexate, a drug widely-used in chemotherapy.
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A tumor can amplify the genetic activity for resisting anti-cancer drugs because the genes in ecDNA rings are repeatedly copied while outside of a chromosome. Worse, as chemotherapy and radiotherapy can damage chromosomes, cancer cells can then reintegrate that circular extrachromosomal DNA back into their genomes.
Shattered chromosomes and amplification of drug-resistance genes has revealed yet another reason why cancers are so effective at evolving to evade treatment.