How whole genome doubling promotes cancer development

Cancer cells that undergo genome doubling affect how DNA is packaged, which may promote cancer development.

Researchers at the Swiss Federal Institute of Technology in Lausanne, and the University of Lausanne, Switzerland, found that whole genome doubling (WGD) can weaken chromatin organisation in the cell, potentially driving cancer development. WGD is seen in around 30 percent of human cancers, in which the whole cell genome is doubled. This can lead to genomic instability and other mutations that may promote cancer development.

'Changes in the folding and packing of DNA in WGD were initially difficult to detect and interpret. Indeed, the 3D organisation of the DNA was not completely disrupted, but just less precise.' the co-authors of this study, Dr Giovanni Ciriello and Dr Elisa Oricchio told Nature. 'However, when we discovered that this reduction in precision was consistent in many different models and experiments, we were convinced that it was a real effect attributable to WGD.'

The study, published in Nature, involved researchers investigating chromatin organisation within cells lacking the tumour suppressor gene, p53, which made them prone to WGD. Compared to normal cells, these WGD cells showed less stable DNA organisation because of a lack of key proteins involved in the folding and packaging of DNA. This may lead to genetic material becoming mixed that is otherwise kept separate and promote the activation of genes that may contribute to cancer development.

'There are surprisingly few published papers that have evaluated the effect of change in the number of chromosomes in a cell on chromatin organisation and nuclear architecture.' Dr Uri Ben-David from Tel Aviv University in Israel, who was not involved in the study, explained to Nature '…The authors propose that the observed chromatin changes occurred independently of mutations and chromosomal aberrations and are therefore complementary mechanisms that contribute to tumour formation and evolution following WGD.'

As acknowledged by the authors of this study, the changes in the DNA organisation were observed from a few time points and data that was combined from millions of cells. DNA organisation is expected to change over time and show cell-to-cell variability. As a result, further experiments would be required that provide a more high-resolution analysis of the evolution of DNA organisation within these separate cells and how it contributes to cancer development.