Extrachromosomal DNA copy number key to high-level oncogene expression

08 Dec 22

Oncogene expression from extrachromosomal DNA is driven by copy number amplification and does not require spatial clustering in glioblastoma stem cells

A recent study has demonstrated that, contrary to recent reports, the transcriptional output of oncogenes carried on extrachromosomal DNA in glioblastoma stem cells is driven by the copy number of the ecDNA, rather than their spatial localization into transcriptional hubs.

Extrachromosomal DNA (ecDNA) are short circular sections of genetic code that can exist in cancer cells.  They are separate to the genetic code contained in the form of chromosomes.

ecDNA can include the code for cancer genes and, as each cancer cell can have tens or hundreds of ecDNA, this means harmful genes driving cancer can exist at high levels. ecDNA are particularly common in glioblastoma – an aggressive brain cancer which is difficult to treat. 

The study, recently published in eLife, looked at cancer genes on ecDNA in glioblastoma cells under the microscope – using super-resolution imaging and quantitative image analysis - and measured how they are organised in 3D space in order to understand if ecDNA can super-charge cancer gene activity. 

The research team, led by the Wendy Bickmore Research Group at the MRC Human Genetics Unit, and Steven Pollard at the Centre for Regenerative Medicine, brought together scientists from across the College of Medicine and Veterinary Medicine and the School of Mathematics at the University of Edinburgh.  CRM ECAT Clinical Fellow Karin Purshouse was first author of the study.

They found no evidence to show that ecDNA cluster closely together, or with other important parts of a cell’s machinery, in a way that might super-charge the expression of cancer genes.

The researchers set out to understand whether cancer genes that exist on ecDNA produce more of their coded information because each expression of the genes on ecDNA is more powerful than their chromosomal counterparts, or simply due to having lots of copies of ecDNA containing cancer genes. 

They discovered that the most important factor in driving high levels of potentially cancer-causing oncogene transcription is having more copies of ecDNA and their associated cancer genes, rather than specific interactions of ecDNA with each other or with high concentrations of the biomolecular transcriptional machinery, as previously believed.

Glioblastoma remains a cancer for which treatment options are limited, so it is really important to understand more about the underlying biology in order to identify new treatment strategies.  Our research suggests that ecDNA in glioblastoma stem cells may behave differently to how we initially expected.  This is important given that ecDNA are particularly common in glioblastoma cancers and are a possible target for treatment.

Karin Purshouse
ECAT Clinical Lecturer in Medical Oncology at the Centre for Regenerative Medicine

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