Wilms tumor found to contain millions of genetic changes
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 tumors and possibly opening up new or repurposed treatment options.
Concentrating on a type of childhood kidney cancer, known as Wilms tumor, an international team genetically sequenced multiple tumors 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 tumor. This suggests that some childhood tumors 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 tumor, which children are born with, and that this change happens early during development in the womb. They found that these tumors 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 tumors in the future.
Wilms tumor 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 tumor every year.
Previously, it was thought that childhood cancer tumors, like those in Wilms tumor, had a low number of genetic changes, also called genetic variants.
To investigate how and why these tumors 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 tumor. While this can work well for adult tumors, as the cells have had more time to develop, childhood tumors 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 sequencing, otherwise known as nanoseq, and whole-genome sequencing of single-cell-derived organoids to study kidney tumors 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 tumor 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 methods. This means that when the overall number of cells in the tumor is taken into consideration, there are most likely millions of genetic changes per tumor overall, not the low numbers that were previously thought.
Alongside changing our understanding of childhood tumors, this new finding could also have implications for treatment. The researchers suggest that with this number of possible genetic changes, it’s likely that tumors could become resistant to treatments quicker, or that some drugs might not work at all.
However, this discovery could also mean that childhood tumors are better candidates for existing treatments that are currently used for adult tumors, such as immunotherapies.
The team also traced the evolution of the tumors in three children and uncovered a new mutation that causes Wilms tumor. 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 tumor under the microscope and a specific set of RNA changes. Researchers suggest that this could be used to identify these tumors and that, one day, it may be possible to develop specific personalised treatment for certain genetic profiles in Wilms tumor.
Widespread sequencing methods are incredibly useful for a large number of cancer tumors, 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 tumor, 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 tumors as a whole.”
Dr. Henry Lee-Six, co-first author, Wellcome Sanger Institute
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 tumor 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 tumor. Treatment for Wilms tumor has to carefully balance treating the tumor 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 tumors, 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 tumors had much lower numbers of genetic changes than adult tumors. 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 tumors have at least four times more genetic changes per cell than expected, which adds millions more changes per tumor, 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 tumors. 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.”
Lee-Six, H., et al. (2025). High resolution clonal architecture of hypomutated Wilms tumours. Nature Communications. doi.org/10.1038/s41467-025-59854-4.
