New research looked at how cancers arise in children who are predisposed to developing the childhood kidney cancer, Wilms tumour, which could help anticipate the development of tumours before they fully form. These insights could inform genetically tailored treatment plans that could provide children with the most effective care while also minimising side effects.
Researchers at the Cambridge University Hospitals NHS Foundation Trust, Great Ormond Street Hospital, Wellcome Sanger Institute, the University of Würzburg in Germany, and their collaborators, have mapped the genetic differences across 137 children with Wilms tumour.
Wilms tumour is a type of kidney cancer that largely affects children under the age of five. In the UK, about 85 children (opens in a new tab) are diagnosed with Wilms tumour every year.
About 30 per cent of children that develop Wilms tumour are born with inherited genetic changes that increase their likelihood of developing this cancer. This study, published today in Cancer Discovery, suggests that these inherited genetic changes don't just increase the risk of cancer but also affect how these tumours develop - including how well they respond to certain treatments, and whether the child has a higher risk of developing secondary cancers later in life.
At the moment, we treat all children with a predisposition the same, meaning that some children get too much and others too little treatment. Our findings indicate that we may be able to personalise treatment on the basis of genetic information.
Professor Sam Behjati, Cambridge University Hospitals NHS Foundation Trust & Wellcome Sanger Institute
The team indicates that different genetic predispositions give rise to different tumour development pathways and kidney structures, and have identified those that restrict the growth of tumours. They also found that Wilms tumours develop differently in children that are born without genetic predispositions.
Their findings suggest that tailoring treatment and screening programmes to a child’s genetic makeup could improve the quality of care. In the future, this research could lead to ways to guide treatment and develop new therapies based on certain genetic changes.
The study included support from The Little Princess Trust (opens in a new tab), Wellcome, the NIHR Cambridge Biomedical Research Centre and the NIHR GOSH Biomedical Research Centre. A full acknowledgement list can be found on the publication.
Children with Wilms tumour are currently only screened for genetic predisposition if they show specific features, such as tumours in both kidneys. Treatment for these children has to balance removing tumours and reducing the risk of secondary tumours later in life, while preserving as much kidney function as possible.
Childhood cancer treatment can have substantial adverse effects that impact the child living with the condition, and those around them. We believe that it is crucial to fund studies that not only look for ways to improve a young person's chance of survival but also reduce the side effects from treatment.
Phil Brace, Chief Executive, Little Princess Trust
Strategies to spare normal kidney tissue include chemotherapy, certain types of surgery, and extended courses of postoperative chemotherapy, along with close surveillance for recurrence. All of which are demanding for the patient and their family. Using genetics to inform treatment could allow some children to avoid these interventions if their genes show they are unlikely to develop subsequent tumours.
The study included several hundred tissue samples from 137 children with Wilms tumour. 71 of these children had a genetic predisposition, and the others did not.
The team showed that tumour development differed in children with a genetic predisposition. This depended on which gene was affected and when this gene was activated during development in the womb, known as its developmental timing.
Different genetic predispositions to Wilms tumour led to specific sequences of DNA changes during childhood that eventually caused tumour formation. These DNA changes are known as driver mutations, some of which increased the children’s risk of secondary cancers as well as Wilms tumour. In particular, genetic changes in genes – WT1 and TRIM28 – resulted in the accumulation of additional driver mutations in specific pathways, which could be targeted in future drug development.
Certain genetic changes that children are born with can predispose to Wilms tumour. What we show in our research is that cancers develop in different ways, depending on what the underlying genetic change is. This means that in some predispositions we can exactly predict what additional genetic changes lead to cancer development, paving the path to identify treatments that interfere with cancer formation in the first place.
Dr Taryn Treger, Wellcome Sanger Institute, co-first author on the study
Genetic predisposition also impacted the tissue architecture of the kidneys, which could help explain why some children develop non-cancerous kidney growths before cancerous tumours.
Overall, the findings indicate that predisposition may dictate how Wilms tumour develops, with specific patterns depending on the original genetic change. Researchers suggest that in the future, it could be possible to tailor treatment and screening programmes to the type of genetic predisposition a child has, to ensure they are receiving the most effective care.
Phil Brace, Chief Executive of The Little Princess Trust, who supported this research, said: “Childhood cancer treatment can have substantial adverse effects that impact the child living with the condition, and those around them. We believe that it is crucial to fund studies that not only look for ways to improve a young person's chance of survival but also reduce the side effects from treatment. We are hopeful that this research may help tailor treatments in the future.”
Professor Sam Behjati, co-senior author at Cambridge University Hospitals NHS Foundation Trust and the Wellcome Sanger Institute, said: “Our research illustrates the power of collaborative genomic research to answer important clinical questions. At the moment, we treat all children with a predisposition the same, meaning that some children get too much and others too little treatment. Our findings indicate that we may be able to personalise treatment on the basis of genetic information. Moreover, since we now know the precise sequence of genetic changes that lead from predisposition to cancer, we may be able to screen for tumours more effectively and even begin to entertain the possibility of prevention.”