Uncovering the origin of rare childhood cancer guides treatment
Bilateral neuroblastoma cancers in a patient can arise independently from each other, at the very earliest stages of life
New research shows that bilateral neuroblastoma cancers within a patient can arise independently from each other. The finding that such tumours have not spread – metastasised – from one site to another has important implications for understanding the roots of neuroblastoma and may promote better treatments.
Researchers from the Wellcome Sanger Institute, the University of Cambridge, Cambridge University Hospitals NHS Foundation Trust, Great Ormond Street Hospital for Children NHS Trust and the UCL Great Ormond Street Institute of Child Health studied the genomes of tumours from multiple sites in two patients with the condition. In both cases the tumours within a patient arose separately from each other, with their origins in embryonic development. Their findings, published in the New England Journal of Medicine today, 4th November, may be relevant for treating other types of bilateral tumours.
Neuroblastoma is a highly aggressive childhood cancer. About 100 children each year in the UK are affected. It develops from specialised nerve cells – neuroblasts – left behind from a baby’s development in the womb*.
Neuroblastoma most commonly occurs in one of the adrenal glands above the kidneys. There are several different types of neuroblastoma, with some more aggressive than others. In rare cases, bilateral tumours occur, for example in both adrenal glands.
Similarly to the evolution of species, individual cells in the body are subject to forces of mutation and selection as they grow. These ‘somatic mutations’ are passed from one cell to another as it divides**. Over a lifetime, different mutations accumulate in the DNA of different cells. By comparing the patterns of somatic mutations between tumour cells and healthy cells, it is possible to trace their evolutionary history.
In this new study, researchers at the Wellcome Sanger Institute extensively sequenced the genomes of bilateral neuroblastoma. Evolutionary genomics showed that the neuroblastoma tumours in an individual arose independently at the very earliest stages of life, within a few cell divisions after fertilization. Both children in the study had inherited a genetic mutation that predisposed them to cancer.
“Thanks to advances in sequencing technologies and developments in analysis methods, it has recently become possible to trace the origin of childhood cancer right back to the embryo. It’s a paradigm shift in how we think about tumours, and how they are related to each other before they became tumours. The parallel evolution of independent tumours was an unexpected and fascinating finding, which reveals the very origin of neuroblastoma within the first few divisions of the fertilised egg.”
Tim Coorens, first author of the study from the Wellcome Sanger Institute
Understanding if tumours within a patient are independent or not is vital information for clinicians when deciding the best treatment options. It is usually assumed that tumours at multiple sites are metastatic disease that spread from an original primary tumour. A tumour that has metastasised and spread from one site to another is more aggressive – and requires more intensive treatment – than one that remains within a tissue microenvironment.
“This is the first time we’ve been able to prove that bilateral neuroblastoma tumours can be independent entities. It is essential for each patient that clinicians can make the distinction between an aggressive tumour that is spreading, and a set of more benign tumours that are localised. If tumours haven’t metastasised, we can consider less intensive treatments, with fewer side effects.”
Professor John Anderson, senior author of the study from the UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust
The researchers suspect that other types of bilateral tumours may also have similar patterns of development, and so their findings are important more widely for analysing and treating such cancers.
“Neuroblastoma is one of the most common childhood tumours with around 100 children diagnosed in the UK each year. Yet, it also has one of the lowest survival rates – in its high-risk form, the survival rate is sadly around just 50 per cent.
“We welcome these findings as an important step towards the development of kinder, safer, and more personalised, treatments for children with neuroblastoma which will help reduce the long-term, and often life-limiting, side effects of current aggressive treatments.”
Dr Jasmine Parkinson, Children with Cancer UK Research and Grants Manager
“We are in a world now where genome sequencing tumours is a part of healthcare. It is becoming an important tool in the clinic for treating childhood cancers. Using genomics to analyse a tumour’s origins can give us detailed insight into what we are dealing with and how to tackle it.”
Dr Sam Behjati, lead author of the study from the Wellcome Sanger Institute and Addenbrooke’s Hospital, Cambridge
Professor David Rowitch at University of Cambridge, who was not part of the study commented, “This major finding allows researchers to trace the cell origins of paediatric cancers to their very roots. This information will help doctors tailor therapies for children’s cancer based on a deep understanding of biology.”
Tim H.H. Coorens et. al. Lineage-Independent Tumors in Bilateral Neuroblastoma. N Engl J Med 2020; 383: 1860-5.
Children With Cancer UK and Wellcome.
Children with Cancer UK is the leading national charity dedicated to research into childhood cancer.
We fund research into the causes and treatment of childhood cancers and provide support for families affected by childhood cancer. We have accelerated breakthroughs to improve childhood cancer survival rates and find kinder, more effective treatments with fewer toxic side effects. This ground-breaking research, which would otherwise go unfunded, saves the lives of children with cancer. Children with Cancer UK receives no government funding and relies entirely on the generosity of donations from supporters.
For more information, visit www.childrenwithcancer.org.uk.
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. As part of the Campus development, Royal Papworth Hospital has built a specialist heart and lung hospital, and AstraZeneca is building a new global R&D centre and corporate headquarters. The Campus is one of the government’s National Institute for Health Research (NIHR) comprehensive biomedical research centres. https://www.cuh.nhs.uk/
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, 109 affiliates of the University have won the Nobel Prize.
Founded in 1209, the University comprises 31 autonomous Colleges 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 more than 61,000 people and has in excess of £15 billion in turnover generated annually by the 5,000 knowledge-intensive firms in and around the city. The city publishes 316 patents per 100,000 residents. https://www.cam.ac.uk/
Founded in 1852, Great Ormond Street Hospital (GOSH) 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. Visit www.gosh.nhs.uk
Research at GOSH is underpinned by support from the National Institute of Health Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre (BRC) and Great Ormond Street Hospital Children’s Charity (GOSH Charity).
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 (NIHR) Biomedical Research Centre and has the largest concentration of children’s health research in Europe.
For more information visit www.ucl.ac.uk/child-health
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