Millions of Genetic Changes Found in Childhood Kidney Cancer
The results change the way we view children’s tumors and could open up new or repurposed treatment options.
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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 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 personalized 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 personalized treatment for certain genetic profiles in Wilms tumor.
Reference: Lee-Six H, Treger TD, Dave M, et al. High resolution clonal architecture of hypomutated Wilms tumours. Nat Commun. 2025;16(1):4647. doi: 10.1038/s41467-025-59854-4
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