Root of childhood kidney cancer discovered

Pre-cancerous signatures found in healthy tissue point the way towards new treatment options

A fundamental change in our understanding of the childhood kidney cancer Wilms’ tumour is on the horizon, after the discovery of its earliest genetic root by scientists at the Wellcome Sanger Institute and their collaborators. By comparing genome sequences from normal kidney tissue and tumours, the team identified patches of normal-looking kidney tissue that in fact carried DNA changes that cause Wilms’ tumour.

The study, published in Science, uncovers a novel route by which cancers can form in the first few weeks of life, whereby an early cell gains the DNA modification associated with cancer and proliferates while the kidney is developing. Understanding the root of the cancer promises to improve treatment and help prevent recurrence of Wilms’ tumour. This discovery 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 with around 80 cases per year diagnosed in the UK. Nine out of ten cases are curable by surgery to remove the affected kidney together with chemotherapy and sometimes radiotherapy. Usually the cancer only affects one kidney, but in around 10 per cent of cases both kidneys are affected*. It has been assumed that the cause of Wilms’ tumour is one cell ‘going wrong’ as the kidney develops in the first few weeks of life.

This study is the first to compare healthy kidney tissue with Wilms’ tumour tissue, using comparative genome analysis to investigate the cause of the disease. 66 tumour and 163 normal kidney tissue samples were collected by researchers at Addenbrooke’s Hospital in Cambridge and Great Ormond Street Hospital in London. Scientists at the Wellcome Sanger Institute sequenced DNA from the samples to create 229 whole genome sequences, which were analysed to identify genetic changes between tumours and normal tissue.

In two thirds of children with Wilms’ tumour, DNA 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 which, when looked at down a microscope, appeared to be normal.

These patches were found to have developed from a single rogue cell with a DNA change suppressing the H19 gene. Normally, the function of H19 is to ensure that cells grow in an orderly manner. This particular DNA change is what is known as an epigenetic change, where part of the DNA code becomes ‘invisible’ to the cells, rather than a physical alteration of the person’s DNA***. This epigenetic change ‘turns off’ H19 and enables cells to grow rapidly into pre-cancerous 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 the weed has an extensive root underneath the soil. Now we know we need to look for the patch of soil where the root has taken hold. If we remove that patch, the weed isn’t going to return.”

Due to the likelihood of recurrence, Wilms’ tumour is usually treated by removing the whole kidney. Most people can live a relatively normal life with one kidney, but in the 10 per cent of Wilms’ tumour cases that affect both kidneys, removing them entirely will have life-changing consequences for the patient**.

Dr Kathy Pritchard-Jones, Professor of Paediatric Oncology at the UCL Great Ormond Street Institute of Child Health, said: “Surgery for Wilms’ tumour usually involves removing the whole kidney to ensure no tumour is left behind. However, some children need more precise surgery that preserves their kidney function, especially when they have tumours in both kidneys or are at increased genetic risk of further tumours. This study helps us understand how Wilms’ tumours start off and provides a marker for kidney tissue that is at high risk of forming new tumours. 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.”

As well as changing how we treat Wilms’ tumour, 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 Addenbrooke’s Hospital, 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.”

Phil Brace, Chief Executive of The Little Princess Trust who were one of the funders of the research, said: “The Little Princess Trust are very pleased to have supported this important work. We are very excited to hear the potential impact of what has been discovered and the improved understanding as a result of this project. As a funder of paediatric cancer research, this was one of our earliest supported projects and we are very keen to support more work in this area.”

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Notes to Editors:

*For information about Wilms’ tumour, see the Cancer Research UK website: https://www.cancerresearchuk.org/about-cancer/childrens-cancer/wilms-tumour/about

**More information about living with one kidney is available at the Kidney Research UK website: https://kidneyresearchuk.org/kidney-health-information/questions-about-kidney-disease/living-with-one-kidney/. For information on treatment options in the event of total loss of kidney function, see https://www.kidneycareuk.org/about-kidney-health/treatments/

***An overview of epigenetics is available on the NIH website: https://ghr.nlm.nih.gov/primer/howgeneswork/epigenome

Quote from Wendy Tarplee-Morris, of The Little Princess Trust and a Wilms’ parent: “Although childhood cancer is rare, there are still a significant number of children who are affected by the disease. As a parent who lost my daughter to Wilms’ in 2005, it is very sobering to know that almost 15 years later a child with the same diagnosis is likely to have the same outcome. Therefore, the news of any advances which improve understanding and could potentially lead to preventing childhood cancer is very welcome indeed.”

Selected websites:

The Little Princess Trust

The Little Princess Trust provides free, real-hair wigs for young cancer sufferers or for children and young people experiencing the devastating effects of hair loss. We also fund pioneering, life-saving research into childhood cancers. We use hair donations and fundraising monies sent to us by our amazing supporters, to manufacture and fit our beautiful real hair wigs. Established in 2006, we have supplied more than 8,000 wigs to children and young people and have invested circa £5 million into ground-breaking childhood cancer research. https://www.littleprincesses.org.uk/

About Great Ormond Street Hospital for Children NHS Foundation Trust?

Founded in 1852, Great Ormond Street Hospital is one of the world’s leading children’s hospitals with the broadest range of dedicated, children’s healthcare specialists under one roof in the UK. With more than 252,000 outpatient and 43,000 inpatient visits every year, the hospital’s pioneering research and treatment gives hope to children from across the UK with the rarest, most complex and often life-threatening conditions. As an international centre of excellence in child healthcare, our patients and families are central to everything we do – from the moment they come through the door and for as long as they need us

About the UCL Great Ormond Street Institute of Child Health (ICH)

The UCL Great Ormond Street Institute of Child Health (ICH) is part of the Faculty of Population Health Sciences within the School of Life and Medical Sciences at University College London. Together with its clinical partner Great Ormond Street Hospital for Children NHS Foundation Trust (GOSH), it forms the UK’s only paediatric National Institute for Health Research Biomedical Research Centre and has the largest concentration of children’s health research in Europe. For more information visit http://www.ucl.ac.uk/child-health [ucl.ac.uk]

About Cambridge University Hospitals

Cambridge University Hospitals NHS Foundation Trust (CUH) is one of the largest and best known trusts in the country, delivering high-quality patient care through Addenbrooke’s and the Rosie Hospitals. CUH is a leading national centre for specialist treatment for rare or complex conditions and a university teaching hospital with a worldwide reputation.

CUH is a key partner in Cambridge University Health Partners (CUHP), one of only six academic health science centres in the UK, and is at the heart of the development of the Cambridge Biomedical Campus (CBC), which brings together on one site world-class biomedical research, patient care and education. The Campus is one of the government’s National Institute for Health Research (NIHR) comprehensive biomedical research centres.

UCL – London’s Global University

UCL is a diverse community with the freedom to challenge and think differently.

Our community of more than 41,500 students from 150 countries and over 12,500 staff pursues academic excellence, breaks boundaries and makes a positive impact on real world problems.

We are consistently ranked among the top 10 universities in the world and are one of only a handful of institutions rated as having the strongest academic reputation and the broadest research impact.

We have a progressive and integrated approach to our teaching and research – championing innovation, creativity and cross-disciplinary working. We teach our students how to think, not what to think, and see them as partners, collaborators and contributors.

For almost 200 years, we are proud to have opened higher education to students from a wide range of backgrounds and to change the way we create and share knowledge.

We were the first in England to welcome women to university education and that courageous attitude and disruptive spirit is still alive today. We are UCL. https://www.ucl.ac.uk/

About the University of Cambridge

The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. To date, 107 affiliates of the University have won the Nobel Prize.

Founded in 1209, the University comprises 31 autonomous Colleges, which admit under-graduates and provide small-group tuition, and 150 departments, faculties and institutions. Cambridge is a global university. Its 19,000 student body includes 3,700 international students from 120 countries. Cambridge researchers collaborate with colleagues worldwide, and the University has established larger-scale partnerships in Asia, Africa and America.

The University sits at the heart of the ‘Cambridge cluster’, which employs 60,000 people and has in excess of £12 billion in turnover generated annually by the 4,700 knowledge-intensive firms in and around the city. The city publishes 341 patents per 100,000 residents. http://www.cam.ac.uk [cam.ac.uk]

The Wellcome Sanger Institute

The Wellcome Sanger Institute is a world leading genomics research centre. We undertake large-scale research that forms the foundations of knowledge in biology and medicine. We are open and collaborative; our data, results, tools and technologies are shared across the globe to advance science. Our ambition is vast – we take on projects that are not possible anywhere else. We use the power of genome sequencing to understand and harness the information in DNA. Funded by Wellcome, we have the freedom and support to push the boundaries of genomics. Our findings are used to improve health and to understand life on Earth. Find out more at http://www.sanger.ac.uk or follow us on Twitter, Facebook, LinkedIn and on our Blog.

About Wellcome

Wellcome exists to improve health by helping great ideas to thrive. We support researchers, we take on big health challenges, we campaign for better science, and we help everyone get involved with science and health research. We are a politically and financially independent foundation. https://wellcome.ac.uk/

Media Contact
Matthew Midgley
matthew.midgley@sanger.ac.uk
http://dx.doi.org/10.1126/science.aax1323

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