Wellcome Sanger Institute findings change our understanding of NF-1 - one of the most common inherited genetic conditions

A study of one of the more common inherited genetic conditions, neurofibromatosis type 1 (NF-1), has changed our understanding of why it leads to the growth of tumours.

Genetic changes alone cannot explain it, researchers have now found.

They say finding out more about the factors involved could facilitate early cancer detection in NF-1 patients and even point towards new treatments.

The condition causes brown skin patches, similar to birthmarks, and tumours which are often benign but can become cancerous over time and may cause a range of symptoms depending on where they are. NF-1 can, for example, cause soft tissue and brain tumours that may restrict movement and vision.

It affects around one in 2,500 people, with approximately 25,000 in the UK living with the condition. The symptoms and impact vary greatly from one person to another.

Those with the condition have a genetic change that means one copy of the gene encoding the neurofibromin protein, NF1, does not work.

It was previously thought tumours and brown skin patches occurred when the second copy of the gene was lost. But the new study 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.

The researchers - from the Wellcome Sanger Institute, UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital, Cambridge University Hospitals NHS Foundation Trust (CUH), and their collaborators - also found a pattern of changes in the affected gene that may explain why the nervous system is a common site for these tumours to develop.

The researchers studied nearly 500 tissue samples from a child with NF-1 and compared them to tissues from children without the condition using a new higher resolution sequencing technique. They studied tissue samples from nine adults with NF-1, with similar findings.

Dr Thomas Oliver, co-first author from the Sanger Institute and CUH, 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 NF-1 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.”

Prof 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.”