Predicting how childhood kidney cancers develop

Published in Cancer Discovery, the study suggests that inherited genetic changes predetermine how these tumours develop, how much they respond to certain treatments, and whether the individual affected is at higher risk of secondary cancers later in life.

Researchers at Great Ormond Street Hospital (GOSH), Wellcome Sanger Institute, and collaborators, mapped the genetic differences from 137 children with Wilms tumour. This included 71 children who had a genetic predisposition, some of whom had early symptoms.

The team showed that the tumours developed differently 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.

The different genetic predispositions lead to specific DNA changes in childhood that caused tumours to form, some of which increased the children’s risk of secondary cancers as well as Wilms tumours.

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

In about 30% of children with Wilms tumours, there is an inherited genetic change that increases the risk of developing this cancer.

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 tumour is a type of kidney cancer in children that largely affects children under the age of five. In the UK, about 85 children are diagnosed with Wilms tumour every year.

Currently, treatment for Wilms tumours in predisposed children must balance removing enough of the kidney tumour to help reduce the risk of secondary tumours, while preserving as much kidney function as possible. As well as surgery, children undergo chemotherapy, along with close monitoring 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 tumour, researchers could identify those with a lower risk of secondary tumours and use this to inform surgical approaches and screening programmes, as well as lead to the development of new therapies.

Dr Tanzina Chowdhury, co-author, consultant in paediatric oncology and lead for renal tumour service at GOSH said: “We see around 30 to 50 children every year with a renal tumour, and these findings are significant in moving towards a goal of personalised medicine for each child. Children whose genetic makeup gives them a vulnerability to developing Wilms tumours may be identified by certain features that they have, but in a number of cases, these features are not present or not easily seen. Our research describes the finding of abnormalities in genes not previously shown to have an impact on the likelihood of a child developing a renal tumour and highlights the possibility that there is a relationship between abnormalities in some of these genes and the type of Wilms tumour that may develop.”

Professor Sam Behjati, co-senior author from the Wellcome Sanger Institute, Cambridge University Hospitals NHS Foundation Trust, and GOSH, 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.”