Researchers have uncovered that some childhood cancers have a substantially higher number of DNA changes than previously thought, changing the way we view children's tumours and possibly opening up new or repurposed treatment options.
Concentrating on a type of childhood kidney cancer, known as Wilms tumour, an international team genetically sequenced multiple tumours at a resolution that was previously not possible. This collaboration included researchers at the Wellcome Sanger Institute, University of Cambridge, Princess Máxima Center for Pediatric Oncology, the Oncode Institute in the Netherlands, Great Ormond Street Hospital, and Cambridge University Hospitals NHS Foundation Trust.
They uncovered many more genetic changes per cancer cell than expected, adding up to millions of changes per tumour. This suggests that some childhood tumours could be eligible for treatments such as immunotherapy.
In the study, published today (29 May) in Nature Communications, the team also describes a single, spontaneous genetic change that causes a rare type of Wilms tumour, which children are born with, and that this change happens early during development in the womb. They found that these tumours have a particular appearance under the microscope and genetic profile, implying that it could be possible, in the future, to develop personalised therapeutics and tailor clinical plans for those with this genetic change.
This research challenges the widely held notion that childhood cancers have a very low number of genetic changes and instead suggests that there could be effective adult treatments that could be adapted for childhood tumours in the future.
Wilms tumour is a type of kidney cancer that largely affects children under the age of five. In the UK, about 85 children are diagnosed with Wilms tumour every year1.
Previously, it was thought that childhood cancer tumours, like those in Wilms tumour, had a low number of genetic changes, also called genetic variants.
To investigate how and why these tumours present so early in life, the team at the Sanger Institute and their collaborators applied the latest genomic sequencing techniques to understand more about how and when these genetic changes occurred.
Bulk whole genome sequencing methods allow researchers to find genetic changes that are shared by all the cells in the tumour. While this can work well for adult tumours, as the cells have had more time to develop, childhood tumours have fewer shared genetic changes, meaning that the large number of mutations that are not shared by all cells are missed.
To overcome this, the team used two cutting-edge techniques: nanorate sequencing2, otherwise known as nanoseq, and whole-genome sequencing of single-cell-derived organoids3 to study kidney tumours at much higher resolution. These methods allow scientists to find genetic changes that might be present in just a single cell of a cancer.
The team used these methods to genetically sequence Wilms tumour samples from four children, aged up to six months. They found that a single cancer cell had an additional 72 to 111 genetic changes on top of the ones already identified via bulk whole genome sequencing methods4. This means that when the overall number of cells in the tumour is taken into consideration, there are most likely millions of genetic changes per tumour overall, not the low numbers that were previously thought.
Alongside changing our understanding of childhood tumours, this new finding could also have implications for treatment. The researchers suggest that with this number of possible genetic changes, it's likely that tumours could become resistant to treatments quicker, or that some drugs might not work at all.
However, this discovery could also mean that childhood tumours are better candidates for existing treatments that are currently used for adult tumours, such as immunotherapies5.
The team also traced the evolution of the tumours in three children and uncovered a new mutation that causes Wilms tumour. This single change in the FOXR2 gene was found to happen while the kidney was developing in the womb, and is associated with a particular appearance of the tumour under the microscope and a specific set of RNA changes. Researchers suggest that this could be used to identify these tumours and that, one day, it may be possible to develop specific personalised treatment for certain genetic profiles in Wilms tumour.
Dr Henry Lee-Six, co-first author at the Wellcome Sanger Institute, said: "Widespread sequencing methods are incredibly useful for a large number of cancer tumours, especially in adults. However, they fail to capture the true genetic complexity of cancers, particularly those that occur in the youngest children. With these latest genomic sequencing techniques, we can now see a much more detailed picture of Wilms tumour, which can occur in newborns. This could help us understand this condition in more detail, and may change the way we view and treat childhood tumours as a whole."
Dr Jarno Drost, co-senior author at the Princess Máxima Center for Pediatric Oncology and the Oncode Institute in the Netherlands, said: "Being able to trace the evolution of a tumour can uncover crucial information about how and why it develops. In this study, we uncovered a single genetic change that occurred during development and caused this subset of Wilms tumour. Treatment for Wilms tumour has to carefully balance treating the tumour and lowering the risk of recurrence, while minimising the impact this can have on a young child's quality of life and their family. By understanding the genetic changes that cause tumours, and in this case, identifying different genetic subsets, it could lead to more targeted treatment options, something that every child deserves."
Professor Sam Behjati, co-senior author at the Wellcome Sanger Institute and Cambridge University Hospitals NHS Foundation Trust, said: "It has been a widely held belief that childhood tumours had much lower numbers of genetic changes than adult tumours. However, thanks to the development of new genomic sequencing tools, we have been able to show that, at least in these cases, it is not true. Our findings suggest that childhood tumours have at least four times more genetic changes per cell than expected, which adds millions more changes per tumour, highlighting that what we could see before was just the tip of the iceberg. This has implications for both childhood kidney cancer and possibly other childhood tumours. If we understand childhood cancer fully, we can develop new ways to treat it or repurpose existing treatments to get options to those who need them as quickly as possible."
