Decoding the history of cancer

30th September 2019

Why is cancer more common in some organs compared to others? Dr Ruben van Boxtel in the Netherlands has been searching for the answer in stem cells.

Some organs are much more likely to develop cancer than others. Research suggests that the difference might be down to the number of times stem cells in that organ divide. It makes sense – every time a stem cell divides, it has to replicate its DNA to pass a copy on to the new daughter cells. And every time a cell copies DNA, there is a chance of an error occurring, a genetic mutation. So the more a cell divides, the more likely it is to accumulate mutations that drive cancer.

Spotting signatures

Finding the underlying cause of how and why this happens has been the focus of Ruben’s research project. Ruben studied stem cells over generations of replication and division. His work has helped to spot "signatures" left behind in the DNA by the accumulation of mutations over time.

In 2016, Ruben's research showed that there wasn't much difference in the rate of genetic mutations in stem cells from different organs. A surprising result considering the difference in cancer incidence in different organs.

“This suggests that the gradual accumulation of more and more ‘bad luck’ DNA errors over time cannot explain the difference we see in cancer incidence – at least for some cancers,” said Ruben.

Answering questions about cancer

So what else could explain the difference? Maybe it’s not the rate of mutation, but instead the types of mutation likely to emerge in a particular organ. Ruben went to work answering this question. His research showed that the processes causing mutations in stem cells were different in different organs. This provided some explanation to the varied incidence of cancer between organs.

To gain further insight, Ruben knew he would need to look closer at how specific types of mutation form. So his team took normal stem cells and knocked out a specific gene. Without this gene, the stem cells couldn't correct a type of DNA error that occurs as the cell divides.

As the stem cells divided over generations, they spotted a pattern of mutations emerging in the DNA. They called this pattern ‘signature 30’. This signature was identical to one that researchers had found before - in the DNA from a group of women with a rare type of breast cancer. So the team looked closer at the genetics of these women. They found that they carried a mutation to the same gene Ruben had knocked out in his experiments. This suggests that when this gene isn't working it causes a very specific pattern of genetic mutations to occur over time. And this pattern of mutations helps cancer to develop.

The mutations to the gene Ruben was studying are the type of mutations that can inherited from your parents (known as a germline mutation). This means that if cancer DNA from a patient contains ‘signature 30’, it's likely they could be carrying a heritable genetic mutation. One that predisposes them and their children to cancer.

So what could this mean for patients?

This information can have important implications for patients and their families. But Ruben’s work is still proof-of-principle. He has developed a technique for studying how cancer-causing mutations accumulate in different organs. And he has shown that it can identify mutational signatures with clinical relevance. But there is still some way to go before the technique is ready for the clinic.

Ruben isn’t stopping here. He has now secured further funding to pursue the clinical application of his research. The next step in a journey to take his discovery from bench to bedside.

The gradual accumulation of more and more ‘bad luck’ DNA errors over time cannot explain the difference we see in cancer incidence – at least for some cancers
Dr Ruben van Boxtel,