Genetic changes alone don’t fully explain tumor growth in NF-1, pointing to other contributing factors. This insight may improve early detection and treatment strategies.
New research challenges the previous belief that genetic changes alone determine the location and growth of tumors in individuals with neurofibromatosis type 1 (NF-1). The findings suggest that additional factors play a role, which could lead to earlier cancer detection and potential new treatments for NF-1 patients.
A team of researchers from the Wellcome Sanger Institute, UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital, and Cambridge University Hospitals NHS Foundation Trust investigated NF-1, a genetic condition associated with specific tumor types.
Their study, published in Nature Genetics, revealed that the genetic mutations linked to tumor formation are present in normal tissues throughout the body. This suggests that genetic changes alone are insufficient for tumor development, highlighting the need to explore other contributing factors.
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 tumors to develop.
Understanding what other factors are involved in developing these tumors could help inform monitoring programs for patients with NF-1, who require regular screening to detect tumors early on and could potentially require multiple surgeries and chemotherapy.
In the future, refining our knowledge of why tumors grow in some places and not others may help us identify the patients most likely to need early medical intervention.
Implications Beyond NF-1
This model of tumor 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 tumors. While the tumors are often benign, they can become cancerous over time and may cause a range of symptoms depending on where they are. For example, NF-1 can cause soft tissue and brain tumors 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 condition. 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 tumors and brown skin patches occurred when the second copy of the gene was lost.
Findings from Tissue Analysis
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 tumors and skin changes but instead can be found throughout other tissues of the child with NF-1 as well. This suggests that, whilE advantageous to the affected cells, the mutation is insufficient to cause tumor 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 tumors 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 tumor 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 personalized care for these patients, such as better identifying who is at greater risk of developing tumors, and adjusting screening to intervene early on and minimize 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 tumor 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 tumors in individuals with NF-1. Our findings fundamentally question this decade-old paradigm and force us to rethink how tumors arise, to pave the way for better screening, prevention, and treatment of cancers.”
Reference: “Cancer-independent somatic mutation of the wild-type NF1 allele in normal tissues in neurofibromatosis type 1” by Thomas R. W. Oliver, Andrew R. J. Lawson, Henry Lee-Six, Anna Tollit, Hyunchul Jung, Yvette Hooks, Rashesh Sanghvi, Matthew D. Young, Timothy M. Butler, Pantelis A. Nicola, Taryn D. Treger, Stefanie V. Lensing, G. A. Amos Burke, Kristian Aquilina, Ulrike Löbel, Isidro Cortes-Ciriano, Darren Hargrave, Mette Jorgensen, Flora A. Jessop, Tim H. H. Coorens, Adrienne M. Flanagan, Kieren Allinson, Inigo Martincorena, Thomas S. Jacques and Sam Behjati, 25 February 2025, Nature Genetics.
DOI: 10.1038/s41588-025-02097-2
This research includes funding from Wellcome, the Brain Tumour Charity, Great Ormond Street Hospital Children’s Charity, and others.
Never miss a breakthrough: Join the SciTechDaily newsletter.
Follow us on Google and Google News.