Researchers map genetic differences across children with Wilms tumor

Genetically tailored treatment plans for children with a type of kidney cancer could help provide the most effective care while minimizing side effects as much as possible.

Researchers at the Wellcome Sanger Institute, Cambridge University Hospitals NHS Foundation Trust, Great Ormond Street Hospital, the University of Würzburg, and their collaborators, have mapped the genetic differences across children with a type of childhood kidney cancer called Wilms tumor.

In about 30 per cent of children with Wilms tumor, there is an inherited genetic change that increases the risk of developing this cancer. This study, published today (23 January) in Cancer Discovery, a journal of the American Association for Cancer Research, suggests that inherited genetic changes predetermine how these tumors develop, how much they respond to certain treatments, and whether the individual affected is at higher risk of secondary cancers later in life.

The team indicates that different genetic predispositions give rise to different tumor development pathways and kidney structures, and have identified those that restrict the growth of tumors. They also found that Wilms tumors develop differently in those without genetic predispositions.

Their findings suggest that tailoring treatment and screening programmes to a child's genetic makeup could ensure that everyone is receiving the most effective care. In the future, this research could help develop new therapies for certain genetic changes and identify children who may need less invasive surgery.

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 year¹.

While these tumors can occur through a spontaneous genetic change during development in the womb, in about 30 per cent of cases, an underlying genetic predisposition can increase the risk of developing Wilms tumor. Traditionally, children with Wilms tumor are screened for predisposition if they show specific features, such as tumors in both kidneys.

Currently, treatment for Wilms tumor in predisposed children has to balance removing enough of the kidney tumor to help reduce the risk of secondary tumors later in life, while preserving as much kidney function as possible. Strategies to spare normal kidney tissue include chemotherapy, certain types of surgery, and extended courses of postoperative chemotherapy, along with close surveillance for recurrence.

The clinical management of children with a known predisposition differs from that of children with a spontaneous genetic change, due to the increased risk. By understanding more about how genetics influences the development of Wilms tumor, researchers could identify those with a lower risk of secondary tumors and use this to inform surgical approaches and screening programmes, as well as lead to the development of new therapies.

In this new study, researchers genetically mapped several hundred tissue samples from 137 children with Wilms tumor. This included 71 children who had a genetic predisposition, some of whom had early symptoms.

The team showed that tumor 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 tumor were found to lead to specific DNA changes in childhood that caused tumor formation. These DNA changes are known as driver mutations, some of which increased the children's risk of secondary cancers as well as Wilms tumor. 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.

Genetic predisposition also impacted the tissue architecture of the kidneys, which could help explain why some children develop non-cancerous kidney growths before cancerous tumors.

Overall, their findings indicate that predisposition may dictate how Wilms tumor develops, with specific patterns depending on the 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.

Dr Taryn Treger, co-first author at the Wellcome Sanger Institute, said: "Certain genetic changes that children are born with can predispose to Wilms tumor. 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."

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."

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 tumors more effectively and even begin to entertain the possibility of prevention."

Professor Sam Behjati, co-senior author at the Wellcome Sanger Institute and Cambridge University Hospitals NHS Foundation Trust