Root of childhood kidney cancer discovered

A study into a childhood cancer called Wilms’ tumour has uncovered a genetic cause of the disease, paving the way to improved treatments and the potential to one day screen for cancers like this before they develop.

By comparing genetic information from normal kidney tissue and tumours, scientists at the Wellcome Sanger Institute and researchers at the UCL Great Ormond Street Institute of Child Health (ICH), identified patches of normal-looking kidney tissue that in fact carried genetic changes known to cause Wilms’ tumour. This new understanding could lead to better treatments that target not only Wilms’ tumour itself, but normal-looking kidney tissue where cancer may be ‘lying in wait’.

The study, published today (6th December 2019) in Science, uncovers a new way cancers can form when a baby is just starting to develop in the womb, whereby an early cell undergoes genetic changes that cause it to replicate more quickly while the kidney is developing. The discovery therefore also raises the possibility of one day being able to screen for cancers like this before tumours develop.

Wilms’ tumour is a form of kidney cancer mainly affecting children under five years of age. Though kidney cancers in children are rare, Wilms’ tumour is the most common type.

Wilms’ tumour is usually treated by removing the whole kidney. Nine out of ten cases are curable by this approach, together with chemotherapy and sometimes radiotherapy. In around 10 per cent of cases, both kidneys are affected*. For these children, removing both kidneys will have life-changing consequences and some may need more precise surgery that preserves their kidney function.

The new findings could revolutionise the approach to treatment for Wilms’ tumour. Dr Kathy Pritchard-Jones, Professor of Paediatric Oncology at ICH, said: “This study helps us understand how Wilms tumours start off and provides a marker for healthy-looking kidney tissue that is at high risk of forming new tumours. The study has also found several new genes that are mutated in Wilms’ tumour. Together, this new information helps us understand who is at high risk and why some tumours come back. My hope is that in future we’ll be able to develop treatments that focus on these patches of abnormal tissue without having to sacrifice one or both kidneys.”

This study, which was supported by funding from GOSH Charity, is the first to compare healthy kidney tissue with Wilms’ tumour tissue, using comparative genome analysis to investigate the cause of the disease. Samples were collected at Great Ormond Street Hospital and Addenbrooke’s Hospital in Cambridge. Scientists at the Wellcome Sanger Institute sequenced DNA from the samples to create 229 whole genome sequences, which were analysed to identify genetic changes in tumours and normal-looking tissue.

In two thirds of children with Wilms’ tumour, genetic changes associated with the disease were found to be shared by both normal kidney tissue and tumour tissue. This allowed the researchers to hone in on patches of genetically abnormal cells in what looked like normal tissue.

These patches were found to have developed from a single rogue cell with a genetic modification that suppresses the H19 gene. Normally, the function of H19 is to ensure that cells grow in an orderly manner. The modification seen in Wilms’ patients, however, blocks H19 and enables cells to grow rapidly, creating patches of kidney tissue from which Wilms’ tumour can arise.

Tim Coorens, first author of the study from the Wellcome Sanger Institute, said: “A good analogy for what we found is that Wilms’ tumour is not just an isolated weed on an otherwise well maintained field. We discovered that underneath the soil there is an extensive root. Now we know we have to look for the patch of soil where the root has taken hold. If we remove that, the weed isn’t going to return.”

As well as potentially changing how Wilms’ tumour is treated, these findings open up the possibility of one day screening for this and similar cancers.

Dr Sam Behjati, lead author of the study from the Wellcome Sanger Institute and University of Cambridge, said: "The discovery of the genetic root of Wilms' tumour signals a shift in our understanding of this particular cancer and childhood cancer more generally. Our findings represent a radical departure from how we think about Wilms’ tumour because we never expected to find the root of cancer in normal-looking tissue. It may even pave the way for us to begin to think about preventing childhood cancer.”

This study was principally funded by The Little Princess Trust, the St. Baldrick’s Foundation and Wellcome. Additional funding was received from CRUK, NIHR, The Royal College of Surgeons of England and Great Ormond Street Hospital Children’s Charity, including generous support of the Hugh and Catherine Stevenson Trust and the Welton Foundation.