Extra chromosomal DNA in tumours fuels cancer growth

Circular DNA existing outside chromosomes can drive cancer growth and is a potential drug target, according to three papers published this week in Nature.

Conducted with funding from Cancer Grand Challenges, this research demonstrated that these DNA structures, known as extrachromosomal DNA (ecDNA), are hugely prevalent in a range of cancers and can amplify genes that promote cancer and modulation of the immune system.

'There are rules normal cells follow. One of the ways cancer wins is that it doesn't play by the same rules', said Professor Howard Chang, a physician-scientist at Stanford University who co-led two of the three studies. 'What we are doing is figuring out what extra moves it has in its repertoire.'

Chromosomes, large structures which carry the DNA within a cell's nucleus, contain regions called 'centromeres' which ensure that when a cell divides, each new daughter cell will have one copy of that chromosome.

However, ecDNA, which often arises during the early stages of cancer development, does not have a centromere. This means that after replication, ecDNA is distributed more randomly across daughter cells, allowing certain cells to accumulate a very large number of copies. If a particular ecDNA carries a gene linked with cancer development or treatment resistance, this rapid replication suggests a mechanism for how the growth of a cancer can be promoted.

Until recently, the overall prevalence of ecDNA in cancer was not known. In the first of these three studies, over 15,000 samples sequenced as part of Genomics England's 100,000 Genomes Project were analysed for the presence of ecDNA, which was detected in over 17 percent of samples.

The study also demonstrated that ecDNA amplifies the expression not only of cancer driver genes, but also of genes involved in immunomodulation and inflammation, raising additional questions about how ecDNA promotes tumour growth.

Professor Charles Swanton, the deputy clinical director of the Francis Crick Institute, London, who co-led this study, said 'Our understanding of ecDNA is a step forward in building a complete picture of the complex biology of cancer. These circles of rogue DNA are a unique way for the tumour to hide from the immune system and evolve resistance to treatment.'

The complex dynamics of how ecDNA is inherited were investigated further in a second study, which showed that different ecDNA species in the same cell are often inherited together, providing a further competitive advantage to cells that carry the whole range of ecDNA species. This finding appears to violate Gregor Mendel's third law of inheritance, which stipulates that the inheritance of DNA between daughter cells at one region occurs independently of that at another region.

'When you have two different DNA molecules with a Mendelian type of inheritance, you expect a lot of cells with one molecular or the other,' said Professor Chang. 'But what we found was that most cells have both ecDNA species. So, if you have more of ecDNA flavour A, you also have more flavour B.'

The increase in transcription of cancer genes due to ecDNA then formed the basis of the third paper, which used the conflict between transcription and replication, which is heightened in ecDNA, as a specific target for ecDNA-positive cancers.

Since DNA transcription and replication both involve machinery moving along the DNA, facilitating collisions could cause cells to die. Experiments showed that inhibiting CHK1, a gene involved in regulating DNA replication, specifically killed ecDNA-positive cancers.

The researchers also showed that a CHK1-inhibiting drug, in combination with targeted therapy, demonstrated increased anti-tumour activity in gastric cancer models containing ecDNA. While CHK1 inhibitors have been suggested for treating cancers with high levels of replication, there are not yet any approved due to insufficient potency and potential off-target effects.

Dr Chris Bailey, clinical research scientist at the Francis Crick Institute, said, 'These rogue pieces of DNA create even more genetic variation within a tumour, something that we know is associated with cancer spread and resistance to treatment... If we could target ecDNA specifically, we might be able to boost response to standard cancer therapies.'