ecDNA challenges law of genetics, groundbreaking new studies find Premium

Discover the pivotal role of extrachromosomal DNA (ecDNA) in cancer biology and its implications for future treatments.

Once brushed aside as a curiosity, extrachromosomal DNA (ecDNA) is now taking centrestage in the complex field of cancer biology. Scientists first discovered it as a small fragment of genetic material in cancer cells 50 years ago. Because it was present in only 1.4% of tumours, they didn’t consider it to be important.

But more sophisticated genomic techniques later revealed their mistake: one study published in 2017 revealed ecDNA is present in nearly 40% of cancer cell lines and in up to 90% of patient-derived brain tumour samples, revealing its pivotal role in cancer biology.

On November 6, three papers were published in the journal Nature by a team called eDyNAmiC — an international collaboration led by Stanford University professor Paul Mischel. The studies explore how ecDNA is formed and contributes to the progression of cancer and drug resistance.

Importantly, the findings also challenge a fundamental law of genetics.

In normal human cells, the nucleus contains 23 pairs of chromosomes that enclose the DNA. There are some natural processes that can damage DNA. For example, in chromothripsis, which occurs in some cancers, the chromosomes are broken and rearranged. Cells can also make mistakes in the DNA when making copies of it to imbue in new cells. Such processes could cause a small part of the DNA to break away from the main chromosome and form a circular structure that floats freely inside the nucleus. This is ecDNA.

One of the three studies was led by eDyNAmiC members Mariam Jamal-Hanjani and Charles Swanton, both professors at University College London. They analysed the mutation patterns in tumours before and after the formation of ecDNA. They identified various environmental factors, including smoking, exposure to certain substances, and genetic mutations,  to be triggers of DNA damage that could lead to the formation of ecDNA.

In the same study, the researchers attempted a comprehensive analysis of samples from nearly 15,000 cancer patients from U.K.’s 100,000 Genomes Project, covering 39 tumour types. They validated their findings using a method called fluorescence in-situ hybridisation (or FISH), which specifically looks for certain cancer-related genes in tissue samples.