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Decoding cancers history

For the past three years, Dr Ruben van Boxtel has been busy at Prinses Máxima Center for Pediatric Oncology in the Netherlands, trying to decipher the historical archive recorded in the DNA of cancer. Perplexed by the question of why some organs are far more likely to develop cancer than others are, he began searching for the answer in stem cells found in the organs of our body.

Cancer is caused by an accumulation of genetic mutations to a cell’s DNA. These mutations pile on top of each other, disrupting core processes that ultimately lead to a chaotic explosion of cell growth and division. If cancer is caused by an accumulation of mutations over time, then the amount, or rate of mutation, must be different in different organs. The higher the ‘mutational load’, the more likely that organ is to develop cancer.

What is a stem cell?

Stem cells are cells found in our body that are able to "differentiate", or turn, into any type of cell in the body. Adult stem cells are found in all our tissues and act as a repair system, replenishing adult tissues with new cells.

Just bad luck

A ground-breaking (and controversial) piece of research published in 2015 revealed that the variation in cancer risk between organs could be explained by the number of times stem cells in that organ divide. It makes sense – every time a cell divides, it has to replicate its DNA to pass a copy the new daughter cell. And every time DNA is copied, there is 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.

This led to some rather irresponsible reporting of the research, with many media articles proclaiming that because the replication rate of stem cells is part of our natural biology, then the majority of cancer must be down to bad luck - despite any actual experimental evidence to show this. That aside, the research did reveal new insight into the role stem cells may play in the varying rates of cancer between organs.

And this has been the crux of Ruben’s research over the last three years. By studying stem cells over generations of replication and division, Ruben has been shining a light on the genetic signatures left behind by the accumulation of mutations. Comparing the signatures of stem cells from different organs, he hoped to be able to identify the biological processes responsible for the accumulation of mutations.

How many errors?

Ruben’s project supported by Worldwide Cancer Research kicked off in January 2016 and it didn’t take long for the first breakthrough. In October that year, he published research showing that genetic mutations accumulate over the course of a human lifetime in stem cells across various tissues. Surprisingly, the actual rate of genetic mutations in stem cells didn’t vary much at all (it’s around 40 new mutations arising per year) between tissues from different organs, even when comparing organs with extreme variation in cancer incidence.

“We were surprised to find roughly the same mutation rate in stem cells from organs with different cancer incidence,” said Ruben. “This suggests that simply 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.”

So what else could explain the difference? Perhaps it’s not the rate of mutation, but instead the types of mutation likely to emerge in a particular organ. Ruben went to work studying in detail the processes that were causing specific types of mutation in stem cells. His research revealed that the underlying processes that cause mutations were different in stem cells from different organs, offering some explanation to the varied incidence of cancer.

Signature 30

But to understand the true impact of the different processes driving mutations, Ruben knew he would need to look deeper into how specific types of mutation form and how these lead to specific patterns of mutation over time as stem cells divide. His team took normal stem cells and knocked out a gene, called NTHL1, which prevented the cells from correcting a particular type of DNA error that occurs as the cell divides. As the stem cells divided, they spotted a recognisable mutational signature emerging in the DNA. Dubbed ‘signature 30’, this mutational footprint was identical to one previously seen in the tumour DNA from a group of women with a rare type of breast cancer. Closer inspection on the genetics of these patients revealed that they carried a mutation to the NTHL1 gene, one that stops it working, just like in Ruben’s experiments.

Importantly, the mutations to the NTHL1 gene are the type of mutations that can be passed on through families (called a germline mutation). This means that a cancer patient showing high levels of ‘signature 30’ in their tumour is likely to be carrying a genetic mutation that predisposes them and their children to cancer.

While this information can have important implications for patients and their families, Ruben’s work is proof-of-principle at this stage. He has developed a precise technique for studying how cancer-causing mutations accumulate in different organs and shown that it can be used to identify mutational signatures with clinical relevance. Ruben isn’t stopping here, however. With his findings, he has secured more funding to pursue the clinical application of his research, and take his discovery from bench to bedside.

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