image: Histological image of cerbellum sample from a patient with Nf-1
Credit: Thomas Oliver / Wellcome Sanger Institute
Despite what was previously thought, new research has shown that genetic changes alone cannot explain why and where tumours grow in those with genetic condition neurofibromatosis type 1 (NF-1). Understanding more about the factors involved could, in the future, facilitate early cancer detection in NF-1 patients and even point towards new treatments.
Researchers from the Wellcome Sanger Institute, UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital, Cambridge University Hospitals NHS Foundation Trust, and their collaborators, focused on NF-1, a genetic condition that causes specific types of tumours, and investigated how and why these developed.
The study, published today (25 February) in Nature Genetics, reports that the genetic changes thought to cause tumours can be found in normal tissues throughout the body, suggesting that other factors are also necessary for tumour development.
They also uncovered a pattern of changes in the affected gene, NF1, that may explain why the nervous system in particular is a common site for these tumours to develop.
Understanding what other factors are involved in developing these tumours could help inform monitoring programmes for patients with NF-1, who require regular screening to detect tumours early on and could potentially require multiple surgeries and chemotherapy.
In the future, refining our knowledge of why tumours grow in some places and not others may help us identify the patients most likely to need early medical intervention.
This model of tumour development is not unique to NF-1, raising the possibility that similar events occur in related genetic conditions, meaning many more could benefit from tailored management.
NF-1 is a genetic condition that causes brown skin patches, similar to birthmarks, and tumours1. While the tumours are often benign, they can become cancerous over time and may cause a range of symptoms depending on where they are1. For example, NF-1 can cause soft tissue and brain tumours that may restrict movement and vision.
The symptoms and impact of NF-1 can vary greatly from person to person. It is one of the most common inherited genetic conditions, impacting around one in 2500 people, with approximately 25,000 people in the UK living with this condition2. Those with NF-1 have a genetic change that means one copy of the gene encoding the neurofibromin protein, NF1, does not work. It was previously thought that tumours and brown skin patches occurred when the second copy of the gene was lost.
In a new study, researchers from the Sanger Institute, UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital, Cambridge University Hospitals NHS Foundation Trust, and their collaborators, studied nearly 500 tissue samples from a child with NF-1 and compared them to tissues from children without the condition.
They found that changes causing a loss of NF1 gene function were not limited to tumours and skin changes but instead can be found throughout other tissues of the child with NF-1 as well. This suggests, whilst advantageous to the affected cells, the mutation is insufficient to cause tumour formation.
For this research, the team applied a new sequencing technology that allowed them to look at genetic changes at a higher resolution than was previously possible and studied additional tissue samples from nine adults with NF-1, showing similar findings.
The team found a pattern of mutations across all patients that showed these were particularly common in tissues of the nervous system. This is a common place for tumours to form in those with NF-1, which can help explain why these tissues are specifically impacted.
Dr Thomas Oliver, co-first author from the Wellcome Sanger Institute and Cambridge University Hospitals NHS Foundation Trust, said: “We were astonished to see such extensive genetic changes in the normal tissues of patients with NF-1, seemingly without consequence. This is contrary to our understanding of tumour development in the condition and other related conditions. Additional factors must clearly play a role, perhaps including the cell type and anatomical location affected. Whilst further investigation is needed, I hope this work represents the first step towards developing more personalised care for these patients, such as better identifying who is at greater risk of developing tumours, and adjusting screening to intervene early on and minimise complications.”
Professor Thomas Jacques, co-senior author from UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital, said: “NF-1 can have many different impacts on a person’s life. In order to better treat and support those with NF-1, we have to understand more about what is going on at a biological and genetic level, especially in the parts of the body that are most affected, such as the brain and nervous system. Our study showed that these areas of the body have a different pattern of DNA changes, suggesting that if we look further, there could be a potential target for new therapies to help treat or stop tumour development.”
Professor Sam Behjati, co-senior author from the Wellcome Sanger Institute and Cambridge University Hospitals NHS Foundation Trust, said: “Loss of the second NF1 gene had always been thought to cause tumours in individuals with NF-1. Our findings fundamentally question this decade-old paradigm and force us to rethink how tumours arise, to pave the way for better screening, prevention, and treatment of cancers.”
ENDS
Contact details:
Rachael Smith
Press Office
Wellcome Sanger Institute
Cambridge, CB10 1SA
07827979492
Email: press.office@sanger.ac.uk
Notes to Editors:
- NHS. Neurofibromatosis type 1, overview and symptoms pages. Available at: https://www.nhs.uk/conditions/neurofibromatosis-type-1/ [Accessed February 2025]
- Nerve Tumours UK. What is neurofibromatosis type 1? Available at: https://nervetumours.org.uk/what-are-nerve-tumours/what-is-nf1
Publication:
T. R. W. Oliver, A. R. J . Lawson, H. Lee-Six, et al. (2025) Cancer-independent, second somatic NF1 mutation of normal tissues in neurofibromatosis type 1. Nature Genetics. DOI: 10.1038/s41588-025-02097-2
Funding:
This research includes funding from Wellcome, the Brain Tumour Charity, Great Ormond Street Hospital Children’s Charity, and others. A full acknowledgment list can be found in the publication.
Selected websites:
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Journal
Nature Genetics
Article Title
Cancer-independent, second somatic NF1 mutation of normal tissues in neurofibromatosis type 1
Article Publication Date
25-Feb-2025